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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention pertains to power drills for automatically drilling holes through a workpiece. More particularly, the invention pertains to devices for monitoring the operation of the drill and for automatically controlling its operation so that the drill performs in a desired manner.
2. Description of the Prior Art
There are many inventions in the prior art which in some manner automatically control the operation of a power drill. For instance, L. W. Hirsch in U.S. Pat. No. 3,051,023 describes an automatic drill having an axial thrust sensor which monitors the drilling resistance encountered by a drill bit and which retracts the drill bit to avoid breaking the bit when the drilling resistance is excessive. Hirsch, however, makes no provision for sensing when the drill has penetrated through the workpiece. Under circumstances where normal drilling resistance is encountered, the drill bit retracts only when it has advanced a preselected distance.
U.S. Pat. No. 2,857,789 by Robinson is similar to that of Hirsch in that the drill bit automatically retracts when the drilling resistance is excessive. After the drill bit has penetrated the workpiece, it advances rapidly to a preselected position and then automatically retracts. Again, no provision is made for sensing drill bit break-through and for the retraction of the bit immediately thereafter
U.S. Pat. No. 3,259,023 by R. F. Rieger et al., U.S. Pat. No. 3,584,524 by Langenbach, U.S. Pat. No. 3,107,903 by Newton, and U.S. Pat. No. 3,545,310 by Porath et al. similarly deal with devices for avoiding excessive loads on drill bits in power drills so as to reduce drill breakage, by stopping the advance of the drill bit or by automatically retracting the drill bit or by giving a warning signal. None of these patents provide for the immediate retraction of the bit following drill bit break-through.
In the inventions of the prior art, when the drill bit has penetrated through the workpiece, the bit continues to advance until reaching some preselected position. Where there are no parts of an assembly located adjacent to the far surface of the workpiece, penetration by the drill through the workpiece to a point beyond that necessary to complete the hole causes no problem and the inventions of the prior art can be used successfully in such circumstances. However, where some parts of an assembly are located in close proximity to the far side of the workpiece, some means must be included for limiting the penetration of the drill bit beyond that necessary to complete the hole. If an automatic drill is used to drill only flat panels of constant thickness, a preselected limit switch, such as that described in the prior art, can be used to avoid excessive penetration. However, if the panels being drilled are not flat or if they vary in thickness, means other than those described in the prior art must be used to avoid damaging assemblies located near the far surface of the workpiece. The invention disclosed in this specification senses the moment when the drill bit breaks through the far surface of the workpiece and causes the drill bit to retract immediately after the hole is completed, thus avoiding damage to nearby assemblies. Furthermore, the invention needs no adjustment to drill holes in surfaces of different thickness. Also, because the drill advances only as far as is needed to complete drilling of the hole, the time required to drill each hole is reduced.
SUMMARY OF THE INVENTION
This invention monitors the axial thrust exerted on a drill bit by the power drill. When the drill bit has penetrated entirely through the panel being drilled, the axial force exerted by the drill bit upon the drill spindle decreases suddenly and this sudden decrease in axial force is used to trigger an automatic mechanism for withdrawing or retracting the drill bit from the workpiece.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a functional diagram of the mechanical portions of the invention;
FIG. 2 is a detailed illustration of the axial thrust sensor; and
FIG. 3 is a functional block diagram of the electrical control circuitry used in the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The invention is an improvement on a power drill, such as the Winslow Spacematic Model 6000, manufactured by Deutsch Fastener Corporation, 7001 West Imperial Highway, Los Angeles, Calif. 90045. The Spacematic Drill is an air-powered drill, parts of which are depicted functionally in FIG. 1. Referring to FIG. 1, the drill body 1 has a work clamp 2 which is slidably attached thereto. Work clamp 2 has an expandable collar 3 which is inserted into a previously drilled hole in workpiece 4. Also slidably attached to the body 1 is a draw rod 5 which in turn is connected to lift finger 6 which is slidably located within collar 3. When trigger valve 7 is placed in the "on" position as depicted in FIG. 1, air from an air supply passes through trigger valve 7 into chamber 8 located within drill body 1. The air in chamber 8 pushes on piston 9 causing it and draw rod 5 to which it is attached to move and retract lift finger 6 within collar 3. The end of lift finger 6 which has an expanded cross section is thereby retracted partially into collar 3, causing collar 3 to expand within the previously drilled hole so as to firmly hold the work clamp 2 against workpiece 4.
The continued introduction of air into chamber 8 causes further displacement of piston 9 relative to drill body 1 which in turn causes drill body 1 to slide along the cylindrical portion of clamp 2 towards workpiece 4. Drill motor 10, drill spindle 11 and drill bit 12, which are attached to drill body 1, are carried by the motion of drill body 1 towards workpiece 4, thus causing drill bit 12 to be advanced towards and brought into contact with workpiece 4.
Operation of trigger valve 7 also causes main air valve 38 to operate (move to the right in FIG. 1), which, in turn, directs air from the air supply to the air powered drill motor 10. The air supplied to drill motor 10 through pneumatic line 40 causes the motor to rotate which, in turn, through gears 13, rotates spindle 11 which, in turn, rotates drill bit 12 so as to drill through workpiece 4.
Included within drill body 1 is a piston 14 which is attached to work clamp 2, which piston moves within an oil-filled chamber 15 in drill body 1 to dampen the motion of drill body 1 as it advances towards workpiece 4. The rate of advancement is controlled by needle valve 16a located within body passage 16 connecting the fore and aft portions of chamber 15. Bypass valves 17 located within piston 14 allow drill body 1 to retract quickly from workpiece 4.
If, during the drilling process, trigger valve 7 is released, the air in chamber 8 vents through trigger valve 7. The reduced air pressure at the left-hand end of main air valve 38 allows main air valve 38 to move to the left, thus admitting air into chamber 18 within drill body 1 which air drives piston 9 to the left, thus causing drill body 1 to move to the right relative to lift finger 5 and work clamp 2, thus retracting drill bit 12 from the workpiece and eventually causing lift finger 6 to move to the left relative to collar 3, thus releasing work clamp 2 and drill body 1 from the workpiece.
When main air valve 38 moves to the left, it also turns off the air supply to drill motor 10, thus stopping rotation of drill bit 12.
The invention disclosed here consists of the addition to the power drill described above of a sensor to detect when drill bit 12 has penetrated through or "broken through" workpiece 4, and the addition of electronic circuitry to trigger the mechanism for retracting drill bit 12 when drill bit "break-through" occurs.
Referring again to FIG. 1, axial thrust sensor 19 is attached to the end of spindle 11 to sense the amount of axial thrust exerted on spindle 11 by drill body 1 through axial thrust sensor 19. Referring now to FIG. 2, which shows in detail the construction of axial thrust sensor 19. The end of spindle 11 is supported within housing 20 of axial thrust sensor 19 by means of bearing 21. Bearing 21 consists of ball bearings located in two circumferential ball races so as to transfer axial forces to thrust washer 22 and radial forces to housing 20. The outer race of bearing 21 is slidably located within housing 20 so that an axial load on spindle 11 will cause bearing 21 to push against thrust ring 22 which in turn compresses piezoelectric disc 23. Preload screw 40 exerts a preselected axial force on preload washer 25 which, in the absence of an axial load on spindle 11, imposes a preselected amount of axial compression on piezoelectric disc 23, thrust ring 22 and bearing 21. Piezoelectric disc 23 is made out of a piezoelectric material, such as quartz, and can be in the form of a disc, a washer, or any other shape suitable for withstanding and sensing axial compression loads on the sensor. Axial thrust sensors such as that depicted in FIG. 2 are well known in the art and are commercially available. However, such a sensor has not been used previously in conjunction with a power drill as a drill break-through sensor.
Changes in the axial compression of piezoelectric disc 23 cause layers of positive and negative charges to appear on opposing surfaces of piezoelectric disc 23, which charges, in turn, produce a voltage between electrical conductors 24. Under constant compression, the surface charges on piezoelectric disc 23 quickly "leak" and decay to zero. Later, when the axial compression on piezoelectric disc 23 is reduced, charges opposite to that which appeared upon compression, momentarily appear upon opposing surfaces of piezoelectric disc 23 and in turn create a voltage between connectors 24 which is opposite in polarity to that produced by compression. Thus, in operation, when drill bit 12 first strikes workpiece 4, a positive voltage momentarily appears between conductors 24. This voltage then decays and remains near zero during the drilling process until drill bit 12 breaks through workpiece 4. "Break-through" suddenly reduces the amount of axial compression on piezoelectric disc 23, thus producing a momentary negative voltage between conductors 24. The positive and negative voltages appearing between conductors 24 are applied to electric circuitry which in turn controls the operation of the power drill.
Referring now to FIG. 1, when drill bit 12 breaks through workpiece 4, the electrical circuitry causes air valve 39 to operate and vent the air within chamber 8. The reduced pressure within chamber 8 also causes main air valve 38 to move to the left (in FIG. 1) which in turn shuts off drill motor 10, and introduces air into chamber 18 which causes drill bit 12 to retract and work clamp 2 to be released from workpiece 4.
As described above, the drilling operation is initiated by placing trigger valve 7 in the "on" position which causes main air valve 38 to move to the right, thus opening the air passage to drill motor 10. In addition to operating drill motor 10, the air from main air valve 38 operates motion switch 26, the operation of which signals to the electronic control circuitry that the drilling operation has begun.
Referring now to FIG. 3, which is a functional block diagram illustrating the operation of the electronic control circuitry. The voltage output of piezoelectric disc 23 of FIG. 2 is input to DC amplifier 27 shown in FIG. 3. The amplified signal from DC amplifier 27 is input to low pass filter 28, which filter in the preferred embodiment is a simple resistor and capacitor combination that operates as an integrator with a time constant of approximately 50 milliseconds. Other low-pass filters, such as an LC filter, however, could be used in its place. Filter 28 removes the higher frequency fluctuations from the output of piezoelectric disc 23 when drill bit 12 first strikes workpiece 4, and from the negative pulse output by piezoelectric disc 23 when drill bit 12 breaks through workpiece 4.
The output from filter 28 is input to negative pulse threshold detector 29 and into positive pulse threshold detector 30. Negative pulse threshold detector 29 compares its input to a preselected negative threshold and outputs a positive voltage during the time that its input is more negative than the preselected threshold. Positive pulse threshold detector 30 compares its input to a preselected positive threshold and outputs a positive voltage during the time that its input voltage is more positive than the preselected threshold.
When the power drill begins to operate, air from main air valve 38 closes motion switch 26, illustrated in FIG. 1. The closing of motion switch 26 triggers the operation of motion sense and delay generator 31 in FIG. 3. Motion sense and delay generator 31 is a one-shot multivibrator which outputs a positive pulse for a period of 1.3 seconds following the closing of motion switch 26. The output of motion sense and delay generator 31 operates inhibit gate 32.
The output from negative pulse threshold detector 29 passes through inhibit gate 32 to the input of break-through delay generator 33 only when there is no output being received by inhibit gate 32 from motion sense and delay generator 31. Break-through delay generator 33 is a one-shot multivibrator which generates a positive pulse of 0.05 of a second in duration whenever it receives a positive input.
The output of positive pulse threshold detector 30 is input to initial contact delay generator 34 which is a one-shot multivibrator and which generates a 0.5 second positive pulse following receipt of the input signal. The output of initial contact delay generator 34 operates inhibit gate 35. The output of motion sense delay generator 31 also is input to inhibit gate 35. The pulse output from motion sense delay generator 31 is differentiated and clipped internally by inhibit gate 35 yielding a negative pulse 1.3 seconds after the closing of motion switch 26. Inhibit gate 35 transmits this internal negative pulse to OR gate 36 only if at the time there is no inhibiting signal input to inhibit gate 35 from initial contact delay generator 34.
OR gate 36 receives the output from inhibit gate 35 and also receives and differentiates internally the output it receives from break-through delay generator 33. Whenever OR gate 36 receives a negative pulse from inhibit gate 35 or generates internally a negative pulse by differentiating the output of break-through generator 33, then OR gate 36 outputs a positive pulse to reverse delay and solenoid driver 37. Reverse delay and solenoid driver 37 is a one-shot multivibrator. An input causes reverse delay and solenoid driver 37 to output a positive pulse 1.3 seconds in length. This output is connected to air valve 39 shown in FIG. 1, and causes air valve 39 to open for a period of 1.3 seconds which releases the air from chamber 8 shown in FIG. 1, which in turn shuts off drill motor 10 and causes drill bit 12 to retract from workpiece 4 and work clamp 2 to be released from workpiece 4 as described above.
The delay of 0.05 second introduced by break-through delay generator 33 allows drill bit 12 to penetrate completely through workpiece 4 but not significantly beyond the far surface of the workpiece before drill bit 12 is withdrawn or retracted by operation of reverse delay and solenoid driver 37. If drill bit 12 is broken or if there is no bit in the drill, or there is an existing hole under the bit, then the trailing edge of the pulse from motion sense delay generator 31, which occurs 1.3 seconds after the drilling operation begins, triggers reverse delay and solenoid driver 37 and causes the drill bit 12 to retract, releases work clamp 2 and stops the drilling operation. However, if drill bit 12 strikes workpiece 4 between 0.8 seconds and 1.3 seconds after motion switch 26 closes, the positive pulse from piezoelectric disc 23 triggers initial contact delay generator 34, and causes inhibit gate 35 to operate so that the negative pulse, that is generated internally by inhibit gate 35 and which corresponds to the trailing edge of the pulse from motion sense delay generator 31, does not pass through inhibit gate 35. As a consequence, reverse delay and solenoid driver 37 is not triggered and the drilling operation continues until drill-bit break-through occurs.
In order to simplify the description of the electronic circuitry, a particular polarity has been attributed to each of the pulses generated within the various portions of the electronic circuitry. However, a particular polarity at each point in the circuitry is not required for operation of the invention. The polarity of each of these pulses could be reversed, if related changes in the circuitry were made, and the invention would still operate properly. The delay times for the various one-shot multivibrators are typical of the values used in the preferred embodiment. In a specific application, however, the actual values would have to be adjusted in accord with the parameters of the particular drill used as part of the invention.
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An improved power drill having means for sensing when the drill bit has penetrated through the workpiece and for then retracting the drill bit from the workpiece. An electrical signal responsive to the axial force between the drill and the drill bit is used to sense when the drill bit pierces the workpiece. A sudden decrease in the axial force triggers a mechanism for retracting the drill bit from the workpiece. Means are included to detect broken bits, missing bits and previously drilled holes.
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[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/520,916, filed Nov. 18, 2003, the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a combination toaster/caramelizer oven that is capable of toasting and/or caramelizing food products. More particularly, the present invention relates to a combination toaster/caramelizer oven that is capable of toasting food products using infrared heating or, by inserting a platen between the food products, caramelizing food products. Still more particularly, the present invention relates to a combination toaster/caramelizer oven that is capable of using infrared heating for toasting food products and/or caramelizing food products that are transported on a conveyor.
[0004] 2. Description of the Related Art
[0005] In the fast food industry, there is an ongoing need for rapid high quality toasting of food products. Fast food establishments have a need for toasting flat buns or flat breads of different thicknesses for sandwiches. Also, fast food establishments need to both toast food products during their breakfast operation and later caramelize the surface of food products during their afternoon and dinner operations. Due to the crowded foodservice equipment configurations of most fast food establishments, it would be highly desirable to not have to include two separate pieces of equipment, such as a separate toaster and a separate caramelizer.
[0006] The same fast food establishments may have a need to caramelize bread for sandwiches, may also need to toast muffins and pastries that are normally not caramelized. The toasting and heating of the muffins and pastries must be even and quick to meet customer expectations.
[0007] Therefore, there is a continued need to provide quick and rapid heating of food products of different types by the fast food industry. The present inventors have also discovered that there is a need for an oven which has the capability of both toasting and caramelizing food products.
SUMMARY OF THE INVENTION
[0008] A combination toaster/caramelizer oven for treating food products comprising: a housing; at least one heating element; a removable platen; and at least one conveyor disposed opposite the platen for conveying the food products through the housing, wherein the platen is disposed between the heating element and the conveyor.
[0009] Preferably, the heating element is an infrared heating element and the conveyor is an endless belt-type conveyor.
[0010] Optionally, the oven comprises at least a first conveyor and a second conveyor in spaced relationship to either the heating element and/or the platen to define first and second toasting and/or caramelizing paths, respectively. The first toasting path comprises a first product inlet and a first product outlet opposite the first product inlet and the second toasting path comprises a second product inlet and a second product outlet opposite the second product inlet. It is preferable, that the platen be disposed opposite to both the first and second conveyors.
[0011] The heating element are typically fixedly secured to an upper surface of the housing and the housing further comprises guide rails for receiving the removable platen. It is also preferable that the spacing between the conveyor and either the heating elements or the removable platen is adjustable. Also, the spacing between the first conveyor and either the heating elements or the removable platen is adjustable and wherein the spacing between the second conveyor and either the heating element or the removable platen is adjustable, wherein the first and second conveyors are adjustable independent of each other, whereby food products of differing dimensions can be either toasted or caramelized to substantially the same degree while passing through the oven at substantially the same time.
[0012] Additionally, the conveyor is in spaced relationship to either the heating elements or the platen to define a toasting and/or caramelizing path, wherein the toasting and/or caramelizing path comprises a food product inlet and a food product outlet, wherein the food product outlet is disposed at an end of the conveyor opposite to the food product inlet, and wherein the oven further comprises an outlet tray which is operably associated with the housing to receive the food products exiting the food product outlet. Optionally, the outlet tray is heated.
[0013] According to another embodiment of the present invention, the combination toaster/caramelizer oven can be angularly adjustable from a horizontal position to a vertical position.
[0014] Still yet another embodiment of the present invention provides a caramelizer oven for caramelizing food products comprising: a housing; at least one heating element; a platen; at least one conveyor disposed opposite the platen for conveying the food products through the housing; and at least one moisture injector that introduces moisture to the surface of the food product which is in contact with the platen. During operation, the conveyor is capable of pressing the food product against the platen to caramelize the food product.
[0015] The conveyor is in spaced relationship to the platen to define a caramelizing path, wherein the caramelizing path comprises a food product inlet and a food product outlet, and wherein the at least one moisture injector is disposed about that portion of the platen adjacent to the food product inlet. In this embodiment it is preferable to have the heating element embedded within the platen. The heating element heats water to form steam which is passed through the moisture injectors into the food products.
[0016] A method of caramelizing food products in an oven having at least one heating element and a platen, the method comprising: conveying food products through the oven along a toasting path; providing moisture (e.g., steam) to the food products; and caramelizing the moisture laden food products by contacting a surface of the food products with the platen which has been heated via the heating element.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Other and further objects, advantages and features of the present invention will be understood by reference to the following specification in conjunction with the accompanying drawings, in which like reference characters denote like elements of structure and:
[0018] FIG. 1 is a perspective view of a first embodiment of the combination toaster/caramelizer oven of the present invention;
[0019] FIG. 2 is a front view of the combination toaster/caramelizer oven of FIG. 1 ;
[0020] FIG. 3 is a perspective view of a second embodiment of the combination toaster/caramelizer oven of the present invention;
[0021] FIG. 4 is a front view of the combination toaster/caramelizer oven of FIG. 3 ;
[0022] FIG. 5 a is a perspective view of a third embodiment of the combination toaster/caramelizer oven of the present invention, having four combination toaster/caramelizer oven modules;
[0023] FIG. 5 b is a perspective view of the third embodiment of the combination toaster/caramelizer oven of the present invention, having separate moisture portions in the four combination toaster/caramelizer oven modules;
[0024] FIG. 6 is a perspective view of a fourth embodiment of the combination toaster/caramelizer oven of the present invention;
[0025] FIG. 7 is a cross-sectional view of the combination toaster/caramelizer oven of the embodiment of FIG. 6 ; and
[0026] FIG. 8 is a view of the combination toaster/caramelizer oven of the embodiment of FIG. 6 , with the platen removed.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] Referring to FIGS. 1 and 2 , a first embodiment of the combination toaster/caramelizer oven 10 of the present invention includes a pair of combination toaster/caramelizer oven modules 20 and 40 disposed side by side in a combination toaster/caramelizer oven housing 12 . Module 20 includes a first upper endless conveyor 22 and a first lower endless conveyor 24 . Module 40 includes a second upper endless conveyor 42 and a second lower endless conveyor 44 . Modules 20 and 40 have a metallic plate or platen 30 disposed between upper conveyors 22 and 42 and lower conveyors 24 and 44 . Infrared heater elements 26 heat food products 36 and function as rollers as part of upper conveyors 22 and 42 and lower conveyors 42 and 44 . Infrared heater elements 26 also heat platen 30 to caramelize food products when they come in close contact with platen 30 .
[0028] The upper conveyors 22 and 42 are adjustable toward and away from platen 30 so as to adjust for food products 36 of different heights. For example, cam adjusters 48 may be provided to raise and lower conveyers 22 and 42 . Food products 36 , which are being caramelized, are inserted at an upper inlet 16 (to the right in FIG. 1 ) and pressed against the platen 30 by upper conveyors 22 and 42 while being conveyed to an outlet 34 (to the left in FIG. 1 ). The infrared heater elements 26 heat platen 30 to a temperature that will caramelize food products 36 . Infrared heater elements 26 are capable of heating much more quickly than traditional conductive heaters. Examples of food products that are caramelized include bun halves, flat bread, sandwich rolls and the like. When the food products 36 exit outlet 14 , they slide down inner housing to a tray 46 .
[0029] Food products 36 , which are not being caramelized, are conveyed by lower conveyors 24 and 44 from an inlet 18 (to the right in FIG. 1 ) toward an outlet 38 (to the left in FIG. 1 ). Lower conveyors 24 and 44 are spaced from platen 30 so that those food products 36 being carried are not pressed against platen 30 , but rather are heated by the infrared heater elements 26 . Examples of food products for which may not require caramelizing include muffins, bagels, sliced bread and the like. When the food products exit the outlet, they slide down a frame portion to tray 46 .
[0030] The height of inlets 16 and 18 are independently adjustable in the two modules 20 and 40 of FIGS. 1 and 2 to accommodate food products of different heights. For example, module 20 can be adjusted to caramelize bun tops and module 40 can be adjusted to caramelize bun bottoms. In addition, modules 20 and 40 may be angularly adjustable between the horizontal position shown in FIGS. 1 and 2 the vertical position to any desired angular position from zero to 90°.
[0031] Tray 46 catches food products 36 after they has been toasted or caramelized. Tray 46 incorporates vulcanized heating using resistive coils, electrical heating or lamps. Tray 46 has a Teflon® coating to prevent food products 36 from sticking. Tray 46 prevents food products 36 from cooling before they are consumed. Tray 46 is an optional feature particularly for commercial use.
[0032] It will be apparent to those skilled in the art that the combination toaster/caramelizer oven embodiment of FIGS. 1 and 2 may employ more or fewer modules than the two modules that are shown.
[0033] Referring to FIGS. 3 and 4 , a second embodiment of combination toaster/caramelizer oven 50 of the present invention includes three combination toaster/caramelizer oven modules 52 , 54 and 56 disposed side by side and spaced from platen 66 . Each module 52 , 54 and 56 includes a conveyor 58 , 60 and 62 , respectively. Food products 36 , which are being caramelized, are inserted at an inlet 68 (to the right in FIG. 3 ) and pressed against a surface of platen 66 by conveyors 58 , 60 and 62 while being conveyed to an outlet 70 (to the left in FIG. 3 ). Platen 66 is located between infrared heating elements 72 above, and conveyors 58 , 60 and 62 below that support and transport food products 36 from inlet 68 to outlet 70 . When food products 36 exit outlet 70 , they slide down a frame portion to tray 46 . In this embodiment tray 46 is also heatable to maintain the temperature of food products before consumption.
[0034] The platen 66 is shaped and dimensioned for easy removal to expose the infrared heating elements 72 to the food products 36 for toasting. In the preferred embodiment, platen 66 is formed as a flat metallic plate that is easily removable. Platen 66 is inserted into brackets in housing 12 and held in place by it own weight. Alternatively, platen 66 can be formed as a U-shaped structure with the infrared heater being disposed in the U portion. Platen 66 is inserted in combination toaster/caramelizer oven frame and mates with mating parts in the combination toaster/caramelizer oven frame 12 and is secured by one or more suitable fastening elements (not shown). For removal, the fastening elements are unfastened, and the U-shaped structure is easily removed.
[0035] The inlet height is adjustable independently in the three modules to accommodate food products 36 of different sizes. In addition, the modules may be angularly adjustable to any desired angular position from zero to 90°, zero being the horizontal position and 90° being the vertical position.
[0036] It will be apparent to those skilled in the art that the combination toaster/caramelizer oven embodiment of FIGS. 3 and 4 may employ more or fewer modules than the three that are shown.
[0037] Referring to FIG. 5 a , a third embodiment of the combination toaster/caramelizer oven 80 of the present invention includes four combination toaster/caramelizer oven modules 82 , 84 , 86 and 88 disposed side by side and spaced from platens 90 . Each module 82 , 84 , 86 and 88 includes a conveyor 92 , 94 , 96 and 98 , respectively, disposed in spaced apart relationship to platens 90 . Food products 36 , which are being caramelized, are inserted at an inlet 102 (to the top in FIG. 5 a ) and pressed against platen 90 by conveyor 92 , 94 , 96 and 98 while being conveyed to an outlet 104 (to the bottom in FIG. 5 ). Platens 90 are heated by an infrared heater elements 106 that may be disposed on the opposite side thereof with respect to the caramelizing side as shown in FIGS. 3 and 4 . Alternatively, the infrared heater elements 106 are embedded in platens 90 . When food products 36 exit outlet 104 , they slide down inner housing 110 .
[0038] In a region of the platens 90 adjacent inlet 102 , one or more steam injectors 108 are disposed in the platen to inject moisture into the food products 36 . One or more steam injectors 108 are located only at the portion of platens 90 near inlet 102 . One or more steam injectors 108 are centrally located beneath platens 90 to provide even distribution of moisture in food product 36 . The caramelizing process then occurs along the remainder of platens 90 towards outlet. Moisture injection is used to maintain moisture levels in bread during the caramelizing process. Additionally, moisture injection may, optionally, be used to inject additional flavors into bread using spices in the water. Moisture injection refreshes food products that may become dry if they are not immediately consumed. In this embodiment, platens 90 are not removable. Alternatively, as shown in FIG. 5 b , steam injectors 108 are located on a separate unit 112 from infrared elements 106 .
[0039] In this embodiment, the inlet height is adjustable independently in the three modules to accommodate food products 36 of different sizes. In addition, the modules may be angularly adjustable to any desired angular position from zero to 90°, zero being the horizontal position and 90° being the vertical position.
[0040] It will be apparent to those skilled in the art that the combination toaster/caramelizer oven embodiment of FIG. 5 may employ more or fewer modules than the four that are shown.
[0041] In each of the three embodiments, the width of the modules can be varied to accommodate food products of various shapes. For example, an elongated roll may be arranged side ways on a wider conveyor.
[0042] A fourth embodiment of combination toaster/caramelizer oven is shown in FIGS. 6 through 8 . Referring to FIG. 6 , combination toaster/caramelizer oven 120 has a housing 122 , a platen 124 and an endless conveyor 130 . Housing 122 also has in inlet 136 into which food products are placed for transport on conveyer 130 from inlet 136 to outlet 140 . Combination toaster/caramelizer oven 120 also has a heating tray 142 onto which food products fall after being either toasted or caramelized. Platen 124 has variable thickness to accommodate food products of different heights. For example, side 126 has a lower surface to caramelize bun bottoms and side 128 has a higher surface to accommodate but tops, which are generally thicker.
[0043] FIG. 7 shows a cross-section view of combination toaster/caramelizer oven 120 , in which platen 124 is in a partially removed position. Platen 124 is held in position under its own weight as it rests against brackets 144 connected to the side of housing 122 . Infrared heater element 146 is placed above platen 124 . When caramelizing is needed for food products, platen 124 is installed. Alternatively, when toasting is desired, platen 124 is removed and food products on conveyor 130 are toasted by heater element 146 .
[0044] A method for toasting food products in the combination toaster/caramelizer oven of the present invention will be described with regard to FIG. 5 . Food products 36 are placed in inlet 102 on any of platens 90 beneath conveyors 92 , 94 , 96 or 98 . Flat food products are transported form inlet 102 to outlet 104 by movement of conveyors 92 , 94 , 96 and 98 . Moisture is provided to food products 36 when they are placed on platens 90 by steam injectors 108 . Steam injectors 108 are located centrally in platens 90 . Steam is provided to food products 36 before the caramelizing process begins. Once food products 36 have been transported along platens 90 to outlet 104 , the caramelization is completed and the food products slide down inner housing for further preparation to be consumed. FIG. 8 shows combination toaster/caramelizer oven 120 with platen 124 removed.
[0045] The present invention having been thus described with particular reference to the preferred forms thereof, it will be obvious that various changes and modifications may be made therein.
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A combination toaster/caramelizer oven for treating food products comprising: a housing; at least one heating element; a removable platen; and at least one conveyor disposed opposite the platen for conveying the food products through the housing, wherein the platen is disposed between the heating element and the conveyor. Optionally, the caramelizer oven can further include at least one moisture injector that introduces moisture to the surface of the food product which is in contact with the platen.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND OF THE INVENTION
[0003] This invention relates to small boats and more particularly to outrigger stabilizers for a kayak or canoe.
[0004] 1. Field of the Invention
[0005] It is well known that canoes or kayaks and other small watercraft are easily upset by sudden movement of an occupant or rough water in which waves against the boat side, tilt it over in an upsetting fashion.
[0006] This invention stabilizes such small boats by providing an outrigger on each side of the boat easily connected with or removed from the boat.
[0007] 2. Description of the Prior Art
[0008] Prior art generally discloses a plurality of different designs and apparatus for stabilizing small water craft.
[0009] U.S. Pat. No. 3,763,813, issued Oct. 9, 1973 to Holtz for Inflatable Canoe And Outrigger for small boats of the inflatable type which illuminates the use of metallic connections and uses fixer fit between adjacent components to rigidly support an outrigger laterally of the boat.
[0010] This invention is believed distinctive over this and similar patents by providing outriggers overlying and projecting laterally of a small boat for quickly and easily removably connecting a pair of floatation members to respective ends of the outriggers laterally of a boat and rigidly positioned relative to the boat.
[0011] U.S. Pat. No. 1,369,670, issued Feb. 22, 1921 to Kauffman for Boat and Design Patent No. 271,095, issued Oct. 25, 1983 to Paster for Commando Landing Craft are believed good examples of the further state-of-the-art for outriggers, pivotally connected to opposite sides of the boat and the rigid positioning of outriggers adjacent the sides of a boat.
BRIEF SUMMARY OF THE INVENTION
[0012] A pair of adapters, transversely overlie respective end portions of a small boat, such as a kayak or canoe and are clamp connected thereto for supporting a pair of outriggers or spars extending transversely of the boat. The remote ends of the spars support respective ends of cylindrical floatation members or buoys having upwardly curved closed end portions by brackets depending from the respective end of each of spar for maintaining the buoys in laterally spaced parallel relation with the boat for dampening lateral tipping motion of the boat.
[0013] The principal object of this invention is to provide outriggers connecting buoys with a small boat, such as a kayak or canoe.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0014] [0014]FIG. 1 is a top view;
[0015] [0015]FIG. 2 is a front end elevational view;
[0016] [0016]FIG. 3 is a side elevational view;
[0017] [0017]FIG. 4 is a fragmentary perspective view, to a larger scale, looking upward at the bottom surfaces of a boat surrounding clamp bracket, per se; and,
[0018] [0018]FIG. 5 is a fragmentary perspective view, to a different scale, of the area enclosed by the arrow 5 of FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The reference numeral 10 indicates the apparatus as a whole comprising a small boat such as a kayak or canoe 12 having a pair of spars or outriggers 18 and 20 extending transversely of the respective end portions 14 and 16 of the boat and connected thereto intermediate their ends by a pair of clamp means or adapters 22 and 24 , as presently explained. The respective end portions of the spars projecting beyond the respective sides of the boat support floatation means such as a pair of buoyant tubes 26 and 27 , by a plurality of brackets four (4), in the example shown, of forward and rearward pairs of brackets 28 - 30 and 32 - 34 , respectively. Since the adapters 22 - 24 and pairs of brackets 28 - 34 are respectively identical, only one of each is described in detail in the interest of brevity.
[0020] Referring more particularly to FIGS. 2 and 4 the reference numeral 22 indicates the adapter which is U-shaped strap-like in general configuration having an arcuately bowed upwardly bight portion 36 as viewed in FIG. 4, for transverse contiguous contact with the arcuate peripheral surface at respective end portions of the boat 12 and having relatively short upstanding legs 38 and 40 at respective end portions of the bight portion 36 respectively terminating laterally in horizontal wings 42 - 44 . A length of tubular material, such as a sleeve 46 , extends between and overlies the wings 44 and 42 and is rigidly secured thereto as by welding. The sleeve 46 is centrally provided with a transverse aperture 48 , for the purposes presently explained. A short length of box tubing is secured to the adapter at the juncture of the respective leg and wing to form horizontal sleeves 50 and 52 which longitudinally support the respective end portions of elongated bars 54 and 56 at respective sides of the boat to enable tying equipment, not shown, to the boat. The adapter 22 is secured to the forward end portion of the boat 12 by a flexible buckle equipped band or strap 57 , such as a ratchet tie down, overlying the bight portion 36 and extending through apertures 53 in the respective end portion of the bight portion 36 , and transversely of the boat peripheral surface. The spars 18 and 20 are longitudinally inserted into the respective adapter tube 46 and fastened intermediate their ends by a pin 49 , not shown, extending through the sleeve aperture 48 and a cooperating aperture in the respective spar.
[0021] The buoyant tubes 26 - 27 are identical and only one is described in the interest of brevity. Tube 26 is substantially equal in length with the boat and of a selected diameter and is characterized by arcuately upturned end portions 60 and 62 . Each end of the tube 26 is provided with an expansion plug 72 contacting the inner periphery of the tube to form a water tight tube, which may be used for storing equipment.
[0022] Referring now to FIG. 5, the bracket 28 is generally inverted U-shape having a horizontal bight portion 64 extending transversely of the buoyant tube and includes a pair of legs 66 and 68 having tabs 70 at their depending ends which are apertured and secured to the wall forming the buoyant tube 26 . Each end portion of each spar is slideably received in a tube 75 longitudinally overlying the bight portion 64 . Each tube 75 is transversely apertured as at 77 for similarly securing the spar end portions within the respective tube 75 .
[0023] Obviously the invention is susceptible to changes or alterations without defeating its practicability. Therefore, I do not wish to be confined to the preferred embodiment(s) shown in the drawing(s) and described herein.
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A small boat stabilizer is formed by a pair of elongated tubular buoys secured in laterally spaced parallel relation to respective end portions of the boat by spars extending transversely of respective ends of the boat and secured thereto by adapters.
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The present invention relates to lubricant compositions which are stabilized against oxidative degradation. The stabilization is carried out by the addition of at least two specific additives.
SUMMARY OF THE INVENTION
It is known and customary to add additives to lubricants based on mineral or synthetic oils in order to improve their performance characteristics. Additives against oxidative degradation of the lubricants, the so-called antioxidants, are of particular importance. Oxidative degradation of lubricants plays a significant role especially in motor oils because of the high temperatures prevailing in the combustion chambers of the engines and the presence, in addition to oxygen, of oxides of nitrogen (NO x ) which act as oxidation catalysts.
Aromatic amines, for example alkylated diphenylamines or alkylated phenothiazines, are used inter alia as antioxidants for lubricants. EP-A-149,422 or GB-A-1,090,688, for example, disclose such amines. The use of such aromatic amines in combination with other antioxidants, for example with triarylphosphites, thiodipropionates or phenolic antioxidants, is also known, for example from EP-A-49,133.
We have found that a combination of aromatic amines with sterically hindered amines is a highly suitable antioxidant for lubricants.
The invention provides a lubricant composition which comprises
(A) a mineral or a synthetic base oil or a mixture of such oils,
(B) at least one aromatic amine of the formula I or II, ##STR2## in which R 1 is C 1 -C 18 alkyl, C 7 -C 9 phenylalkyl, C 5 -C 12 cycloalkyl, phenyl, C 7 -C 18 alkylphenyl, C 7 -C 18 alkoxyphenyl or naphthyl, R 2 is phenyl, C 7 -C 18 -alkylphenyl, C 7 -C 18 alkoxyphenyl or naphthyl, R 3 is hydrogen, C 1 -C 12 alkyl, benzyl, allyl, methallyl, phenyl or a group --CH 2 SR 4 , R 4 is C 4 -C 18 alkyl, --CH 2 COO(C 4 -C 18 alkyl) or --CH 2 CH 2 COO(C 4 -C 18 alkyl), and R 5 and R 6 independently of one another are H, C 1 -C 18 alkyl or C 7 -C 9 phenylalkyl, and
(C) at least one sterically hindered amine.
DETAILED DESCRIPTION OF THE INVENTION
As C 1 -C 12 alkyl, R 3 may be linear or branched alkyl and may be, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl or dodecyl. As C 1 -C 18 alkyl, R 1 , R 5 and R 6 may in addition also be, for example, tetradecyl, pentadecyl, hexadecyl or octadecyl. As C 4 -C 18 alkyl, R 4 may also be, for example, n-butyl, tert-butyl, n-hexyl, tert-octyl, n-dodecyl or octadecyl.
As C 7 -C 9 phenylalkyl, R 1 , R 5 and R 6 may be, for example, benzyl, 2-phenylethyl, α-methylbenzyl, 2-phenylpropyl or α, α-dimethylbenzyl.
As C 7 -C 18 alkylphenyl, R 1 and R 2 may have linear or branched alkyl groups. Examples are tolyl, ethylphenyl, isopropylphenyl, tert-butylphenyl, sec-pentylphenyl, n-hexylphenyl, tert-octylphenyl, iso-nonylphenyl or n-dodecylphenyl. R 1 and R 2 may also be mixtures of alkylphenyl groups, such as those produced in industrial alkylations of diphenylamine with olefins. The alkyl group is preferably in the para position of the aromatic amine.
As the component (B), a compound of the formula I or II is preferably used in which R 1 is C 1 -C 4 alkyl, C 7 -C 9 phenylalkyl, cyclohexyl, phenyl, C 10 -C 18 alkylphenyl or naphthyl, R 2 is C 10 -C 18 alkylphenyl or phenyl, R 3 is hydrogen, C 1 -C 8 alkyl, benzyl, allyl or a group --CH 2 SR 4 , R 4 is C 8 -C 18 alkyl or --CH 2 COO(C 8 -C 18 alkyl), and R 5 and R 6 independently of one another are H, C 1 -C 12 alkyl or C 7 -C 9 phenylalkyl.
Of the compounds of the formula I those are particularly preferred in which R 1 and R 2 independently of one another are phenyl or C 10 -C 18 alkyl-phenyl and R 3 is hydrogen.
Of the compounds of the formula II those are particularly preferred in which R 3 is hydrogen and R 5 and R 6 independently of one another are H or C 4 -C 12 alkyl.
Examples of compounds of the formula I are:
diphenylamine,
N-allyldiphenylamine
4-isopropoxydiphenylamine
N-phenyl-1-naphthylamine
N-phenyl-2-naphthylamine
di-4-methoxyphenylamine
d-[4-(1,3-dimethylbutyl)phenyl]amine
di-[4-(1,1,3,3-tetramethylbutyl)phenyl]amine
tert-octylated N-phenyl-1-naphthylamine
industrial mixtures obtained by reacting diphenylamine with diisobutylene (mono-, di- and trialkylated tert-butyl- and tert-octyldiphenylamine)
phenothiazine
N-allylpenothiazine
3,7-di-tert-octylphenothiazine
industrial mixtures obtained by reacting phenothiazine with diisobutylene
Particularly preferred component (B) is 4,4'-di-tert-octyldiphenylamine or 3,7-di-tert-octylphenothiazine or an industrial mixture obtained by reacting diphenylamine with diisobutylene, particularly a mixture which contains the following components:
a) not more than 5% by weight of diphenylamine,
b) 8-15% by weight of 4-tert-butyldiphenylamine,
c) 24-32% by weight of 4-tert-octyldiphenylamine, 4,4'-di-tert-butyldiphenylamine and 2,4,4'-tri-tert-butyldiphenylamine,
d) 23-34% by weight of 4-tert-butyl-4'-tert-octyldiphenylamine, 2,2'- and 3,3'-di-tert-octyldiphenylamine and 2,4-di-tert-butyl-4'-tert-octyldiphenylamine,
e) 21-34% by weight of 4,4'-di-tert-octyldiphenylamine and 2,4-di-tert-octyl-4'-tert-butyldiphenylamine.
The component (C) may be any cyclic or acyclic sterically hindered amine. The preferred component (C) is a compound which contains at least one group of the formula III ##STR3## in which R is hydrogen or methyl. R as hydrogen is preferred. The compounds in question are derivatives of polyalkylpiperidines, particularly of 2,2,6,6-tetramethylpiperidine. These polyalkylpiperidines preferably carry one or two polar substituents or a polar spiro ring system in the 4-position.
The following classes of polyalkylpiperidines are particularly important:
a) compounds of the formula IV ##STR4## in which n is an integer of 1 to 4, preferably 1 or 2, R is hydrogen or methyl, R 11 is hydrogen, oxyl, hydroxyl, C 1 -C 12 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 7 -C 12 aralkyl, C 1 -C 18 alkoxy, C 5 -C 8 cycloalkoxy, C 7 -C 9 phenylalkoxy, C 1 -C 8 alkanoyl, C 3 -C 5 alkenoyl, C 1 -C 18 alkanoyloxy, benzyloxy, glycidyl or a group --CH 2 CH(OH)--Z, in which Z is hydrogen, methyl or phenyl, R 11 being preferably H, C 1 -C 4 alkyl, allyl, benzyl, acetyl or acryloyl and R 12 being, when n is 1, hydrogen, C 1 -C 18 alkyl which is uninterrupted or interrupted by one or more oxygen atoms, cyanoethyl, benzyl, glycidyl, a monobasic radical of an aliphatic, cycloaliphatic, araliphatic, unsaturated or aromatic carboxylic acid, carbamic acid or a phosphorus-containing acid or a monovalent silyl radical, preferably a radical of an aliphatic carboxylic acid having 2 to 18 carbon atoms, of a cycloaliphatic carboxylic acid having 7 to 15 carbon atoms, of an α,β-unsaturated carboxylic acid having 3 to 5 carbon atoms or of an aromatic carboxylic acid having 7 to 15 carbon atoms, R 12 being, when n is 2, C 1 -C 12 alkylene, C 4 -C 12 alkenylene, xylylene, a dibasic radical of an aliphatic, cycloaliphatic, araliphatic or aromatic dicarboxylic acid, dicarbamic acid or a phosphorus-containing acid or a divalent silyl radical, preferably a radical of an aliphatic dicarboxylic acid having 2 to 36 carbon atoms, a cycloaliphatic or aromatic dicarboxylic acid having 8 to 14 carbon atoms or an aliphatic, cycloaliphatic or aromatic dicarbamic acid having 8 to 14 carbon atoms, R 12 being, when n is 3, a tribasic radical of an aliphatic, cycloaliphatic or aromatic tricarboxylic acid, an aromatic tricarbamic acid or a phosphorus-containing acid or a trivalent silyl radical, and R 12 being, when n is 4, a tetrabasic radical of an aliphatic, cycloaliphatic or aromatic tetracarboxylic acid.
Any C 1 -C 12 alkyl substituents present are, for example, methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-hexyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.
As C 1 -C 18 alkyl, R 11 or R 12 may be, for example, the above groups and additionally, for example, n-tridecyl, n-tetradecyl, n-hexadecyl or n-octadecyl.
As C 3 -C 8 alkenyl, R 11 is, for example, 1-propenyl, allyl, methallyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-octenyl and 4-tert-butyl-2-butenyl.
As C 3 -C 8 alkynyl, R 11 is preferably propargyl.
As C 7 -C 12 aralkyl, R 11 is particularly phenethyl and above all benzyl.
As C 1 -C 8 alkanoyl, R 11 is , for example, formyl, propionyl, butyryl, octanoyl, but preferably acetyl; and as C 3 -C 5 alkenoyl, R 11 is particularly acryloyl.
As a monobasic radical of a carboxylic acid, R 12 is a radical, for example, of acetic acid, caproic acid, stearic acid, acrylic acid, methacrylic acid, benzoic acid or β-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid.
As a dibasic radical of a dicarboxylic acid, R 12 is a radical, for example, of malonic acid, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, maleic acid, itaconic acid, phthalic acid, dibutylmalonic acid, dibenzylmalonic acid, butyl(3,5-di-tert-butyl-4-hydroxybenzyl)malonic acid or bicycloheptenedicarboxylic acid.
As a tribasic radical of a tricarboxylic acid, R 12 is a radical, for example, of trimellitic acid, citric acid or nitrilotriacetic acid.
As a tetrabasic radical of a tetracarboxylic acid, R 12 is the tetrabasic radical, for example, of butane-1,2,3,4-tetracarboxylic acid or of pyromellitic acid.
As a dibasic radical of a dicarbamic acid, R 12 is a radical, for example, of hexamethylenedicarbamic acid or 2,4-toluylenedicarbamic acid.
Preferred compounds of the formula IV are those in which R is hydrogen, R 11 is hydrogen or methyl, n is 2 and R 12 is the diacyl radical of an aliphatic dicarboxylic acid having 4 to 12 carbon atoms.
Examples of polyalkylpiperidine compounds of this class are the following compounds:
1) 4-hydroxy-2,2,6,6-tetramethylpiperidine
2) 1-allyl-4-hydroxy-2,2,6,6-tetramethylpiperidine
3) 1-benzyl-4-hydroxy-2,2,6,6-tetramethylpiperidine
4) 1-(4-tert-butyl-2-butenyl)-4-hydroxy-2,2,6,6-tetramethylpiperidine
5) 4-stearoyloxy-2,2,6,6-tetramethylpiperidine
6) 1-ethyl-4-salicyloyloxy-2,2,6,6-tetramethylpiperidine
7) 4-methacryloyloxy-1,2,2,6,6-pentamethylpiperidine
8) 1,2,2,6,6-pentamethylpiperidin-4-yl-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate
9) di-(1-benzyl-2,2,6,6-tetramethylpiperidin-4-yl) maleate
10) di-(2,2,6,6-tetramethylpiperidin-4-yl) succinate
11) di-(2,2,6,6-tetramethylpiperidin-4-yl) glutarate
12) di-(2,2,6,6-tetramethylpiperidin-4-yl) adipate
13) di-(2,2,6,6-tetramethylpiperidin-4-yl) sebacate
14) di-(1,2,2,6,6-pentamethylpiperdin-4-yl) sebacate
15) di-(1,2,3,6-tetramethyl-2,6-diethylpiperidin-4-yl) sebacate
16) di-(1-allyl-2,2,6,6-tetramethylpiperidin-4-yl) phthalate
17) 1-hydroxy-4-cyanoethyloxy-2,2,6,6-tetramethylpiperidine
18) 1-acetyl-2,2,6,6-tetramethylpiperidin-4-yl acetate
19) tri-(2,2,6,6-tetramethylpiperidin-4-yl) trimellitate
20) 1-acryloyl-4-benzyloxy-2,2,6,6-tetramethylpiperidine
21) di-(2,2,6,6-tetramethylpiperidin-4-yl) diethylmalonate
22) di-(1,2,2,6,6-pentamethylpiperidin-4-yl) dibutylmalonate
23) di-(1,2,2,6,6-pentamethylpiperidin-4-yl) butyl-(3,5-di-tert-butyl-4-hydroxybenzyl) malonate
24) di(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate
25) di(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate
26) hexane-1',6'-bis(4-carbamoyloxy-1-n-butyl-2,2,6,6-tetramethylpiperidine)
27) toluene-2',4'-bis(4-carbamoyloxy-1-n-propyl-2,2,6,6-tetramethylpiperidine)
28) dimethyl-bis(2,2,6,6-tetramethylpiperidin-4-oxy)silane
29) phenyl-tris(2,2,6,6-tetramethylpiperidin-4-oxy)silane
30) tris(1-propyl-2,2,6,6-tetramethylpiperidin-4-yl) phosphite
31) tris(1-propyl-2,2,6,6-tetramethylpiperidin-4-yl) phosphate
32) phenyl[bis-(1,2,2,6,6-pentamethylpiperidin-4-yl)] phosphonate
33) 4-hydroxy-1,2,2,6,6-pentamethylpiperidine
34) 4-hydroxy-N-hydroxyethyl-2,2,6,6-tetramethylpiperidine
35) 4-hydroxy-N-(2-hydroxypropyl)-2,2,6,6-tetramethylpiperidine
36) 1-glycidyl-4-hydroxy-2,2,6,6-tetramethylpiperidine
b) compounds of the formula (V) ##STR5## in which n is the integer 1 or 2, R and R 11 have the meaning defined in a), R 13 is hydrogen, C 1 -C 12 alkyl, C 2 -C 5 hydroxyalkyl, C 5 -C 7 cycloalkyl, C 7 -C 8 aralkyl, C 2 -C 18 alkanoyl, C 3 -C 5 alkenoyl, benzoyl or a group of the formula ##STR6## and when n is 1, R 14 is hydrogen, C 1 -C 18 alkyl, C 3 -C 8 alkenyl, C 5 -C 7 cycloalkyl, C 1 -C 4 alkyl substituted by a hydroxyl, cyano, alkoxycarbonyl or carbamide group, glycidyl, a group of the formula --CH 2 --CH(OH)--Z or the formula --CONH--Z, in which Z is hydrogen, methyl or phenyl; when n is 2, R 14 is C 2 -C 12 alkylene, C 6 -C 12 arylene, xylylene, a --CH 2 --CH(OH)--CH 2 -- group or a --CH 2 --CH(OH)--CH 2 --O--D--O-- group, in which D is C 2 -C 10 alkylene, C 6 -C 15 arylene, C 6 -C 12 cycloalkylene, or, if R 13 is not alkanoyl, alkenoyl or benzoyl, R 14 can also be a dibasic radical of an aliphatic, cycloaliphatic or aromatic dicarboxylic acid or dicarbamic acid or also the group --CO--, or when n is 1, R 13 and R 14 together can be the dibasic radical of an aliphatic, cycloaliphatic or aromatic 1,2- or 1,3-di-carboxylic acid.
Any C 1 -C 12 alkyl or C 1 -C 18 alkyl substituents present have the meaning already defined in a).
Any C 5 -C 7 cycloalkyl substituents present are particularly cyclohexyl.
As C 7 -C 8 aralkyl, R 13 is particularly phenylethyl or above all benzyl. As C 2 -C 5 hydroxyalkyl, R 13 is particularly 2-hydroxyethyl or 2-hydroxypropyl.
As C 2 -C 18 alkanoyl, R 13 is for example propionyl, butyryl, octanoyl, dodecanoyl, hexadecanoyl, octadecanoyl, but preferably acetyl, and as C 3 -C 5 alkenoyl, R 13 is particularly acryloyl.
As C 2 -C 8 alkenyl, R 14 is for example allyl, methallyl, 2-butenyl, 2-pentenyl, 2-hexenyl or 2-octenyl.
As C 1 -C 4 alkyl substituted by a hydroxyl, cyano, alkoxycarbonyl or carbamide group, R 14 can be, for example, 2-hydroxyethyl, 2-hydroxypropyl, 2-cyanoethyl, methoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-aminocarbonylpropyl or 2-(dimethylaminocarbonyl)ethyl.
Any C 2 -C 12 alkylene substituents present are, for example, ethylene, propylene, 2,2-dimethylpropylene, tetramethylene, hexamethylene, octamethylene, decamethylene or dodecamethylene.
Any C 6 -C 15 arylene substituents present are, for example, o-, m- or p-phenylene, 1,4-naphthylene or 4,4'-diphenylene.
As C 6 -C 12 cycloalkylene, D is especially cyclohexylene.
Preferred compounds of the formula V are those in which n is 1 or 2, R is hydrogen, R 11 is hydrogen or methyl, R 13 is hydrogen, C 1 -C 12 alkyl or a group of the formula ##STR7## and when n=1, R 14 is hydrogen or C 1 -C 12 alkyl, and when n=2, R 14 is C 2 -C 8 alkylene.
Examples of polyalkylpiperidine compounds of this class are the following compounds:
37) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)hexamethylene-1,6-diamine
38) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)hexamethylene-1,6-diacetamide
39) bis(2,2,6,6-tetramethylpiperidin-4-yl)amine
40) 4-benzoylamino-2,2,6,6-tetramethylpiperidine
41) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-dibutyladipamide
42) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-dicyclohexyl-2-hydroxypropylene-1,3-diamine
43) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-p-xylylenediamine
44) N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)succindiamide
45) di(2,2,6,6-tetramethylpiperidin-4-yl) N-(2,2,6,6-tetramethylpiperidin-4-yl)-aminodipropionate
46) The compound of the formula ##STR8## 47) 4-(bis-2-hydroxyethylamino)-1,2,2,6,6-pentamethylpiperidine 48) 4-(3-methyl-4-hydroxy-5-tert-butylbenzoamido)-2,2,6,6-tetramethylpiperidine
49) 4-methacrylamido-1,2,2,6,6-pentamethylpiperidine
c) compounds of the formula (VI) ##STR9## in which n is the integer 1 or 2, R and R 11 have the meaning defined in a), and when n is 1, R 15 is C 2 -C 8 alkylene or C 2 -C 8 hydroxyalkylene or C 4 -C 22 acyloxyalkylene, and when n is 2, R 15 is the group (--CH 2 ) 2 C(CH 2 --) 2 .
As C 2 -C 8 alkylene or C 2 -C 8 hydroxyalkylene, R 15 is for example ethylene, 1-methylethylene, propylene, 2-ethylpropylene or 2-ethyl-2-hydroxymethylpropylene.
As C 4 -C 22 acyloxyalkylene, R 15 is for example 2-ethyl-2-acetoxymethylpropylene.
Examples of polyalkylpiperidine compounds of this class are the following compounds:
50) 9-aza-8,8,10,10-tetramethyl-1,5-dioxaspiro[5.5]undecane
51) 9-aza-8,8,10,10-tetramethyl-3-ethyl-1,5-dioxaspiro[5.5]undecane
52) 8-aza-2,7,7,8,9,9-hexamethyl-1,4-dioxaspiro[4.5]decane
53) 9-aza-3-hydroxymethyl-3-ethyl-8,8,9,10,10-pentamethyl-1,5-dioxaspiro[5.5]undecane
54) 9-aza-3-ethyl-3-acetoxymethyl-9-acetyl-8,8,10,10-tetramethyl-1,5-dioxaspiro[5.5]undecane
55) 2,2,6,6-tetramethylpiperidine-4-spiro-2'-(1',3'-dioxan)-5'-spiro-5"-(1",3"-dioxan)-2"-spiro-4"'-(2"',2'",6"',6"'-tetramethylpiperidine).
d) compounds of the formulae VIIA, VIIB and VIIC ##STR10## in which n is the integer 1 or 2, R and R 11 have the meaning defined in a), R 16 is hydrogen, C 1 -C 12 alkyl, allyl, benzyl, glycidyl or C 2 -C 6 alkoxyalkyl, and when n is 1, R 17 is hydrogen, C 1 -C 12 alkyl, C 3 -C 5 alkenyl, C 7 -C 9 aralkyl, C 5 -C 7 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 2 -C 6 alkoxyalkyl, C 6 -C 10 aryl, glycidyl or a group of the formula --(CH 2 )p--COO--Q or the formula --(CH 2 )p--O--CO--Q, in which p is 1 or 2 and Q is C 1 -C 4 alkyl or phenyl, and when n is 2, R 17 is C 2 -C 12 alkylene, C 4 -C 12 alkenylene, C 6 -C 12 arylene, a group --CH 2 --CH(OH)--CH 2 --O--D--O--CH 2 --CH(OH)--CH 2 --, in which D is C.sub. 2 -C 10 alkylene, C 6 -C 15 arylene, C 6 -C 12 cycloalkylene or a group --CH 2 CH(OZ')CH 2 --(OCH 2 CH(OZ')CH 2 ) 2 --, in which Z' is hydrogen, C 1 -C 18 alkyl, allyl, benzyl, C 2 -C 12 alkanoyl or benzoyl, T 1 and T 2 independently of one another are hydrogen, C 1 -C 18 alkyl or C 6 -C 10 aryl or C 7 -C 9 aralkyl which are unsubstituted or substituted by halogen or C 1 -C 4 alkyl, or T 1 and T 2 together form with the carbon atom connecting them a C 5 -C 12 cycloalkane ring.
Any C 1 -C 12 alkyl substituents present are, for example, methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-hexyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.
Any C 1 -C 18 alkyl substituents present can be, for example, the groups defined above and additionally also, for example, n-tridecyl, n-tetradecyl, n-hexadecyl or n-octadecyl.
Any C 2 -C 6 alkoxyalkyl substituents present are, for example, methoxymethyl, ethoxymethyl, propoxymethyl, tert-butoxymethyl, ethoxyethyl, ethoxypropyl, n-butoxyethyl, tert-butoxyethyl, isopropoxyethyl or propoxypropyl.
As C 3 -C 5 alkenyl, R 17 is, for example, 1-propenyl, allyl, methallyl, 2-butenyl or 2-pentenyl.
As C 7 -C 9 aralkyl, R 17 , T 1 and T 2 are particularly phenethyl or above all benzyl. Any cycloalkane ring formed by T 1 and T 2 together with the carbon atom can be, for example, a cyclopentane, cyclohexane, cyclooctane or cyclododecane ring.
As C 2 -C 4 hydroxyalkyl, R 17 is, for example, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxybutyl or 4-hydroxybutyl.
As C 6 -C 10 aryl, R 17 , T 1 and T 2 are especially phenyl, α- or β-naphthyl which are unsubstituted or substituted by halogen or C 1 -C 4 alkyl.
As C 2 -C 12 alkylene, R 17 is, for example, ethylene, propylene, 2,2-dimethylpropylene, tetramethylene, hexamethylene, octamethylene, decamethylene or dodecamethylene.
As C 4 -C 12 alkenylene, R 17 is particularly 2-butenylene, 2-pentenylene or 3-hexenylene.
As C 6 -C 12 arylene, R 17 is, for example, o-, m- or p-phenylene, 1,4-naphthylene or 4,4'-diphenylene.
As C 2 -C 12 alkanoyl, Z' is, for example, propionyl, butyryl, octanoyl, dodecanoyl, but preferably acetyl.
As C 2 -C 10 alkylene, C 6 -C 15 arylene or C 6 -C 12 cycloalkylene, D has the meaning defined in b).
Examples of polyalkylpiperidine compounds of this class are the following compounds:
56) 3-benzyl-1,3,8-triaza-7,7,9,9-tetramethylspiro[4.5]decane-2,4-dione
57) 3-n-octyl-1,3,8-triaza-7,7,9,9-tetramethylspiro[4.5]decane-2,4-dione
58) 3-allyl-1,3,8-triaza-1,7,7,9,9-pentamethylspiro[4.5]decane-2,4-dione
59) 3-glycidyl- 1,3,8-triaza-7,7,8,9,9-pentamethylspiro[4.5]decane-2,4-dione
60) 1,3,7,7,8,9,9-heptamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione
61) 2-iso-propyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxo-spiro[4.5]-decane
62) 2,2-dibutyl-7,7,9,9-tetramethyl-1-oxa-3,8-diaza-4-oxospiro[4.5]decane
63) 2,2,4,4-tetramethyl-7-oxa-3,20-diaza-21-oxodispiro 5.1.11.2]-heneicosane
64) 2-butyl-7,7,9,9-tetramethyl-1-oxa-4,8-diaza-3-oxospiro[4.5]decane
65) 8-acetyl-3-dodecyl-1,3,8-triaza-7,7,9,9-tetramethylspiro[4.5]decane-2,4-dione
or the compounds of the following formulae: ##STR11##
e) compounds of the formula VIII ##STR12## in which n is the integer 1 or 2 and R 18 is a group of the formula ##STR13## in which R and R 11 have the meaning defined in a), E is --O-- or --NR 11 --, A is C 2 -C 6 alkylene or --(CH 2 ) 3 --O--, and x is the integers 0 or 1, R 19 is the same as R 18 or is one of the groups --NR 21 R 22 , --OR 23 , --NHCH 2 OR 23 or --N(CH 2 OR 23 ) 2 , and when n is 1, R 20 is the same as R 18 or R 19 , and when n=2, R 20 is a group --E--B--E--, in which B is C 2 -C 6 alkylene which is uninterrupted or interrupted by --N(R 21 )--, R 11 is C 1 -C 12 alkyl, cyclohexyl, benzyl or C 1 -C 4 hydroxyalkyl or a group of the formula ##STR14## R 22 is C 1 -C 12 alkyl, cyclohexyl, benzyl, C 1 -C 4 hydroxyalkyl, and R 23 is hydrogen, C 1 -C 12 alkyl or phenyl, or R 21 and R 22 together are C 4 -C 5 -alkylene or C 4 -C 5 oxaalkylene, for example ##STR15## or R 21 and R 22 in each case are also a group of the formula ##STR16##
Any C 1 -C 12 alkyl substituents present are, for example, methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-hexyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.
Any C 1 -C 4 hydroxyalkyl substituents present are, for example, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl or 4-hydroxybutyl.
C 2 -C 6 alkylene as A is, for example, ethylene, propylene, 2,2-dimethylpropylene, tetramethylene or hexamethylene.
C 4 -C 5 alkylene or C 4 -C 5 oxaalkylene as R 21 and R 22 together are, for example, tetramethylene, pentamethylene or 3-oxapentamethylene.
Examples of polyalkylpiperidine compounds of this class are the compounds of the following formulae: ##STR17##
f) oligomers or polymeric compounds whose recurring structural unit comprises a 2,2,6,6-tetraalkylpiperidine radical of the formula (I), particularly polyesters, polyethers, polyamides, polyamines, polyurethanes, polyureas, polyaminotriazines, poly(meth)acrylates, poly(meth)acrylamide and their copolymers which comprise such radicals.
Examples of 2,2,6,6-polyalkylpiperidine light stabilizers of this class are the compounds of the following formulae where m is an integer of 2 to about 200. ##STR18## in which R and R 11 have the meaning defined in a).
Preferred compounds of the formula IX are those in which R is hydrogen or methyl and R 11 is hydrogen or methyl.
Examples of such compounds are:
95) 2,2,6,6-tetramethyl-4-piperidone (triacetonamine)
96) 1,2,2,6,6-pentamethyl-4-piperidone
97) 2,2,6,6-tetramethyl-4-piperidon-1-oxyl
98) 2,3,6-trimethyl-2,6-diethyl-4-piperidone
The amount of (B) and (C) added to the base oil (A) depends on the type of the base oil and the desired degree of stabilization. Generally the total of (B) and (C) is 0.1 to 2% by weight, preferably 0.5 to 1% by weight, based on (A). The ratio of (B) to (C) can vary within wide limits; (B) is generally the quantitatively dominant component. The ratio (B):(C) is preferably 3-5:1.
The component (A) is a mineral or synthetic base oil, such as is normally used for the production of lubricants. Synthetic oils may be, for example, esters of polycarboxylic acids or of polyols; they may also be aliphatic polyesters or poly-α-olefins, silicones, phosphoric acid esters or polyalkylene glycols. The lubricant may also be a grease based on an oil and a thickener. Such lubricants are described, for example, in D. Klamann "Schmierstoffe und artverwandte Produkte" ["Lubricants and Related Products"], Verlag Chemie, Weinheim 1982.
The lubricant may additionally contain other additives, for example other antioxidants, metal passivators, rust inhibitors, viscosity index improvers, pour point depressants, dispersants, surfactants or antiwear additives.
EXAMPLES OF PHENOLIC ANTIOXIDANTS
1. Alkylated Monophenolics
2,6-di-tert-butyl-4-methylphenol, 2,6-di-tert-butylphenol, 2-tert-butyl-4,6-dimethylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-iso-butylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, o-tert-butylphenol.
2. Alkylated Hydroquinones
2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol.
3. Hydroxylated Thiodiphenyl Ethers
2,2'-thio-bis(6-tert-butyl-4-methylphenol), 2,2'-thio-bis(4-octylphenol), 4,4'-thio-bis(6-tert-butyl-3-methylphenol), 4,4'-thio-bis(6-tert-butyl-2-methylphenol).
4. Alkylidene Bisphenols
2,2'-methylene-bis(6-tert-butyl-4-methylphenol), 2,2'-methylene-bis(6-tert-butyl-4-ethylphenol), 2,2'-methylene-bis[4-methyl-6-(?-methylcyclohexyl)phenol], 2,2'-methylene-bis(4-methyl-6-cyclohexylphenol), 2,2'-methylene-bis(6-nonyl-4-methylphenol), 2,2'-methylene-bis(4,6-di-tert-butylphenol), 2,2'-ethylidene-bis(4,6-di-tert-butylphenol), 2,2'-ethylidene-bis(6-tert-butyl-4-isobutylphenol or -5-isobutylphenol), 2,2'-methylene-bis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylene-bis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylene-bis(2,6-di-tert-butylphenol), 4,4'-methylene-bis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-di(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3'-tert-butyl-4'-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methylphenyl)dicyclopentadiene, bis[2-(3'-tert-butyl-2'-hydroxy-5'-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate.
5. Benzyl Compounds
1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, bis(3,5-di-tert-butyl-4-hydroxybenzyl) sulfide, isooctyl 3,5-di-tert-butyl-4-hydroxybenzylmercaptoacetate, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithiol terephthalate, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl) isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate, dioctadecyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate, monoethyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate calcium salt.
6. Acylaminophenols
4-hydroxylauranilide, 4-hydroxystearanilide, 2,4-bis-octylmercapto-6-(3,5-di-tert-butyl-4-hydroxyanilino)-s-triazine, octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate.
7. Esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid
with monohydric or polyhydric alcohols, for example with methanol, diethylene glycol, octadecanol, triethylene glycol, 1,6-hexanediol, pentaerythritol, neopentyl glycol, trishydroxyethyl isocyanurate, thiodiethylene glycol, bishydroxyethyloxalic acid diamide.
8. Esters of β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid
with monohydric or polyhydric alcohols, for example with methanol, diethylene glycol, octadecanol, triethylene glycol, 1,6-hexanediol, pentaerythritol, neopentyl glycol, tris-hydroxyethyl isocyanurate, thiodiethylene glycol, dihydroxyethyloxalic acid diamide.
9. Amides of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid
for example N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamine, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamine, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazine.
EXAMPLES OF OTHER ANTIOXIDANTS
aliphatic or aromatic phosphites, esters of thiodipropionic acid or of thiodiacetic acid, or salts of dithiocarbamide acid or dithiophosphoric acid.
EXAMPLES OF METAL DEACTIVATORS FOR EXAMPLE FOR COPPER
triazoles, benzotriazoles and their derivatives, tolutriazoles and their derivatives, 2-mercaptobenzothiazole, 2-mercaptobenzotriazole, 2,5-dimercaptobenzotriazole, 2,5-dimercaptobenzothiadiazole, 5,5'-methylenebisbenzotriazole, 4,5,6,7-tetrahydrobenzotriazole, salicylidenepropylenediamine, salicylaminoguanidine and their salts.
EXAMPLES OF RUST INHIBITORS
a) Organic acids and esters, metal salts and anhydrides thereof, for example: N-oleoylsarcosine, sorbitol monooleate, lead naphthenate, alkenylsuccinic anhydride, for example dodecenylsuccinic anhydride, alkenylsuccinic acid hemiesters and hemi-amides, and 4-nonylphenoxyacetic acid.
b) Nitrogenous compounds, for example:
I. primary, secondary or tertiary aliphatic or cycloaliphatic amines and amine salts of organic and inorganic acids, for example oil-soluble alkylammonium carboxylates.
II. heterocyclic compounds, for example: substituted imidazolines and oxazolines.
c) Phosphorus compounds, for example: amine salts of partial esters of phosphoric acid or partial esters of phosphonic acid, zinc dialkyldithiophosphates.
d) Sulfur compounds, for example: barium dinonylnaphthalenesulfonates, calcium petroleum sulfonates.
EXAMPLES OF VISCOSITY INDEX IMPROVERS
polyacrylates, polymethacrylates, vinylpyrrolidone/methacrylate copolymers, polyvinylpyrrolidones, polybutenes, olefin copolymers, styrene/acrylate copolymers, polyethers.
EXAMPLES OF POUR POINT DEPRESSANTS
polymethacrylate, alkylated naphthalene derivatives.
EXAMPLES OF DISPERSANTS/SURFACTANTS
polybutenylsuccinamides or -imides, polybutenylphosphonic acid derivatives, basic magnesium, calcium and barium sulfonates and phenolates.
EXAMPLES OF ANTIWEAR ADDITIVES
compounds containing sulfur and/or phosphorus and/or halogen, such as sulfurized vegetable oils, zinc dialkyldithiophosphates, tritolylphosphate, chlorinated paraffins, alkyl sulfides, aryl disulfides and aryl trisulfides, triphenylphosphorothionates, diethanolaminomethyltolyltriazole, di(2-ethylhexyl)aminomethyltolyltriazole.
The addition of phenolic antioxidants and/or of aliphatic and aromatic phosphites or phosphonites which are capable of increasing the stabilizing effect of the components (B) and (C), is particularly important.
Examples of suitable phosphites and phosphonites are: triphenyl phosphite, decyldiphenyl phosphite, phenyldidecyl phosphite, tris(nonylphenyl) phosphite, trilauryl phosphite, trioctadecyl phosphite, distearylpentaerythritol diphosphite, tris(2,4-di-tert-butylphenyl) phosphite, diisodecylpentaerythritol diphosphite, bis(2,4-di-tert-butylphenyl)pentaerythritol diphosphite, tristearylsorbitol triphosphite, tetrakis(2,4-d-tert-butylphenyl)-4,4'-biphenylene diphosphonite, bis(2,6-di-tert-butyl-4-methylphenyl)pentaerythritol diphosphite.
The individual additives are dissolved in the oil. To speed up the dissolution, the oil may be first heated or the additives may be first dissolved in a solvent.
The lubricant may also contain solid lubricant additives, for example graphite or molybdenum sulfide.
The examples below elucidate the invention in greater detail. The parts and percentages are parts and percentages by weight, unless stated otherwise.
EXAMPLE 1
The induction period of the oxidation of the oil samples by air containing 400 ppm of NO 2 is determined under isothermal conditions using a differential scanning calorimeter (Du Pont Thermoanalysator 1090). The measurement is carried out at 170° C. at a pressure of 8 bar. A reference mineral oil (Aral 136) containing 1% by volume of 1-decene added in order to boost its susceptibility to oxidation, is used as the base oil. The following amine stabilizers are added to the oil.
Aromatic Amines
A-1 An industrial mixture produced by reacting diphenylamine with diisobutylene, comprising
a) 3% of diphenylamine
b) 14% of 4-tert-butyldiphenylamine,
c) 30% of 4-tert-octyldiphenylamine, 4,4'-di-tert-butyldiphenylamine and 2,4,4'-tri-tert-butyldiphenylamine,
d) 29% of 4-tert-butyl-4'-tert-octyldiphenylamine, 2,2'- and 3,3'-di-tert-octyldiphenylamine and 2,4-di-tert-butyl-4'-tert-octyldiphenylamine,
e) 18% of 4,4'-di-tert-octyldiphenylamine,
f) 6% of 2,4-di-tert-octyl-4'-tert-butyldiphenylamine.
A-2 3,7-di-(tert-octyl)phenothiazine
Hindered Amines
H-1 di(2,2,6,6-tetramethylpiperidin-4-yl) sebacate
H-2 2,2,6,6-tetramethyl-4-piperidone
H-3 di(2,2,6,6-tetramethylpiperidin-4-yl) succinate
H-4 di(1,2,2,6,6-pentamethylpiperidin-4-yl) sebacate
H-5 2,3,6-trimethyl-2,6-diethyl--piperidone
H-6 2,2,6,6-tetramethyl-4-butylaminopiperidine
Table 1 lists the induction periods. The higher the induction period, the greater is the antioxidative effect of the stabilizer additives.
TABLE 1______________________________________Aromatic Hindered Induction periodamine amine (min)______________________________________-- -- 430.55% of A-1 -- 800.45% of A-1 0.10% of H-1 91.50.45% of A-1 0.10% of H-2 91.50.45% of A-1 0.10% of H-3 90.050.45% of A-1 0.10% of H-4 900.45% of A-1 0.10% of H-5 84.50.45% of A-1 0.10% of H-6 89______________________________________
EXAMPLE 2
Oxidation of hydrocarbons gives rise to oxygen-containing groups, for example hydroxyl, carboxyl or ester groups. Infra-red spectroscopy allows the amount of such groups to be measured and to determine therefrom the effect of the antioxidants. For this purpose samples of a reference mineral oil (Aral® 136) containing 1% by volume of 1-decene added in order to boost its susceptibility to oxidation, is heated under isothermal conditions in air containing 400 ppm of NO 2 , for 12 hours at a pressure of 8 bar. The IR absorption at 1730 cm -1 and 1630 cm -1 is then determined. The greater these values, the greater is the effect of the stabilizers. Tables 2a and 2b demonstrate the results at various temperatures.
TABLE 2a______________________________________Oxidation at 120° C. IR AbsorptionStabilizer at 1730 cm.sup.-1 at 1630 cm.sup.-1______________________________________0.55% of A-1 0.471 1.0510.45% of A-1 + 0.10% of H-2 0.392 0.8390.45% of A-1 + 0.10% of H-3 0.424 0.8630.45% of A-1 + 0.10% of H-5 0.396 0.673______________________________________
TABLE 2b__________________________________________________________________________Oxidation at 150° C. IR AbsorptionStabilizer at 1730 cm.sup.-1 at 1630 cm.sup.-1__________________________________________________________________________0.55% of A-1 0.557 1.8510.45% of A-1 + 0.10% of H-4 0.353 1.5000.65% of A-1 0.384 1.5990.45% of A-1 + 0.10% of H-4 + 0.10% of phenol B*) 0.330 1.2790.45% of A-1 + 0.10% of A-2 + 0.10% of H-4 0.340 1.443__________________________________________________________________________ *)phenol B = compound of the formula ##STR19##
EXAMPLE 3
The oxidation characteristics of the lubricating oils stabilized according to the invention were also tested by the TOST (turbine oxidation stability test) method according to ASTM D-943. For this purpose 60 ml of water are added to 300 ml of a mineral oil (Mobil STOC K 305) and the oil is heated in the presence of iron or copper wire at 95° C. for 1000 hours, while oxygen is passed through. The measured parameters are formation of acids by determining the neutralization value TAN (mg of KOH/g of oil) and the amount of sludge formed.
For the stabilization either the amine A-1 is used on its own or in admixture with the hindered amine H-7 (2,2,6,6-tetramethyl-4-dodecyloxypiperidine), the total concentration of the stabilizers being always 0.25%, based on the oil.
______________________________________A-1 H-7 TAN (mg KOH/g of oil) Sludge (mg)______________________________________100% -- 0.46 3095% 5% 0.38 2790% 10% 0.30 2475% 25% 0.31 27______________________________________
EXAMPLE 4
By analogy with Example 1, the induction period of the oxidation is measured at 170° C. For this purpose the following hindered amines are used:
H-8 N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)hexamethylenediamine
H-9 N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)pentamethylenediamine
H-10 4-(methoxypropylamino)-2,2,6,6-tetramethylpiperidine
TABLE 4______________________________________Aromatic Hindered Induction periodamine amine (min)______________________________________-- -- 480.55% of A-1 -- 860.45% of A-1 0.10% of H-8 950.45% of A-1 0.10% of H-9 960.45% of A-1 0.10% of H-10 89______________________________________
EXAMPLE 5
The induction period of the oxidation is determined at 170° C. as described in Example 1. The following aromatic amine is used for this purpose:
A-3 N-(p-octylphenyl)-1-naphthylamine
TABLE 5______________________________________Aromatic Hindered Induction periodamine amine (min)______________________________________0.55% of A-3 -- 52.80.45% of A-3 0.10% of H-7 66______________________________________
EXAMPLE 6
Oxidation resistance can be also determined by measuring the viscosity increase when the oil is treated with oxygen at elevated temperature.
For this purpose a stream of oxygen (1 liter/h) is passed through the oil at 150° C. for 70 hours. The susceptibility of the oil to oxidation is first boosted by the addition of a catalytic amount of copper naphthenate. The viscosity of the oil is measured before and after the oxidation using an Ubbelode viscometer.
TABLE 6______________________________________ Percentage viscosityOil increase______________________________________base oil 168%base oil containing 3.4%0.6% of A-1 and0.15% of H-8______________________________________
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A lubricant based on a mineral or synthetic oil is stabilized against oxidative degradation by the addition of a mixture comprising at least one specified aromatic amine of the formula I ##STR1## and at least one sterically hindered amine. The lubricant may contain other antioxidants or other additives. It is preferably used as motor oil.
| 2 |
FIELD OF THE INVENTION
[0001] This invention relates to a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psycho-pathological disturbances and stress, by administration of 4-(2-Butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)pyrazolo-[1,5-a]-1,3,5-triazine, its enantiomer and pharmaceutically acceptable salts as a corticotropin releasing factor receptor ligand.
BACKGROUND OF THE INVENTION
[0002] Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)—derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci . ( USA 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
[0003] Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
[0004] In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984) F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
[0005] It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].
[0006] Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
[0007] The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G.F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide , E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
[0008] It has been further postulated that CRF has a role in cardiovascular or heart-related diseases as well as gastrointestinal disorders arising from stress such as hypertension, tachycardia and congestive heart failure, stroke, irritable bowel syndrome post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see E. D. DeSouza, C. B. Nemeroff, Editors; Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide , E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990) and C. Maillot, M. Million, J. Y. Wei, A. Gauthier, Y. Tache, Gastroenterology, 119, 1569-1579 (2000)].
[0009] Over-expression or under-expression of CRF has been proposed as an underlying cause for several medical disorders. Such treatable disorders include, for example and without limitation: affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia, hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress [for reviews see J. R. McCarthy, S. C. Heinrichs and D. E. Grigoriadis, Cuur. Pharm. Res., 5, 289-315 (1999); P. J. Gilligan, D. W. Robertson and R. Zaczek, J. Medicinal Chem., 43, 1641-1660 (2000), G. P. Chrousos, Int. J. Obesity, 24, Suppl. 2, S50-S55 (2000); E. Webster, D. J. Torpy, I. J. Elenkov, G. P. Chrousos, Ann. N.Y. Acad. Sci., 840, 21-32 (1998); D. J. Newport and C. B. Nemeroff, Curr. Opin. Neurobiology, 10, 211-218 (2000); G. Mastorakos and I. Ilias, Ann. N.Y. Acad. Sci., 900, 95-106 (2000); M. J. Owens and C. B. Nemeroff, Expert Opin. Invest. Drugs, 8, 1849-1858 (1999); G. F. Koob, Ann. N.Y. Acad. Sci., 909, 170-185 (2000)].
[0010] The following publications each describe CRF antagonist compounds; however, none disclose the compounds provided herein: WO95/10506; WO99/51608; WO97/35539; WO99/01439; WO97/44308; WO97/35846; WO98/03510; WO99/11643; PCT/US99/18707; WO99/01454; and, WO00/01675.
SUMMARY OF THE INVENTION
[0011] In accordance with one aspect, the present invention provides a novel compound, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism; and hypoglycemia in a mammal.
[0012] The present invention provides a novel compound that binds to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compound of the present invention is useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.
[0013] According to another aspect, the present invention provides a novel compound of Formula (I) (described below) which is useful as an antagonist of the corticotropin releasing factor. The compound of the present invention exhibits activity as a corticotropin releasing factor antagonist and appears to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such a compound of Formula (I), and methods of using such a compound for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
[0014] The use of competitive binding assays is considered particularly valuable for screening candidates for new drugs, e.g. to identify new CRF ligands or other compounds having even greater or more selective binding affinity for CRF receptors, which candidates would therefore be potentially useful as drugs. In the assay, one determines the ability of the candidate ligand to displace the labelled compound.
[0015] Therefore, another embodiment of the invention includes the use of a compound of the invention is a binding assay, wherein one or more of the compounds may be joined to a label, where the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescers, chemiluminescers, specific binding molecules, particles, e.g. magnetic particles, and the like.
[0016] Another embodiment of the invention is directed to the use of the compounds of the invention (particularly labeled compounds of this invention) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds. Labeled compounds of the invention may be used for in vitro studies such as autoradiography of tissue sections or for in vivo methods, e.g. PET or SPECT scanning. Particularly, preferred compounds of the invention are useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF1 receptor.
DETAILED DESCRIPTION OF THE INVENTION
[0017] [1] In a first embodiment, the present invention provides a compound of Formula (I):
[0018] and stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
[0019] [2] In another embodiment, the present invention provides a compound of embodiment [1], isomers thereof, stereoisomeric forms thereof, mixtures of stereoisomeric forms thereof, pharmaceutically acceptable prodrugs thereof, or pharmaceutically acceptable salt forms thereof, wherein said compound is 4-((R)-2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazine.
[0020] [3] In another embodiment, the present invention provides a compound of any one of embodiments [1] to [2], pharmaceutically acceptable prodrugs thereof, or pharmaceutically acceptable salt forms thereof, wherein said compound is substantially free of its (S) stereoisomer
[0021] [4] In another embodiment, the present invention provides a compound of embodiment [1], wherein said compound is 4-(2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazine.
[0022] [5] In another embodiment, the present invention provides a compound of embodiment [1], wherein said compound is 4-((R)-2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazine.
[0023] [6] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0024] [7] In another embodiment, the present invention provides a method of antagonizing a CRF receptor in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0025] [8] In another embodiment, the present invention provides a method of treating a disorder manifesting hypersecretion of CRF in a warm-blooded animal, comprising administering to the animal a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0026] [9] In another embodiment, the present invention provides a method for the treatment of a disorder, the treatment of which can be effected or facilitated by antagonizing CRF, comprising administering to the mammal a therapeutically effective of a compound of any one of embodiments [1] to [5].
[0027] [10] In another embodiment, the present invention provides a method of antagonizing a CRF receptor in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0028] [11] In another embodiment, the present invention provides a method of treating anxiety or depression in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0029] [12] In another embodiment, the present invention provides a method for screening for ligands for CRF receptors, which method comprises:
[0030] a) carrying out a competitive binding assay with a CRF receptor, a compound of any one of embodiments [1] to [5] which is labelled with a detectable label, and a candidate ligand; and
[0031] b) determining the ability of said candidate ligand to displace said labelled compound.
[0032] [13] In another embodiment, the present invention provides a method for detecting CRF receptors in tissue comprising:
[0033] a) contacting a compound of any one of embodiments [1] to [5], which is labelled with a detectable label, with a tissue, under conditions that permit binding of the compound to the tissue; and
[0034] b) detecting the labelled compound bound to the tissue.
[0035] [14] In another embodiment, the present invention provides a method of inhibiting the binding of CRF to a CRF-1 receptor, comprising contacting a compound of any one of embodiments [1] to [5] with a solution comprising cells expressing the CRF1 receptor, wherein the compound is present in the solution at a concentration sufficient to inhibit the binding of CRF to the CRF-1 receptor.
[0036] [15] In another embodiment, the present invention provides a article of manufacture comprising:
[0037] a) a packaging material;
[0038] b) a compound of any one of embodiments [1] to [5] ; and
[0039] c) a label or package insert contained within said packaging material idicating that said compound is effective for treating anxiety or depression.
[0040] [16] The present invention also comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of any one of embodiments [1] to [5].
[0041] Definitions
[0042] As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids of basic residues such as amines, for example, acetic, benzenesulfonic, benzoic, amphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like; and alkali or organic salts of acidic residues such as carboxylic acids, for example, alkali and alkaline earth metal salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.
[0043] Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
[0044] “Pharmaceutically acceptable prodrugs” as used herein means any covalently bonded carriers which release the active parent drug of Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula (I) are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” means compounds that are rapidly transformed in vivo to yield the parent compound of formula (I), for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethysilyl) monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs p. 113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
[0045] “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
[0046] As used herein to describe a compound, the term “substantially free of its (S) stereoisomer” means that the compound is made up of a significantly greater proportion of its (R) stereoisomer than of its optical antipode (i.e., its (S) stereoisomer). In a preferred embodiment of the invention, the term “substantially free of its (S) stereoisomer” means that the compound is made up of at least about 90% by weight of its (R) stereoisomer and about 10% by weight or less of its (S) stereoisomer.
[0047] In a more preferred embodiment of the invention, the term “substantially free of its (S) stereoisomer” means that the compound is made up of at least about 95% by weight of its (R) stereoisomer and about 5% by weight or less of its (S) stereoisomer. In an even more preferred embodiment, the term “substantially free of its (S) stereoisomer” means that the compound is made up of at least about 99% by weight of its (R) stereoisomer and about 1% or less of its (S) stereoisomer. In another preferred embodiment, the term “substantially free of its (S) stereoisomer” means that the compound is made up of nearly 100% by weight of its (R) stereoisomer. The above percentages are based on the total amount of the combined stereoisomers of the compound.
[0048] The term “therapeutically effective amount” of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
[0049] As used herein, the term “labeled” is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g. radioisotope, fluorescers, enzyme, antibodies, particles such as magnetic particles, chemiluminescer, P 32 , I 131 , and At 211 , etc.
Syntheses
[0050] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s) . The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture.
[0051] The present invention includes all stereoisomeric forms of the compounds of the formula I. Centers of asymmetry that are present in the compounds of formula I can all independently of one another have S configuration or R configuration. The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of an intermediate during the synthesis. The present invention also includes all tautomeric forms of the compounds of formula (I).
[0052] The compound of Formula (I) may be prepared from using the procedures outlined in Scheme 1.
[0053] A compound of Formula (II), where X=F, may be treated with a metal alkoxide (e.g. sodium methoxide, potassium methoxide; pre-formed or generated in situ) in an inert solvent to generate an intermediate of Formula (III). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.
[0054] Alternatively, a compound of Formula (II), where X=OH, may be treated with an alkylating agent in the presence of a base in an inert solvent to generate an intermediate of Formula (III). Alkylating agents include, but are not limited to, haloalkanes (e.g. CH 3 I), dialkyl sulfates (e.g. Me 2 SO 4 ) or alkyl trifluoro-sulfonates (e.g. CH 3 O 3 SCF 3 ).
[0055] Bases may include, but are not limited to, alkali metals, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal carbonates, alkaline metal carbonates, transition metal carbonates (e.g. silver carbonate), alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bicarbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine).
[0056] Inert solvents may include, but are not limited to, halocarbons (1 to 8 carbons, 1 to 8 halogens), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 50° C. to 150° C.
[0057] A compound of Formula (III) may be transformed to a compound of Formula (IV) by reaction with a brominating agent in the presence or absence of an additive in an inert solvent. Brominating agents include, but are not limited to, N-bromosuccinimide-2,2′-azobisisobutyro-nitrile (AIBN), N-bromophthalimide-2,2′-azobisiso-butyronitrile (AIBN)), bromine. Additives include, but are not limited to, alkali metal phosphates (e.g. K 3 PO 4 , Na 3 PO 4 ), alkali metal hydrogen phosphates (e.g. Na 2 HPO 4 , K 2 HPO 4 ), alkali metal dihydrogen phosphates (e.g. NaH 2 PO 4 , KH 2 PO 4 ). Inert solvents include, but are not limited to, halocarbons (1 to 6 carbons, 1 to 6 halogens (preferably chlorine), water, N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one). Reaction temperatures range from 0° C. to 200° C. (preferably 20° C. to 120° C).
[0058] A compound of Formula (IV) may be converted to a compound of Formula (V) by sequential reactions with (1) an alkyl lithium in an inert solvent at temperatures ranging from −100° C. to 50° C.; (2) a compound of the Formula B(OR a ) 3 (where R a is branched or straight chain alkyl of 1 to 20 carbons) at temperatures ranging from −100° C. to 50° C. and (3) an acid in the presence or absence of water at temperatures ranging from −100° C. to 100° C. Alkyl lithiums may be branched or straight chain compounds containing 1 to 20 carbons. Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene).
[0059] Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.
[0060] A compound of Formula (VII) may be produced by reaction of a compound of Formula (V) with a compound of Formula (VI) in the presence of a complex or salt of palladium or nickel, a base and an inert solvent. Complexes of palladium or nickel include, but are not limited to, phosphine complexes such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , NiCl 2 (PPh 3 ) 2 , or [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium. Bases may include, but are not limited to, alkali metals, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkaline metal carbonates (e.g. barium carbonate), transition metal carbonates (e.g. silver carbonate) or trialkyl amines (e.g. triethyl amine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −100° C. to 100° C.
[0061] An intermediate of Formula (VII) may be reacted with a base in the presence of an inert solvent to afford a compound of Formula (VIII), where M is an alkali metal cation (e.g. sodium or potassium). Bases may include, but are not limited to, alkali metal hydroxides (e.g. NaOH or KOH), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide) or alkaline earth metal hydroxides. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0° C. to 150° C.
[0062] Compounds of Formula (VIII) may be treated with hydrazine-hydrate in the presence of an acid and an inert solvent at temperatures ranging from 0° C. to 200° C., preferably 70° C. to 150° C., to produce compounds of Formula (IX). Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.
[0063] Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).
[0064] A compound of Formula (IX) may be reacted with compounds of Formula H 3 C(C═NH)OR C (where R C is alkyl (1-6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at temperatures ranging from 0° C. to 200° C. to produce a compound of Formula (X). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used.
[0065] Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloroethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran. Preferred temperatures range from 0° C. to 100° C.
[0066] A compound of Formula (X) may be converted to an intermediate compound of Formula (XI) by treatment with compounds C═O(R d ) 2 (where R d is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from −50° C. to 200° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine).
[0067] Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).
[0068] A compound of Formula (XI) may be treated with a halogenating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. to give a halogenated intermediate (XII) (where X is halogen). Halogenating agents include, but are not limited to, SOCl 2 , POCl 3 , PCl 3 , PCl 5 , POBr 3 , PBr 3 or PBr 5 . Bases may include, but are not limited to, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably N,N-diethylaniline).
[0069] Inert solvents may include, but are not limited to, N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one) or aromatic hydrocarbons (preferably benzene or toluene) Preferred reaction temperatures range from 20° C. to 200° C.
[0070] A compound of Formula (XII) may be reacted with an alkyl amine in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80 to 250° C. to generate compounds of Formula (I). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine).
[0071] Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloroethane). Preferred reaction temperatures range from 0° C. to 140° C.
[0072] The compounds of the invention may be prepared as radiolabeled compounds by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14 C), hydrogen (preferably 3 H), sulfur (preferably 35 S), or iodine (preferably 125 I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
[0073] Tritium labeled probe compounds may also conveniently be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
[0074] Receptor autoradiography (receptor mapping) may be carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention.
EXAMPLES
[0075] Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on a Varian VXR or Unity 300 FT-NMR instruments (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer or a Hewlett Packard 5988A model spectrometer (using chemi-ionization (CI) with NH 3 as the carrier gas, electrospray (ESI), atmospheric pressure chemi-ionization (APCI) or gas chromatography (GC)). Melting points were recorded on a MelTemp 3.0 heating block apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during workup were made with indicator paper.
[0076] Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Otherwise, parts and percentages are by weight. Commonly used abbreviations are: DMF (N,N-dimethylformamide), EtOH (ethanol), MeOH (methanol), EtOAc (ethyl acetate), HOAc (acetic acid), DME (1,2-diethoxyethane) and THF (tetrahydrofuran).
[0077] The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.
EXAMPLE 1
Preparation of 2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one
[0078] A. 2-Methoxy-6-methylpyridine
[0079] Sodium (31.0 g, 1.35 mol) was added portionwise to methanol (500 mL) over 30 min with stirring in a flask equipped with a reflux cindenser. After the addition was complete, the reaction mixture was allowed to cool to ambient temperature. 2-Fluoro-6-methylpyridine (50 g, 450 mmol) was added portionwise with stirring. The reaction mixture was then heated to reflux temperature and stirred for 48 h. The mix was then cooled to ambient temperature and solvent was removed in vacuo to provide a yellow oil. The residue was taken up in water (500 mL) and three extractions with ether (200 mL) were performed. The combined organic layers were dried over MgSO 4 , filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid: 1 H-NMR(CDCl 3 , 300 MHz): δ 7.44 (dd, 1H , J=8,7), 6.71 (d, 1H, J=7), 6.53 (d, 1H, J=8), 3.91 (s, 3H), 2.45 (s, 3H).
[0080] B. 2-Methoxy-6-methylpyridine
[0081] A mixture of 2-hydroxy-6-methylpyridine (6.85 g, 62.8 mmol), silver carbonate (22.5 g, 81.6 mmol), iodomethane (39.1 mL, 628 mmol) and chloroform (200 mL) was stirred at ambient temperature for 40 h in the dark. The reaction mixture was filtered through celite. The collected solid was washed with ether. The combined filtrates were concentrated in vacuo to give a liquid (6.25 g), which was identical to the product from Part A.
[0082] C. 6-Methoxy-3-bromo-2-methylpyridine
[0083] A mixture of 2-methoxy-6-methylpyridine (17.0 g, 138 mmol) and a solution of disodium hydrogen phosphate (0.15M in water, 250 mL) was stirred at room temperature. Bromine (7.1 mL, 138 mmol) was added dropwise over 15 min via an addition funnel. The reaction mixture was then stirred at room temperature for 4 h. The clear colorless solution was diluted with water (500 mL) and extracted with dichloromethane (200 mL) three times. The combined organic layers were dried over MgSO 4 , filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid. Flash chromatography on silica gel (EtOAc:hexane::1:20) and removal of solvent from the desired combined fractions afforded a clear colorless liquid (15.4 g): 1 H-NMR(CDCl 3 , 300 MHz): δ 7.60 (d, 1H, J=8), 6.46 (d, 1H, J=8), 3.89 (s, 3H), 2.54 (s, 3H).
[0084] D. 6-Methoxy-2-methylpyridine-3-boronic acid
[0085] A solution of 6-methoxy-3-bromo-2-methylpyridine (59.8 g, 296 mmol) in dry THF (429 mL) was cooled with stirring to ˜−78° C. under a nitrogen atmosphere. A solution of n-butyl lithium (2.5 M, 130.4 mL, 326 mmol) in hexane was added dropwise over 30 min. The reaction mixture was stirred for 3 h at ˜−78° C. A solution of tri-isopropyl borate (102.7 mL, 445 mmol) in dry THF (100 mL) was added dropwise over 30 min. The reaction mixture was warmed to ambient temperature with stirring over 16 h. Acetic acid (37.35 g, 622 mmol), then water (110 mL) were added to the reaction mixture with stirring. After 2 h, the layers were separated and the organic layer was concentrated in vacuo. The residue was taken up in 2-propanol (750 mL) and solvent was removed on a rotary evaporator (bath temperature ˜50° C.). The residue was triturated with ether. The product was collected by filtration and dried in vacuo (48.4 g): mp>200° C.; 1 H-NMR(CD 3 OH, 300 MHz): δ 7.83 (d, 1H, J=8), 6.56 (d, 1H, J=8), 3.85 (s, 3H), 2.44 (s, 3H); GC-MS: 168 (M + +H).
[0086] E. 2-Methyl-3-(5-methylisoxazol-4-yl)-6-methoxypyridine
[0087] A mixture of 4-iodo-5-methylisoxazole (18.2 g, 87 mmol), 6-methoxy-2-methylpyridine-3-boronic acid (14.6 g, 87 mmol), sodium bicarbonate (22.0 g, 262 mmol), water (150 mL) and DME (150 mL) was degassed three times with stirring by the application of a vacuum and then introduction of a nitrogen atmosphere. [1,1-Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (2.14 g, 2.6 mmol) was added in one portion. The reaction mixture was degassed as before. The reaction mixture was then stirred at 80° C. for 4 h, then it was cooled to ambient temperature. Three extractions with EtOAc, drying the combined organic layers over MgSO 4 , filtration and removal of solvent in vacuo afforded an oil. Flash chromatography (EtOAc:hexane::1:9) and removal of solvent in vacuo from the desired fractions gave the product (7.15 g): 1 H-NMR(CDCl 3 , 300 MHz): δ 8.16 (s, 1H), 7.33 (d, 1H, J=8), 6.63 (d, 1H, J=8), 3.95 (s, 3H), 2.35 (s, 6H); APCI + -MS: 205 (M + +H).
[0088] F. 1-Cyano-l-(2-methyl-6-methoxypyrid-3-yl)propan-2-one, sodium salt
[0089] A mixture of sodium methoxide (25% w/w, 13 mL, 70 mmol), 2-methyl-3-(5-methylisoxazol-4-yl)-6-methoxypyridine (7.15 g, 35 mmol) and methanol (50 mL) was stirred at room temperature for 16 h. Solvent was removed in vacuo to give a yellow oil. Trituration with ether, filtration and drying in vacuo afforded the crude product as a white solid (9.3 g).
[0090] G. 5-Amino-4-(2-methyl-6-methoxypyrid-3-yl)-3-methylpyrazole
[0091] A mixture of 1-cyano-1-(2-methyl-6-methoxypyrid-3-yl)propan-2-one, sodium salt (9.3 g), hydrazine-hydrate (6 mL, 123.3 mmol) and glacial acetic acid (150 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in 1N HCl and the resulting solution was extracted with EtOAc two times. A 1N NaOH solution was added to the aqueous layer until pH=12. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a viscous oil (5.8 g): 1 H-NMR (CDCl 3 , 300 MHz): 7.37 (d, 2H, J=8), 6.62 (d, 2H, J=8), 3.95 (s, 3H), 2.36 (s, 3H), 2.08 (s, 3H); APCI + -MS: 219 (M + +H); 260 (M + +CH 3 CN).
[0092] H. 5-Acetamidino-4-(2-methyl-6-methoxypyrid-3-yl)-3-methylpyrazole, acetic acid salt
[0093] Ethyl acetamidate hydrochloride (6.46g, 52.2 mmol) was added quickly to a rapidly stirred mixture of potassium carbonate (6.95g, 50.0 mol), dichloromethane (60 mL) and water (150 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×60 mL). The combined organic layers were dried over MgSO 4 and filtered. Solvent was removed by simple distillation and the pot residue, a clear pale yellow liquid, was used without further purification.
[0094] Glacial acetic acid (1.0 mL, 17.4 mmol) was added to a stirred mixture of 5-amino-4-(2-methyl-6-methoxypyrid-3-yl)-3-methylpyrazole (3.8g, 17.4 mmol), ethyl acetamidate free base and dichloromethane (100 mL). The resulting reaction mixture was stirred at room temperature for 16 h; at the end of which time, it was concentrated in vacuo. The residue was triturated with ether, the product was filtered and washed with copious amounts of ether. The white solid was dried in vacuo (5.4 g): 1 H-NMR (CD 3 OH, 300 MHz): 7.43 (d, 2H, J=8), 6.69 (d, 2H, J=8), 4.9 (br s, 2H), 3.93 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.88 (s, 3H); APCI + -MS: 260 (M + +H).
[0095] I. 2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one
[0096] Sodium pellets (3.9 g, 169 mmol) were added portionwise to ethanol (200 mL) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4-(2-methyl-6-methoxypyrid-3-yl)-3-methylpyrazole, acetic acid salt (5.4 g, 16.9 mmol) and diethyl carbonate ( 16.4 mL, 135.3 mmol) were added. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mix was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in water and a 1N HCl solution was added slowly until pH˜6. The aqueous layer was extracted with EtOAc three times; the combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a solid. Trituration with ether, filtration and drying in vacuo afforded a white solid (3.9 g): 1 H-NMR (CD 3 OH, 300 MHz): 7.49 (d, 2H, J=8), 6.69 (d, 2H, J=8), 3.93 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H); APCI + -MS: 286 (M + +H).
EXAMPLE 2
Preparation of 4-((R)-2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazine
[0097] A. 4-Chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolotriazine
[0098] A mixture of 2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 3.9 g, 13.7 mmol), di-isopropyl-ethylamine (9.5 mL, 54.7 mmol), phosphorus oxychloride (5.1 mL, 54.7 mmol) and toluene (75 mL) was stirred at reflux temperature for 4 h. The volatiles were removed in vacuo. The residue was loaded on a pad of silica gel on celite and eluted with a 1:1 mixture of EtOAc and hexane. Solvent was removed in vacuo from the filtrate to give an oil.
[0099] B. 4-((R)-2-butylamino)2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolo-1,3,5-triazine
[0100] A mixture of 4-chloro-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl) [1,5-a]-pyrazolotriazine, (R)-2-butylamine (2.0 mL, 20.5 mmol), di-isopropyl-ethylamine (9.5 mL, 54.7 mmol) and dry THF (25 mL) was stirred at ambient temperature for 18 hours. Solvent was removed in vacuo. Column chromatography of the residue (first using EtOAc:hexane::1:2, then using EtOAc:hexane::1:4) afforded the product. Removal of solvent in vacuo gave a white solid (2.3 g): mp=118.3° C. ; 1 H-NMR (CDCl 3 , 300 MHz): δ 7.41 (d, 1H, J=8), 6.63 (d, 1H, J=8), 6.25 (br d, 1H, J=9), 4.35-4.30 (m, 1H), 3.95 (s, 3H), 2.49 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H), 1.76-1.66 (m, 2H), 1.34 (d, 3H, J=7), 1.02 (t, 3H, J =7); 13 C-NMR (CDCl 3 , 100.52 MHz): δ 163.8, 163.0, 155.7, 153.7, 147.8, 146.6, 141.6, 118.5, 107.4, 106.6, 53.3, 48.2, 29.7, 26.1, 22.9, 20.4, 13.1, 10.3; IR (neat, KBr, cm − 1): 3380 (m) , 3371 (m) , 2968 (m) , 2928 (m) , 2872 (w), 1621 (s), 1588 (s), 1544 (s), 1489 (s), 1460 (s), 1425 (s), 1413 (s) , 1364 (s) , 1346 (m) , 1304 (s) , 1275 (s), 1247 (s) , 1198 (m) , 1152 (m) , 1134 (m) , 1112 (m) , 1034 (s), 1003 (m); ESI(+)-HRMS: Calcd for C 18 H 24 N 6 O: 341.2089; Found: 341.2093 (M + +H). Anal. Calcd for C 18 H 24 N 6 O: C, 63.51, H, 7.12, N, 24.69; Found: C, 63.67, H, 7.00, N, 24.49 .
Utility
[0101] Rat CRF Receptor Binding Assay for the Evaluation of Biological Activity
[0102] Receptor binding affinity to rat cortical receptors was assayed according to the published methods (E. B. De Souza, J. Neuroscience, 7: 88 (1987).
[0103] Curves of the inhibition of [ 125 I-Tyr 0 ]-o-CRF binding to cell membranes at various dilutions of test drug were analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.
[0104] Inhibition of CRF-Stimulated Adenylate Cyclase Activity
[0105] Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl 2 , 0.4 mM EGTA, 0.1% BSA, 1 mm isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 −9 to 10 −6m ) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/ 32 P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [ 3 H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [ 32 P]cAMP from [ 32 P]ATP is performed by sequential elution over Dowex and alumina columns.
[0106] In Vivo Biological Assay
[0107] The in vivo activity of a compound of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990).
[0108] A compound may be tested in any species of rodent or small mammal.
[0109] A compound of this invention has utility in the treatment of imbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.
[0110] A compound of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. It can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
[0111] The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, a compound of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.
[0112] Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
[0113] The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.
[0114] Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.
[0115] Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.
[0116] In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
[0117] Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences”, A. Osol, a standard reference in the field.
[0118] Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
[0119] Capsules
[0120] A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.
[0121] Soft Gelatin Capsules
[0122] A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.
[0123] Tablets
[0124] A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.
[0125] The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.
[0126] Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended
|
Corticotropin releasing factor (CRF) antagonists of Formula (I):
and its use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
| 2 |
BACKGROUND OF THE INVENTION
The invention relates in general to axial flow combines and more specifically to an improved axial flow combine which evens out the grain in the auger/auger pan assembly of the combine.
Heretofore, various combines have been developed for threshing and separating grain such as wheat, milo and the like. See, for example, U.S. Pat. Nos. 3,122,499; to Witzel, 3,439,683; 3,481,342; to Keller, 3,481,342; to Rowland-Hill, 3,556,108; to Knapp, and 3,586,004 to Depawn. None of the above patents disclose or suggest the present invention.
One improvement that has been incorporated in many axial flow combines is the transport cone coupled to the front of the stationary cylinder of the theshing/separating unit thereof to act similar to a funnel to direct the material to be threshed and separated past the impeller of the rotor of the threshing/separating unit. Such a combine is shown in FIG. 1 and is identified by the letter A. Thus, the combine A includes, in general, a threshing/separation unit B having a stationary cylinder C, having a rotor D axially mounted within the cylinder C with an impeller E mounted on the front thereof, and having a funnel-shaped transport cone F attached to the front of the cylinder C about the impeller E; including an auger/auger pan unit G located beneath the cylinder C; including a cleaning unit H located at the discharge end of the auger/auger pan unit G; including a heat unit J for feeding the material to be threshed and separated into the transport cone F; including a grain bin K; including an elevator L for transporting threshed and separated grain from the cleaning unit H to the grain bin k; and including motor M coupled to the rotor D, auger/auger pan unit G, cleaning unit H, Leader unit J and elevator L by an appropriate drive means.
SUMMARY OF THE INVENTION
The present invention is an improvement upon prior transport cone-type axial flow combines. The concept of the present invention is to modify a transport cone-type axial flow combine to even out the flow of threshed and separated grain from the threshing/separating unit on the auger/auger pan unit across the entire width of the auger/auger pan unit.
The improved axial flow seed combine of the present invention is of the type including a threshing/separating unit having a stationary cylinder, having a rotor mounted axially within the cylinder with an impeller attached to the front end thereof, and having a stationary transport cone attached to the front of the cylinder over the impeller; and including an auger/auger pan unit located beneath the threshing/separating unit for catching threshed and separated seeds from the threshing/separating unit. The improvement of the present invention includes, in general, extending at least a predetermined portion of the auger/auger pan unit to a point beneath the transport cone; and providing a plurality of apertures through a predetermined section of the transport cone for allowing threshed and separated seeds to fall through the transport cone onto the extended portion of the auger/auger pan unit.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an elevational view of a prior art transport cone-type axial flow combine with portions thereof broken away for clarity.
FIG. 2 is an elevational view of the improved transport cone-type axial flow combine of the present invention with portions thereof broken away for clarity.
FIG. 3 is an enlarged sectional view substantially as taken on line III--III of FIG. 2.
FIG. 4 is an enlarged sectional view substantially as taken on line IV--IV of FIG. 2.
FIG. 5 is a sectional view as taken on line V--V of FIG. 3.
FIG. 6 is a view substantially as taken on line VI--VI of FIG. 3 with portions of the transport cone and cylinder shown in broken lines for clarity.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The improved axial flow seed combine 11 of the present invention is used in the typical manner to cut, thresh, separate and clean seeds such as grain, beans and the like.
The combine 11 includes a threshing/separating unit 13 having a stationary cylinder 15, having a rotor 17 mounted axially within the cylinder 15 with an impeller 19 attached to the front end thereof, and having a stationary transport cone 21 attached to the front end of the cylinder 15 over the impeller 19. The cylinder 15 is of typical construction well known to those skilled in the art including a solid upper portion 23 having a plurality of spiral transport fins 25 secured to the internal surface of the upper portion 23 to index the material to be threshed and separated axially through the cylinder 15 from the front end toward the rear end thereof, and including an apertured lower portion 27 to permit the passage of threshed and separated seed therethrough. The lower portion 27 is divided into a front concave member 29 and a rear grate member 31. The cylinder 15, including the concave member 29 and grate member 31, may be of any typical construction and operation well known to those skilled in the art. The rotor 17 is rotatably mounted axially of the cylinder 15 by appropriate support bearings or the like. The rotor 17 may be of various specific constructions well known to those skilled in the art. The combine 11 preferably includes a motor/drive unit having a motor 33 and and a drive means 35 extending between the motor 33 and the rotor 17 for causing the rotor to rotate at, for example, 800 revolutions per minute. The combine 11 includes an auger/auger pan unit 37 located beneath the threshing/separating unit 13. The auger/auger pan unit 37 includes a plurality of augers and an auger pan 41 having a plurality of longitudinally directed troughs in the upper surface thereof with an auger located in each trough, e.g., the auger/auger pan unit 37 may be of the four-auger type including a first auger 39a, a second auger 39b, a third auger 39c, and a fourth auger 39d, and including a first trough 43a, a second trough 43b, a third trough 43c, and a fourth trough 43d (see FIG. 3). The augers 39a, 39b, 39c, 39d are rotatably driven by the motor/drive unit whereby the auger pan 41 will serve to catch threshed and separated seeds from the threshing/separating unit 13 and the augers 39a, 39b, 39c, 39d will convey the seed caught by the auger pan 41 toward the rear of the auger pan 41. A header unit 45, also driven by the motor/drive unit, is provided for cutting and feeding the material to be threshed and separated into the threshing/separating unit 13. A cleaning unit 42, also driven by the motor/drive unit, is typically associated with the auger/auger pan unit 37 for cleaning the threshed and separated seeds. The combine 11 also includes a grain bin 47 for holding the threshed and separated seeds and includes an elevator unit 49, also driven by the motor/drive unit, for transporting the cleaned, threshed and separated seeds to the grain bin 47. While the specific construction of the above described elements may vary as will be apparent to those skilled in the art, a more complete disclosure of such elements can be found in Rowland-Hill et al, U.S. Pat. No. 3,481,342, issued Dec. 2, 1969 and Knapp et al, U.S. Pat No. 3,556,108, issued Jan. 19, 1971.
The improvement of the present invention includes extending at least a predetemined portion 51 of the auger/auger pan unit 37 to a point beneath the transport cone 21; and providing a plurality of apertures 53 through a predetermined section of the transport cone 21 for allowing threshed and separated seeds to fall through the transport cone 21 onto the extended portion 51 of the auger/auger pan unit 37. More specifically, it is well known to those skilled in the art that the flow of seeds from the threshing/separating unit 13 to the auger/auger pan unit 37 in the prior art transport cone-type axial flow combines such as shown in FIG. 1 causes certain ones of the troughs of the auger/auger pan unit to overflow while causing other ones of the troughs to receive an inadequate or low amount of seeds. In a four-trough combine as shown in FIG. 3 with the rotor 17 rotating in a clockwise direction as indicated by the arrow 54, the first and second troughs 43a, 43b (i.e., the troughs located on the right-hand side of the combine 11) would frequently,without the improvement of the present invention, be filled to overflowing while the third and fourth troughs 43c, 43d (i.e., the troughs located on the left-hand side of the combine 11) would receive an inadequate or low amount of seeds. The concept of the present invention includes extending the portion of the auger/auger pan unit 37 that would otherwise receive only a small amount of seeds (e.g., the third and fourth troughs 43c, 43d and the third and fourth augers 39c, 39d in a typical four auger transport cone-type axial flow combine as shown in FIG. 3) to a point beneath the transport cone 21 and to provide a plurality of apertures 53 through only the section of the transport cone 21 over the extended portion 51 of the auger/auger pan unit 37 to thereby allow an increase flow of threshed and separated seeds from the threshing/separating unit 13 onto specific, predetermined portion of the auger/auger pan unit 37 that would otherwise receive only a disportionally small amount of seeds. It should be noted that it is estimated at around 70% of the seeds threshed and separated by the threshing/separating unit in a transport cone-type axial flow combine are threshed and separated by the impeller within the transport cone.
The transport cone 21 includes a basically funnel-shaped body member 55 having a front end 57 associated with the header unit 45 for receiving material to be threshed and separated from the header unit 45, having a rear end 59 attached to the front end of the cylinder 15, and having an interior surface 61 extending inwardly from the front end 57 to the rear end 59 thereof. Spiral transport fins 63 are provided on the interior surface 61 to serve to index the material to be threshed and separated from the front end 57 to the rear end 59 thereof and into the cylinder 15. The improvement of the present invention includes providing a plurality of the apertures 53 through the portions of the body member 55 that is in line with the augers 39 and trough 43 of the auger/auger pan unit 37 that normally receive the least amount of threshed and separted seeds. Thus, the apertures 53 are preferably provided through the body member 57 directly above the extended portion 51 of the auger/auger pan unit 37. The portion of the body member 55 having the apertures 53 therethrough may be an integral part of the remainder of the body member 55 or may consist of a separate panel bolted or otherwise fixedly attached to the remainder of the body member 55. The size of the apertures 53 may vary as will be apparent to those skilled in the art but are of sufficient size to allow threshed and separated seeds of the type being combined to pass therethrough.
The augers 39a, 39b, 39c, 39d are of typical construction well known to those skilled in the art with, for example, the augers 39c, 39d merely constructed in a longer length than the augers 39a, 39b to define the extended portions thereof. On the other hand, the extended portions of the augers 39c, 39d may be defined by lengths of typical augers welded or otherwise fixedly attached to the forward ends of the augers 39c, 39d.
The auger pan 41 is of substantially typical construction well known to those skilled in the art with, for example, the troughs 43c, 43d merely extending forward of the troughs 43a, 43b (see FIG. 6). The extended portion of the troughs 43c, 43d may be constructed integral with the remainder of the auger pan 41 or may be constructed as a separated unit welded or otherwise fixedly attached to an existing, typical auger pan 41 with a portion of the existing front wall of the auger pan 41 removed.
The combine 11 is used in the typical manner. However, the extended portion 51 of the auger/auger pan unit 37 and the precisely located apertures 53 through the transport cone 21 will coact to even out the passage of threshed and separated seeds to the auger/auger pan unit 37.
Although the invention has been described and illustrated with respect to a preferred embodiment thereof and a preferred use therefore, it is not to be so limited since changes and modifications can be made therein which are within the full intended scope of the invention.
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Apertures are provided through a section of the transport cone of an axial flow combine and the auger/auger pan unit thereof is extended to a point underneath the apertures through the transport cone to thereby allow even distribution of the threshold seeds across the entire width of the auger/auger pan unit.
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TECHNICAL FIELD
The present description belongs to the field of photoluminescent polymer compounds and devices (for example LED) which exploit their properties.
STATE OF THE ART
Light emitting diodes (LED) are applied in various technical fields. They are generally composed of a film of electroluminescent material deposited on a support. By applying a suitable potential difference, the material emits light at a wavelength depending on the type of material used. LEDs are widely used as components in television or computer screens, in light advertising panels, road signs, etc. Organic light emitting diodes are also known as OLED; of particular interest among these are those having a polymer base (PLED); indeed, in the last few years, the polymers capable of emitting visible light have raised considerable interest for the possibility of constructing cheap and mechanically flexible devices (T. V. Luh, S. Bosu, R. M. Chen; Current Science (2000), 78, No. 11). PLEDs are generally cheaper to construct than the traditional solid state ones: the polymers used are sufficiently soluble in many organic solvents and can be sprayed onto a suitable substrate with a technology similar to that of ink-jet printers, directly producing the devices desired without requiring complicated lithography techniques. PLEDs have appropriate properties for making flat displays, along with good processability, low lighting voltage, quick response time and the possibility of modulating the colour over the entire visible spectrum. PLEDs also permit obtaining good quality films with controlled thickness: they have widely substituted the LEDs based on low molecular weight organic material (monomers, oligomers, etc.), which are normally less stable and harder to work; low molecular weight materials also require deposition through complicated techniques, for example evaporation or sublimation under vacuum; by contrast, polymer systems have a greater thermal stability and can be worked at low cost at room temperature, with techniques that do not require vacuum chambers. In particular, the most commonly used deposition techniques are spin-coating and ink-jet printing.
Polymer materials are not exempt from limitations, however. In particular, depending on the various polymers employed, one or more of the following defects are reported: poor product stability, insufficient miscibility with other polymers (for example amorphous polymers used in the production of transparent PLED, or doping polymers such as polyaniline, useful for improving conductivity), sensitivity to humidity, low quantum yield or drop of the same over time, non-uniformity of the film, generation of short-circuits localised on the film matrix, etc. ( Nature, 357, 1992, p. 477).
Research on PLEDs is thus constantly underway in order to identify further improved polymer/polymerisable organic materials, which maintain or increase the known advantages of PLEDs, for example plasticity/workability, reducing as much as possible the above mentioned limitations.
SUMMARY
New compounds have now been identified of formula (I), E-4,4′-(1,2-ethenediyl) bis[2-(N-alkylamino) benzoates].
in which:
R 1 , R 2 , R 3 , R 4 , independently from each other, represent H; alkyl, alkenyl; aryl; —(CH 2 CH 2 —O) n —CH 3 , (n being e.g. 1-10), and their polymer multiples.
Such compounds are highly photoluminescent and have high quantum yield; they have optimal plasticity and miscibility with amorphous polymers; they allow forming thin, stable and homogenous layers of light-emitting material, obtainable via simple techniques of deposition from solution. One embodiment is a simple, high yield process for obtaining the aforesaid compounds. One further embodiment is the use of compounds of formula (I) in the preparation of electroluminescent devices, for example LEDs, and the devices themselves, thus made. These compounds will be called herein derivatives of 4,4′ stilbenedicarboxylic acid.
DESCRIPTION OF THE FIGURES
FIG. 1 : General synthesis scheme of DASDE
FIG. 2 : 1 H-NMR of nitro stilbenedicarboxylic acid
FIG. 3 : 1 H-NMR of diamino stilbenedicarboxylic acid
FIG. 4
a): NMR detail of the nitro derivative
b): aromatic part of the nitro derivative
c): NMR detail of the amino derivative
d): aromatic part of the amino derivative
FIG. 5 : DSC of the diamino stilbenedicarboxylic acid
FIG. 6 : DSC of DASDE
FIG. 7 : ORTEP projection of the DASDE molecule
FIG. 8 : Absorption and emission spectra of quinine sulphate
FIG. 9 : Calibration line of the standards
FIG. 10 : Absorption and emission spectra of DASDE
FIG. 11 : Calibration lines of the standards and DASDE
FIG. 12 : Emission spectrum of a polyvinylcarbazole film containing 0.3% by weight of DASDE.
DETAILED DESCRIPTION
In the compounds of formula (I), the preferred meaning for R 1 , R 2 , R 3 and R 4 is alkyl. As a non-limiting example, R 1 and R 2 can represent C 1 -C 3 alkyl, for example methyl; R 3 and R 4 can represent C 1 -C 12 alkyl, or C 3 -C 15 alkyl, or C 4 -C 8 alkyl, for example C 6 alkyl. A particularly preferred class of compounds of formula (I) is that in which R 1 ═R 2 and R 3 ═R 4 . A particularly preferred compound of formula (I) is the dimethyl ester of (2,2′ dihexylamino-4,4′ dicarboxy) stilbene acid (DASDE), having structure:
Further preferred compounds of formula (I) are (2,2′diamino-4,4′ dicarboxy)stilbene acid (R 1 ═R 2 ═R 3 ═R 4 ═H), and its corresponding dimethyl ester (R 1 ═R 2 ═CH 3 , R 3 ═R 4 ═H).
One embodiment extends to the polymers obtainable via polymerisation of the monomer of formula (I). Examples of such polymers are polyesters, polyamides or polyoxydiazoles, etc. and can be obtained by means of per se known polymerisation reactions.
As detailed below, the synthesis of the compounds of formula (I) is simple and low-cost. The compounds of formula (I) have shown an optimal solubility in organic solvents and a high ease of deposition in monolayer film, for example by means of spin-coating technique: the films thus obtained have shown optimal morphological stability. The quantum emission yield is particularly high. The compounds of formula (I) moreover have optimal miscibility with amorphous and/or electroconductive polymers, in particular polyvinylcarbazole and polyvinylpyridine, allowing the preparation of transparent LEDs with high structural uniformity, with uniform and reproducible conductivity characteristics. Overall, the aforesaid characteristics allow preparing high quality electroluminescent devices with low production costs; such characteristics are advantageously maintained also for the products deriving from polymerisation of the compounds of formula (I).
In a further embodiment, a method is described for synthesising the compounds of formula (I). In its general form, the method comprises the following characteristic steps:
a) reduction of the (2,2′ dinitro-4,4′dicarboxy)stilbene acid of formula (II) to (2,2′ diamino-4,4′dicarboxy)stilbene acid of formula (Ia), corresponding to the compound of formula (I) in which R 1 ═R 2 ═R 3 ═R 4 ═H.
The further compounds of formula (I) in which at least one of R 1 ,R 2 ,R 3 ,R 4 , is different from H, are obtained by applying the following additional steps:
b) esterification of the 4 and/or 4′ carboxy groups of the compound (Ia), obtaining the compounds of formula (Ib)
The compounds of formula (I) where R 3 and/or R 4 are not H, are obtained by means of:
c) alkylation of the compound (Ia) or (Ib) in the 2 and/or 2′ diamino positions.
The reduction reaction a) can be carried out by means of per se known techniques, for example by heating the compound (II) in an aqueous solvent in presence of sodium sulphide.
The esterification reaction b) can be carried out by means of treatment with a suitable alcohol in acidic conditions; the alcohol used depends on the type of ester substituent desired; for example, methanol leads to products of formula (Ib) where R 1 ═R 2 ═CH 3 , etc. Compounds with R 1 different from R 2 can be obtained by working in selective esterification conditions, for example using half moles of esterifying agent with respect to those necessary for complete esterification, and/or using appropriate protective groups of one of the two —COOH functions, according to per se known techniques.
The alkylation reaction c) can be carried out by treating the compound of formula (Ia) or (Ib) with a suitable alkyl halide, in basic conditions, and in presence of a suitable solvent, for example dimethylformamide. The halide used depends on the type of alkyl substituent desired: for example, hexylbromide leads to products where R 1 ═R 2 ═C 6 H 13 ; compounds with R 1 different from R 2 can be obtained by operating in selective alkylation conditions, e.g. using half moles of alkylating agent with respect to those necessary for complete alkylation, and/or using suitable protective groups of one of the two amine positions, according to per se known techniques.
The dinitroderivative (II) is obtainable, for example by reacting 3-nitro-(4-chloromethyl)benzoic acid (III) with a suitable alcohol in alkaline environment;
The alcohol used is e.g. ethanol; the alkali is e.g. KOH. 3-nitro-(4-chloromethyl)benzoic acid (III) is obtainable, for example, via nitration of 4-chloromethylbenzoic acid (IV)
The reaction can be carried out by treating the compound (IV) with concentrated sulphuric acid and nitric acid.
One embodiment also provides the chemical-physical characterisation of compounds of formula (I), particularly advantageous for applications in PLED devices, both as monomers and as a polymer obtained therefrom. In particular, the compounds are advantageously usable as a single active layer in electroluminescent devices emitting in the visible light range, in particular in the green range.
One embodiment comprises the compounds of formula (I), as previously described, in the preparation of electroluminescent devices, for example LEDs. The preparation of the devices occurs according to per se known techniques: as a non-limiting example, the compound of formula (I), or its polymerised correspondent, is dissolved in a suitable solvent and then deposited onto suitable supports by means of spin coating or jet-printing. In the preparation of the devices, the compound of formula (I) can be used as such, or in blends with the above mentioned amorphous polymers.
The resulting devices (generally diodes) being highly luminescent and with excellent stability, plasticity and transparency, can be used as components, for example, of screens of cellular phones, computers, televisions, photo/videocameras, displays or light indicators for electronic instruments, road signs, lighting devices, etc.
The invention is further illustrated in non-limiting manner by means of the following examples.
EXPERIMENT PART
The innovative monomer, derived from stilbenecarboxylic acid (DASDE), was synthesised by means of nitration, reduction and alkylation reactions. In FIG. 1 , the general synthesis scheme is reported with the related synthesis processes of the various steps for obtaining DASDE.
1. Synthesis of 3-nitro-(4-chloromethyl)benzoic Acid
230 mL of 96% sulphuric acid are poured into a 500 mL flask and 130 mL of fuming nitric acid are slowly added under stirring. The above is cooled through a water and ice bath to a temperature of 0° C. At this point, 10 g (0.0580 mol) of reagent [2] are added, small portions at a time. The reaction continues for about 90 min, in which it is important that the reagent is completely dissolved inside the acid mixture. One then proceeds with the recovery by pouring everything into about 700 mL of water and ice. A solid white substance precipitates, which is filtered off and subsequently washed in a beaker in order to remove the acid residues. The crystallisation occurs in toluene.
Yield: 10.0 g (80%)
m.p.: 144-146° C.
1 H NMR (200 MHz CDCl3) δ 8.76(s, 1H); 8.36(d, 1H); 7.87(d,1H); 5.03(s,2H)
2. Synthesis of (2,2′ dinitro-4,4′dicarboxy)stilbene Acid
45 mL of absolute ethanol are poured into a 250 mL beaker and 5.47 g (0.0970 mol) of KOH are slowly dissolved therein. At this point, 5.00 g (0.023 0 mol) of 3-nitro-(4-chloromethyl)benzoic acid are added.
The precipitation of a brownish powder in the system immediately starts, being the potassium salt of dinitro-stilbenedicarboxylic acid. The system is left to react at room temperature for a time of about 45 minutes. The salt is filtered off under vacuum and is dissolved in about 70 mL of water, if necessary increasing the temperature until complete dissolution occurs.
At this point, the acid is precipitated with HCl, until pH 1 is reached. The solid product is recovered, which we then dry in the stove.
Yield: stoichiometric
1 H NMR (200 MHz DMSO) δ 7.62 (s,2H); 7.89 (d,2H); 8.52 (d,2H); 9.06 (s,2H); 11.0 (s,2H)
3. Synthesis of (2,2′ diamino-4,4′dicarboxy)stilbene Acid
100 mL of distilled water are poured into a 250 mL beaker and 6.90 g (0.0288 mol) of sodium sulphide are dissolved therein. Once the salt is dissolved, 5.00 g (0.0138 mol) of dinitrostilbenedicarboxylic acid are added. The system is kept boiling for a time of 15 min. At this point, under stirring, hydrochloric acid is added up to a pH 4-5. (2,2′ diamino-4,4′dicarboxy)stilbene acid is precipitated, which is re-dissolved and re-precipitated in aqueous solution so to remove possible residues containing sulphur.
The product is dried in an oven at 120° C. Such acid, in organic solution, has luminescence under UV lamp, a quality not shown by the starting dinitro derivative.
Yield: 4.02 g (97%)
1 H NMR (200 MHz DMSO) δ 6.27 (s,4H); 7.05 (s,2H); 7.24 (d,2H); 7.30 (s,2H); 7.46 (d,2H).
4. Synthesis of the Methyl Diester of (2,2′ diamino 4,4′dicarboxy)stilbene Acid
200 mL of methanol were inserted in a 500 mL flask along with 11.6 g (0.0390 mol) of diaminostilbenedicarboxylic acid. 15 mL of 96% sulphuric acid were carefully added under stirring. The system is then left to reflux for about 5 hours. After about two hours, further 50 mL of methanol are added into the flask and the reflux is continued. The colour of the system is red-brown. The recovery is made by pouring into a beaker containing about 600 mL of water and ice, to which a solution of concentrated NaOH is added until pH 8 is reached. At this point, the product is filtered off and further washed in a beaker with 300 mL of water, after which it is dried in a stove at 120° C.
Yield: 12.0 g (94%)
m.p.: 218-222° C.
1 H NMR (200 MHz DMSO) δ 3.89(s,6H); 7.05(s,2H); 7.10(d,2H); 7.15(s,2H); 7.36(d,2H)
5. Synthesis of the Hexyl Derivative of the Methyl Diester of (2,2′diamino-4,4′dicarboxy)stilbene Acid (DASDE)
15.0 g of K 2 CO 3 (0.108 mol) in 40 mL of DMF are poured into a flask, and the system is left under stirring. In the meantime, 4.00 g (0.0122 mol) of the aminostilbene ester are weighed and added inside the flask. The above is left under stirring for about 20 minutes, after which 35.0 mL (0.250 mol) are slowly added of 1-bromohexane. At this point, the system is brought to reflux and the reaction proceeds for two days. On the third day, recovery is carried out by filtering the salts and collecting the solution in DMF in a flask, together with a chloroform solution (2×50 ml) with which the salt was repeatedly washed. All is dried and the result is a very dense oil, also due to the presence of residual salts. An extraction with chloroform is then carried out and the organic phase is dehydrated and once again dried. A clear oil is thus obtained containing the product desired. Such oil is thus poured into a beaker, in which heptane is added, and under stirring, heptane is brought nearly to boiling.
Three extractions are thus made (70, 50, 50 mL) of heptane, so as to extract DASDE and the more alkylated products, leaving the non-alkylated products within the dark oil.
The solution in heptane is brought to boiling and filtered to remove impurities, and finally brought to a small volume (about 50 mL). After cooling, DASDE crystals are obtained, which can be separated, and the mother liquors contain the molecules with a greater number of alkyl chains that can be separated chromatographically.
m.p. 167-169° C.
1 H NMR (200 MHz CDCl3) δ 7.39 (d, 2H); 7.07 (s, 2H); 7.04 (d, 2H); 6.88 (s,2H); 3.89 (s, 6H); 3.35 (t, 4H); 1.63-0.85 (m, 22H).
Spectroscopic Characterisation of the Stilbenedicarboxylic Acid Derivatives
The 1 H-NMR spectra were carried out of the stilbenedicarboxylic acid derivatives. The diagrams related to the dinitro derivative are illustrated in FIG. 2 ; those related to the diamine derivative are illustrated in FIG. 3 . In the reduction step of nitro- to amino groups a substantial change in the aromatic signals is observed, coupled inter alia with a change in the luminescent properties of the molecule, becoming evident after reduction.
FIGS. 4 a - 4 d show the enlargements of the aromatic parts of both compounds, so to better observe their differences.
As evident by comparing the aromatic parts, the reduction of the nitro groups leads to an overall shift of the benzyl protons towards lower σ. In particular, the signal related to the proton d overlaps with that of proton a, and in addition there is a shift towards the outside of the protons c and b, such that the signal d+a is set between the two.
Thermal Characterisation of the Stilbenecarboxylic Acid Derivatives
Differential thermal analyses (DSC) were carried out of the amine derivative of the stilbenecarboxylic ester and of DASDE.
The nitro derivative, obtained in the acid form, was analysed up to 250° C., at which temperature the decomposition starts. At the same temperature, the nitroderivative in ester form also did not show any melting. In FIGS. 5 and 6 we show the thermograms carried out on the two compounds.
As seen from both thermograms, two crystal forms are present. This is more evident in the amine derivative, in which a first melting is observed around 190° C. with partial recrystallisation and melting of the second phase around 215° C.
Crystallographic Characterisation of DASDE
An ORTEP structural characterisation was carried out of DASDE by means of X-ray diffraction on a single crystal. In FIG. 7 , a projection of the molecule is reported.
The thermal ellipsoids are reported at 30% probability level.
Symmetry operation used for generating the equivalent atoms: *=−x, −y, −z. The molecule has a C 2 symmetry and lies on a crystallographic inversion centre.
Below, the bond distances are reported in Angstroms (Å) along with the angles (°) for several selected atoms of interest (tables 1-2).
TABLE 1
Bond distances (Å)
Distance between
atoms
Distances (Å)
C 1 —C 1 *
1.306(4)
C 1 —C 2
1.465(3)
N 1 —C 3
1.372(3)
N 1 —C 10
1.453(3)
H(C 1 )—H(N 1 )
1.983(2)
TABLE 2
Angles between atoms (°)
Angles between
atoms
Degree values (°)
C 10 —N 1 —C 3
121.7(2)
H(N 1 )—N 1 —C 3
120.3(3)
H(N 1 )—N 1 —C 10
118.3(6)
C 2 —C 1 —C 1 *
127.2(3)
H(C 1 )—C 1 —C 2 —C 3
9.6(5)
C 2 —C 3 —N 1 —H(N 1 )
4.5(2)
In the following table (table 3), the crystallographic data are reported along with the details of the data collection.
TABLE 3
Crystallographic data of DASDE
Empirical formula
C 30 H 42 N 2 O 4
Crystal dimensions, mm
0.5 × 0.5 × 0.45
Habit, crystal colour
Prism, yellow
Formula weight
494.66
Temperature (K)
173
Wavelength (Å)
0.71069
Crystal system
monoclinic
Spatial group
P 21/c
a (Å)
10.441(1)
b (Å)
11.848(1)
c (Å)
12.582(1)
β (°)
111.37(1)
Volume (Å 3 )
1449.4(3)
Z, Calculated density (g · cm 3 )
2, 1.464
Absorption coefficient (mm −1 )
0.094
Range of θ (°)
3.34, 27.50
Collected/single reflections
14173/3294 [R(int) = 0.0410]
Data/parameters
3294/173
R1 [a] , wR2 [b] [I > 2σ(I)]
0.0672, 0.1994
R1 [a] , wR2 [b] (all data)
0.1056, 0.2535
Residual electron density (e · Å −3 )
0.476
The crystals adapted for the X-ray diffractometric analysis were obtained from heptane solution via slow evaporation at room T. They have the aspect of small prisms with yellow colour. The data collection for the structural resolution was carried out under nitrogen flow, at 173 K, on a Bruker-Nonius diffractometer kappa CCD, using the radiation Kα of Molybdenum (0.71069 Å).
The structure was resolved with direct methods (SIR 97) [3], subsequent Fourier transforms, and refined with the minimum squares method (SHELXTL) [4]. A semi-empirical correction was carried out by using the program SADABS.
The hydrogen atoms were positioned based upon geometric considerations, with the exception of the olefin and amine hydrogen atoms.
The final refinement was carried out by using anisotropic thermal parameters for all atoms different from hydrogen.
The structural analysis shows that the molecule is nearly planar, with the nitrogen atoms contained in the plane defined by the aromatic rings; moreover, the distance (1.976(3)Å) between the hydrogen atoms H(C 1 ) and H(N 1 ), accounts for the experimental difficulty in obtaining the dialkylated form of this molecule. A second alkyl group, in fact, would be affected by a strong steric hindrance due to the presence of the stilbene proton.
The dialkylation of the nitrogen would then lead to a forced distortion of such system, sacrificing the strong conjugation of the nitrogen with the aromatic ring.
The planar structure of the molecule highlights the extension of the conjugation, responsible for the fluorescence activity, and favours the morphological stability of the polymer films.
Quantum Yields of Photoluminescence
The quantum yield signifies, for a given substance, the ratio between the emitted and absorbed photons. It is therefore a direct indication of the quantity of energy emitted through a mechanism of radiative type.
In order to evaluate the quantum yields, we used a method present in literature, which provides for the comparison of said values with the quantum yields of suitable standards [5-6].
We first estimated the quantum yield of known substances obtained with our equipment, in order to calibrate the method.
The method used requires measuring absorption and photoluminescence of diluted solutions of the fluorescent substances under examination. The standards used are quinine sulphate and fluorescein.
The absorption and fluorescence spectra of the quinine sulphate are reported in FIG. 8 .
The fluorescence spectra were obtained by exciting the samples at a wavelength relative to a maximum absorbance of the sample of less than one.
In such a manner, by comparing the values obtained with the respective emission areas, a series of points are obtained which are aligned along a straight line.
By collecting the data for solutions with different concentrations, straight lines are obtained from whose slope it is possible to obtain the quantum yield of fluorescence via the following expression.
φ x =φ st (Grad x /Grad st )*(η 2 x /η 2 st )
φ(x;st): quantum yield of an unknown sample and a reference sample Grad(x;st): angular coefficient of the line related to an unknown sample and a reference sample η(x,st): refraction index of the solutions (in practice, it is that of the solvent, the solutions being very diluted).
In order to calibrate the method, the quantum yield was calculated of a substance from the quantum yield of the other standard and by comparing the value with that known in literature.
Thus, the quantum yields were calculated of fluorescein dissolved in a solution of 0.1M NaOH and of quinine sulphate dissolved in a solution of 0.1M sulphuric acid. FIG. 9 reports the calibration lines. Table 4 reports the obtained quantum yield values.
TABLE 4
Experimental quantum yields of the standards
Refraction
Quantum
Literature
Substance
index
Gradient
yield
data
Quinine
1.3342 (0.1M
37792
0.546
0.54
sulphate
NaOH)
Fluorescein
1.3344 (0.1M
54683
0.781
0.79
H 2 SO 4 )
The comparison of the obtained data with those of the literature highlights the excellence of the method employed.
Quantum Yield of DASDE
Subsequently, the absorption and emission spectra of the synthesised DASDE were acquired, and the related quantum yield was calculated. FIG. 10 reports the absorption and emission spectra.
The fluorescence spectrum shows an emission maximum at around 530 nm, thus it can be stated that such molecule is a good candidate for making devices which emit in the green range.
The calculated quantum yield of such material is 0.535. In FIG. 11 , the graph is reported showing the DASDE line in comparison with that of the standards which we have used; Table 5 shows the calculated quantum yields.
TABLE 5
Experimental quantum yields
Quantum
Literature
Substance
Refraction index
Gradient
yield
data
Quinine
1.3342 (0.1M
37792
0.546
0.54
sulphate
H 2 SO 4 )
Fluorescein
1.3344 (0.1M
54683
0.781
0.79
NaOH)
DASDE
1.4476
31656
0.535
—
CHCl 3
Table 5 shows that the quantum yield of DASDE which we synthesised is comparable to that of quinine sulphate. This indicates a high emission efficiency for such substance.
The data shown above have indicated a quantum emission efficiency equal to 0.535 for the monomer DASDE, being comparable to the quantum yield of the quinine sulphate (0.546). Such monomer was found to be particularly soluble in most organic solvents and miscible in amorphous polymers of different nature.
In fact, blends were made by using 0.3% by weight of DASDE in polymer matrices, such as and polyvinylpyridine (PVPy) and polyvinylcarbazole (PVK). The films obtained from these blends resulted unaltered after a period of over six months. In addition, strong emissions were registered from the polymer films even with small quantities of DASDE. These data are very promising, also in view of the ease of monomer synthesis and the relatively low cost of the starting reagents.
In addition to being polymerised via dispersed phase, such monomer can be polymerised through the acid functions, thus obtaining polymers of different nature such as polyesters, polyamides or polyoxydiazoles. It is therefore possible to make monolayer polymer devices by means of organic solution deposition, with high quantum efficiency.
The various embodiments above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data sheet incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.
These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
Bibliography
[1] T. V. Luh, S. Bosu, R. M. Chen; Current Science (2000), 78, No. 11.
[2] Ezzat A. Hamed, Ali A. El-Bardan, Nabila M. El-Mallah; J. Chem. Kin. 1996, 28, 283-289.
[3] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J. Appl. Cryst. 32 (1999) 115.
[4] G. M. Sheldrick, SHELX-97 University of Göttingen, Germany 1997
[5] A. T. R. Williams, S. A. Winfield and J. N. Miller, Analyst, 1983, 108, 1067.
[6] S. Dhami, A. J. de Mello, G. Rumbles, S. M. Bishop, D. Phillips and A. Beeby, Photochem. Photobiol., 1995, 61, 341.
|
New, highly photoluminescent compounds are described having structural formula (I)
wherein:
R 1 , R 2 , R 3 , R 4 , independently from each other, represent H; alkyl, alkenyl; aryl; —(CH 2 CH 2 —O) n —CH 3 . These compounds are highly photoluminescent and have high quantum yield; they have optimal plasticity characteristics and optimal miscibility with other amorphous polymers; they lead to the formation of thin, stable and uniform layers of photoluminescent material, obtainable by simple techniques of deposition from solution.
A simple and high yield process is described for obtaining the aforesaid compounds. In addition, the use of the compounds of formula (I) and their polymer derivatives is described in the preparation of electroluminescent devices, for example LEDs.
| 2 |
TECHNICAL FIELD
[0001] The present disclosure relates to the field of organic compound synthesis, more particularly a method for synthesis of glycidylester of tertiary carbonic acid.
BACKGROUND
[0002] Glycidyl tertiary carbonic ester is a highly branched glycidyl ester of α-branch monosaturated aliphatic acid (also referred to as glycidyl ester of branched carboxylic acid). The product can be used to prepare acrylic acid modified resins, polyester modified resins, alcohol acid modified resins and epoxy resins. It can also be used as active diluents for paints. It can significantly improve the properties of paints and is an important raw material for high-quality car paints, coil paints and metal paints.
[0003] Among the present technologies, the preparation of glycidylester of tertiary carbonic acid by the reaction between tertiary carbonic acid and halo substituted monoepoxides is mainly achieved by a two-step method, i.e. the first step is synthesis of intermediate product of halo substituted alcohol ester of tertiary carbonic acid, and the second step is conversion from the intermediate product into the final product glycidylester of tertiary carbonic acid.
[0004] For example, the glycidylester of tertiary carbonic acid could be directly prepared with carbonic acid and epoxy chloropropane, under catalysis of alkali metal hydroxide as well as dehydrochlorination, wherein glycidyl ester, alkali metal salt and water are produced. During this process, several high boiling point byproducts can be produced, with different yields, which may comprise halo substituted alcohol ester derivatives, derivatives produced by the reaction of halo substituted alcohol ester and epoxy chloropropane, and derivatives of glycidyl ester, presenting about 8%-12% of the total weight of the product. As the glycidylester of tertiary carbonic acid is easily deteriorated under heat or acidic or basic condition, therefore, the heating time for its purification by distillation is strictly limited. WO 97/44335 disclosed a method by which a product with a purity of 99% could be obtained. The product has a light color, and the color is stable during storage, but the product yield is relative low, 30% only, thus the cost is relatively high, and the industrial productive value is relatively low.
[0005] A method for the preparation of glycidyl esters of branched monocarboxylic acids was published in Chinese Patent CN99811327.1, wherein in the presence of water and a water-miscible solvent (isopropanol), catalyzed with catalyst (alkali metal hydroxide or alkali metal alkoxide), carboxylic acid reacts with halo substituted epoxides. Then by the dehydrohalogenation via the addition of base in two steps, glycidyl ester, alkali metal salt and water were produced. According to CN99811327.1, color-stable, during storage, glycidyl ester of branched monocarboxylic acids with very high level purity were obtained without distillation, and the content of high boiling point byproducts was lower than 6 wt %.
[0006] However, this method presents the following defects:
[0007] 1. Water-miscible solvent is applied in the first step of catalytic synthesis. Large amount of water was required in this step (total amount of water is 4-13 times of the mole of carbonic acid). Due to the low concentration of saline water produced, it is unavoidable to bring some of the solvent, halo substituted epoxy propane and the product obtained into the diluted saline water while separating the saline water obtained during the first step, resulting in the loss of the solvent, halo substituted epoxy propane and the product. As for the recovery of organics in said diluted saline water, in one hand, raw materials and products would be lost due to incomplete recovery of solvent and thus poor recovery of halo substituted epoxy propane and products produced; in another hand, unrecovered halo substituted epoxy propane and products produced would become waste water or solid waste and then affect the environment.
[0008] 2. Example 1 of CN99811327.1 shows that, large amount of isopropanol was used in the first step of catalytic synthesis, about 35% of the total reaction volume, which causes significant decrease of yield per unit volume. Therefore, this method is not suitable for industrial production. Meanwhile, side reactions between isopropanol and halo substituted epoxy propane will result undesired lost for halo substituted epoxy propane preparation.
[0009] 3. Side reactions may occur during the first dehydrohalogenation by the addition of base because of the presence of halo substituted epoxy propane, resulting in the unnecessary loss of the halo substituted epoxy propane, thus reduced recovery rate of the raw material is decreased, which also causes increase of high boiling point byproducts, and the quality of the product is decreased.
[0010] 4. The amount of epoxy chloropropane in the reaction was about 23% of the total reaction volume during the first dehydrohalogenation, which causes significant decrease of yield per unit volume. Therefore, this method is not suitable for industrial production.
[0011] 5. While recovering halo substituted epoxy propane and solvent that is miscible with water by distillation, not only the recovery rate of the solvent and the halo substituted epoxy propane is reduced in the method because of the above reasons but also the solvent obtained is a mixed solvent, which is not suitable to be reused.
[0012] 6. Second dehydrohalogenation is required for the method because the first dehydrohalogenation is not complete. The hydrolysis of the glycidyl ester is not avoidable during the second dehydrohalogenation. Thus the purity of the product is decreased, additional preparation procedures are required, and the preparation time is prolonged, so it is not suitable for industrial production.
[0013] In addition, a two-step synthesis method for glycidylester of tertiary carbonic acid was disclosed in Chinese patent CN200710056829.3. At first, the halo substituted alcohol ester of tertiary carbonic acid is produced by the reaction of carbonic acid and halo substituted epoxy propane under the catalysis of organic quaternary ammonium salt. Then glycidylester of tertiary carbonic acid, alkali metal salt and water are produced by the dehydrohalogenation via the addition of alkali metal hydroxide. Quaternary ammonium salt is used as a catalyst in this method, which also has some defects: at first, alkali metal hydroxides and alkali metal salts which are not solvable in the organic phase were brought into the organic phase by forming ion pair with tetra-alkyl ammonium ion via quaternary ammonium salt under action of lipophilic ammonium ion, resulting in the emulsification of the glycidyl ester; secondly, the organics can be brought into the aqueous phase by the charge effect of the lipophilic ammonium ion, causing the increase of the COD value of the waste water, thus resulted in more serious environmental pollution and loss of product. In order to solve the problems, the glycidylester of tertiary carbonic acid obtained by synthesis has to be separated and purified by distillation In this process, due to the heat-lability property of glycidylester of tertiary carbonic acid, decrease of the synthesis yield is unavoidable.
[0014] In conclusion, the method for preparing glycidylester of tertiary carbonic acid needs to be improved continuously, to improve the quality of the products, to decrease the cost and the influence to the environment and to be more suitable for industrial production.
SUMMARY
[0015] The present disclosure is aim to provide a simpler and more effective method to significantly increase the product yield per unit volume.
[0016] The present disclosure is also aimed to provide a process for producing glycidylester of tertiary carbonic acid which is more suitable for industrial production with low cost, high purity, light and stable color. The present disclosure also aims to provide an improved technical solution for industrial production which can significantly decrease the consumption of raw materials (mainly the consumption of halo substituted epoxy propane), decrease the production of high boiling point byproducts, decrease the discharge of substances of environment harmful, and decrease steps of production.
[0017] In order to achieve the mentioned purposes, the present disclosure provides a preparation method for glycidylester of tertiary carbonic acid.
[0018] A two-step synthesis of glycidylester of tertiary carbonic acid is adopted to obtain glycidylester of tertiary carbonic acid having 5-20 carbon atoms, preferably 9-13 carbon atoms, which comprises:
[0019] The first step, the preparation of halo substituted alcohol ester of tertiary carbonic acid: in the presence of water and catalyst only, the tertiary carbonic acid reacts with halo substituted epoxides to form halo substituted alcohol ester of tertiary carbonic acid; wherein said water includes pre-added water for the reaction; wherein the catalyst is preferably a basic catalyst.
[0020] More preferably, the excess (unreacted) halo substituted epoxide is removed when the reaction is finished.
[0021] The second step, the preparation of glycidylester of tertiary carbonic acid: a water-miscible solvent is added to dissolve the product obtained in the first step; alkali metal hydroxides or alkali metal alkoxides are added to obtain glycidylester of tertiary carbonic acid. The preferable solvent is low chain aliphatic alcohols, and solvent with low boiling point is more preferable.
[0022] The preparation equation is shown as below:
[0000]
[0023] Wherein R1, R2 and R3 represent alkyl substituents, at least one of which is methyl, the rest of which are linear or branch chain alkyls, the total number of carbon atoms being 3-18; R4-R8 represent hydrogen or alkyls. For example, when the total number of carbon atoms of R1, R2, R3 is 8, and R4-R8 are hydrogen, the glycidylester of tertiary carbonic acid produced is glycidylester of neodecanoic acid by the reaction of neodecanoic acid and epoxy chloride propane. The X in the equation represents halogen, such as chlorine, bromine, iodine; Y represents alkali metal, such as sodium, potassium.
[0024] Simpler and better is the beauty of science. It is found in the present disclosure upon creative imagination and repeated scientific experiments that:
[0025] In the first step of synthesis of glycidylester of tertiary carbonic acid: during the synthesis of halo substituted alcohol ester of tertiary carbonic acid by the reaction of tertiary carbonic acid and halo substituted epoxide in the presence of water and catalyst only, halo substituted alcohol ester of tertiary carbonic acid and a small amount of glycidylester of tertiary carbonic acid can be obtained. The total amount of water is 2-14 times of the mole of tertiary carbonic acid, preferably 3.5-10 times, more preferably 3.7-5 times. The total amount of water includes water added in advance, water contained within the catalyst and water produced during the reaction. The pre-added water mainly acts as a dispersant, which is advantageous for stabilizing the reaction.
[0026] The experiment data of the reaction show that the intermediate product, halo substituted alcohol ester of tertiary carbonic acid, can be synthesized with a very high yield rate by tertiary carbonic acid and halo substituted epoxide under the action of catalyst with only dispersant of water. In addition, halo substituted alcohol ester of tertiary carbonic acid is an intermediate product that is relatively stable. Therefore, it can be produced and separated, and then be used to synthesize glycidylester of tertiary carbonic acid.
[0027] We also found that in the second step of the reaction, i.e., the process of producing glycidylester of tertiary carbonic acid by the dehydrohalogenation of the intermediate product, halo substituted alcohol ester of tertiary carbonic acid, with bases, the presented halo substituted epoxide did not provide any action except causing side reactions and producing impurities. Therefore, before carrying out the second step of the reaction, it is necessary to remove unreacted halo substituted epoxide to recover halo substituted epoxide maximally for reuse, thus lowering the cost.
[0028] In addition, in the second step of the method, alkali metal hydroxides or alkali metal alkoxides are used for the dehydrohalogenation of the intermediate product, halo substituted alcohol ester of tertiary carbonic acid, (in the first step and the second step of the reaction, preferably excess amount of basic compound is added to completely remove halogen hydride), then to prepare glycidylester of tertiary carbonic acid; the residual of alkali metal hydroxide or alkali metal alkoxide is removed, then the low boiling point solvent is removed by distillation to obtain glycidylester of tertiary carbonic acid with high purity. Compared with the techniques in the art, twice dehydrohalogenation is not required in the method of the present disclosure.
[0029] On the basis of the technical solution, the preparation process of the present disclosure further comprises:
[0030] In the first step, after the synthesis reaction of tertiary carbonic acid and halo substituted epoxide, the product is stood to stratify, thus the lower saline water is separated; the unreacted halo substituted epoxide is removed or removed and recovered. The recovered halo substituted epoxide can be reused.
[0031] During said step, the removal of unreacted halo substituted epoxide is achieved, preferably but not limited to, by vacuum distillation.
[0032] In the first step, the catalyst can be one of the following basic catalysts: alkali metal hydroxides, alkali metal carbonates, alkali metal hydrocarbonates or alkali metal alkoxides, preferably sodium hydroxide or potassium hydroxide, wherein the concentration of sodium hydroxides is 30-50 wt %, preferably 40-50 wt %. In the reaction, the maximum amount of a basic catalyst added is 40 mol % of the mole of tertiary carbonic acid, preferably 20-30 mol %, more preferably 20 mol %.
[0033] In the first step, the halo substituted epoxide is epoxy halo propane, preferably epoxy chloropropane.
[0034] In the first step, the amount of added tertiary carbonic acid to halo substituted epoxide is 1:1.5-20 in molar ratio, preferably 1:1.8-20.
[0035] In the first step, the reaction is carried out at 30° C.-110° C. with rapid stirring for 0.5 h -2.5 h.
[0036] In the second step, the specific steps are: water-miscible solvent is added to dissolve the production obtained in the first step, and additional alkali metal hydroxides or alkali metal alkoxides are added to react; the reaction mixture is allowed to stratify after the reaction, and the lower saline water is separated; adjusting the obtained upper organic phase to neutral by adding acidifier or by passing through CO 2 , small amount salt produced is removed. The molar ratio of the amount of added alkali metal hydroxide or alkali metal alkoxide to the tertiary carbonic acid of the first step is 0.9-1.1:1, preferably 1:1.
[0037] Preferably, the second step further comprises: the organic phase neutralized is removed by distillation, and the solvent is recovered; the product obtained after removing the solvent is washed with water to obtain the product, halo substituted alcohol ester of tertiary carbonic acid, by distillation or dehydration with desiccant.
[0038] In the second step, the reaction is completed at 20° C.-80° C. with rapid stirring.
[0039] In the second step, the acidifier is a diluted strong acid or an acidic salt. The diluted strong acid can be selected from the group consisting of diluted sulphuric acid and diluted hydrochloric acid. The acidic salt is preferably sodium dihydrogen phosphate.
[0040] In the second step, the alkali metal hydroxide is preferably sodium hydroxide, the alkali metal alkoxide is preferably sodium alkoxide of 1-6 carbon atoms, wherein the concentration of sodium hydroxide is 15 wt %-40 wt %, preferably 20 wt %-30 wt %.
[0041] In the second step, the solvent is low carbon chain aliphatic alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol, preferably isopropanol. The molar ratio of the amount of the added solvent to the tertiary carbonic acid of the first step is 1-6:1, preferably 1-4:1.
[0042] According to one of the preferred embodiment of the present disclosure, the method comprises the following steps:
[0043] (1) The preparation of halo substituted alcohol ester of tertiary carbonic acid React tertiary carbonic acid with halo substituted epoxide with the molar ratio of the tertiary carbonic acid to the halo substituted epoxide being 1:1.5-20, in the presence of water and in the presence of basic catalyst with the maximum amount of 30 mol % of the mole of tertiary carbonic acid and under rapid stirring at 30-110° C. for 0.5 h-2.5 h; the reaction mixture is allowed to stratify and then the lower saline water is separated; unreacted halo substituted epoxide is removed and recovered by reduced pressure distillation to obtain halo substituted alcohol ester of tertiary carbonic acid and a small amount of glycidylester of tertiary carbonic acid;
[0044] (2) The preparation of glycidylester of tertiary carbonic acid
[0045] All the products obtained from step (1) are dissolved in water-miscible isopropanol; under 20° C.-80° C., preferably 40° C.-60° C. with rapid stirring, alkali metal hydroxide(s) or alkali metal alkoxide(s) with the amount of mole equal to tertiary carbonic acid of step (1) are added to react; the reaction mixture is allowed to stratify after reaction, and the lower saline water is separated; then adjust the obtained upper organic phase to neutral by adding acidifier or by passing through CO 2 , then remove the salt produced; remove the organic phase by distillation, recover the aliphatic alcohol; then wash the obtained product with water to remove the salt remained, obtain the glycidylester of tertiary carbonic acid produced by distillation or dehydration via desiccant.
[0046] The method of the present disclosure can be carried out with batch operation or continuous operation.
[0047] In the step (1), the molar ratio of tertiary carbonic acid to epoxy chloropropane is preferably 1:1.8-20.
[0048] In the step (1), the total amount of water is 2-10 times of the mole of tertiary carbonic acid, preferably 3.5-10 times.
[0049] In the step (1), the reaction is preferably carried out at 50° C.-95° C. with rapid stirring of 1 h-2 h, more preferably 1 h-1.5 h.
[0050] In the step (2), adding all the products obtained from step (1) to the isopropanol with the mole equals to 1-4 times of the mole of tertiary carbonic acid for dissolution; preferably 2-3 times.
[0051] In the step (2), the reaction is carried out at 50° C.-60° C.
[0052] The term “rapid stirring” in steps (1)-(2) means to allow sufficient contact between the aqueous phase and the organic phase.
[0053] The term “distillation” in steps (1)-(2) means to remove the low boiling point head fraction from the reaction mixture initially obtained.
[0054] The tertiary carbonic acid used as raw material in the present disclosure is the tertiary carbonic acid with 5-20 carbon atoms, preferably tertiary carbonic acid with 5-13 carbon atoms, most preferably tertiary carbonic acid with 9-11 carbon atoms.
[0055] The advantages of the present disclosure lie in: the method of the present disclosure only comprises two steps. In the first step, only water is used as solvent, and in the second step, glycidylester of tertiary carbonic acid with high purity can be obtained without halo substituted epoxide. The content of high boiling point byproducts in the final product can reach to lower than 6 wt %, or even lower than 4 wt %; meanwhile, the initial color of the final product is light and stable during storing, and distillation is not required to remove the high boiling point byproducts for purification.
[0056] Besides, the method provides more advantages such as:
[0057] 1. Water, rather than water-miscible solvents, is used as dispersant during synthesis of halo substituted alcohol ester of tertiary carbonic acid in the first step. The difficulty of recovering the halo substituted epoxy propane and halo substituted alcohol ester of tertiary carbonic acid contained in the discharged diluted saline water which is separated after reaction, caused by the addition of water-miscible solvents, is solved. The method of the present disclosure significantly improves the yield of production, lowering the consumption of raw material and decreasing the discharge of the substance that is harmful to the environment.
[0058] 2. After the synthesis of halo substituted alcohol ester of tertiary carbonic acid, the recovery of the excess and unreacted halo substituted epoxide in the product with high yield can be achieved industrially because the boiling point of the intermediate product is relative high, and no other solvent is presented, therefore, the consumption of the raw material is lowered.
[0059] 3. The amount of byproducts produced is decreased in the second step of synthesis of glycidylester of tertiary carbonic acid by carbonic halo substituted alcohol ester as no halo substituted epoxide is presented, the quality of the product is increased and unnecessary consumption of the halo substituted epoxide is avoided.
[0060] 4. The time required for the preparation is shortened because the second dehydrohalogenation by the addition of alkali metal hydroxide after obtaining the glycidylester of tertiary carbonic acid is not required and thus diminishing one preparation step; meanwhile, the decrease of yield by the damage to the produced glycidylester of tertiary carbonic acid by base is avoided, so does the generation of the byproducts that are harmful to the quality of the product.
[0061] 5. The product output per unit volume is significantly increased as no solvent is used in the first step and no halo substituted epoxide is used in the second step, the cost of manufacturing devices is saved, thus it is more suitable for industrial production.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0062] The embodiments below are used to illustrate the present disclosure. However, the extent of the present disclosure is not limited thereto. It can be understood by those skilled in the art that parameters such as reaction temperature, time, amount of addition of raw materials, concentration of raw materials mentioned in the examples below can be adjusted within their effective extent, the reaction processes and the final product obtained in the reactions will be the same. Although it is not provided in the examples below, the other basic catalysts mentioned in the present disclosure such as alkali metal carbonates, alkali metal alkoxides share the same reaction mechanism and property in the reaction of the present disclosure for those skilled in the art. For example, alkoxides with 1-6 carbon atoms are solvable in the reaction medium, and can produce hydroxyl anion, which are similar to the hydroxyl anions produced by sodium hydroxides, and the property of the product will be the same.
Example 1
[0063] (1) The preparation of tertiary carbonic chlorinated alcohol ester
[0064] The initial reaction materials were added to a 1 L reactor equipped with a mechanical stirrer, a water-bath heater and a reflux unit.
[0000]
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Weight
(g)
Volume (mL)
Moles
Molar ratio
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
485.53
411.47
5.25
3.99
Water
94.60
94.60
5.26
4
Total amount
806.13
754.42
The addition of
catalyst
40% sodium
27.05
18.92
0.27
0.21
hydroxide
Total reaction volume
773.34
[0065] The SHINA-10 acid in the above mentioned table and further mentioned below is neodecanoic acid and it is commercially available, wherein, SHINA is the trademark of HEBEI SIYOU ZHUO YUE SCIENCE & TECHNOLOGY LIMITED.
[0066] It should be noted that the “water” in said example and the examples below is the water added before the beginning of the first step reaction.
[0067] Stirring was initialized, under rapid stirring, the initial reaction material was heated to 50° C.-55° C., and then the aqueous solution of sodium hydroxide (40 wt %) was added within 20 min-25 min, with 27.05 g of the aqueous solution added in total.
[0068] In the present example, the molar ratio of tertiary carbonic acid to the total amount of water was 1:4.91, wherein, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water produced in acid base reaction=1:4:0.7:0.21.
[0069] The temperature was raised up to 84° C.-86° C. within 20 minutes then maintained at this temperature for 40 minutes. Then the temperature of the reaction mixture was rapidly dropped to 60° C.-70° C. Stirring was stopped, stood for 5-10 minutes to allow the two phases of the reaction mixture stratified sufficiently, 94.76 g of lower saline water was discharged. The upper organic phase was distilled with reduced pressure with rotating film evaporator in oil-bath under 100° C., 353.6 g of epoxy chloropropane was removed, and 342 g of tertiary carbonic chlorinated alcohol ester with small amount of glycidylester of tertiary carbonic acid were obtained.
[0070] (2) The preparation of glycidylester of tertiary carbonic acid
[0071] All the mixture of tertiary carbonic chlorinated alcohol ester and glycidylester of tertiary carbonic acid were added to the 1 L reactor equipped with a mechanical stirrer, a water-bath heater and a reflux unit, and then 236.79 g of isopropanol was added.
[0000]
(2) The synthesis of glycidylester of tertiary carbonic acid
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
Initial reaction
material
Products of (1)
342
Isopropanol
236.79
301.6
3.94
3.00
Sum
648.51
The addition of
sodium hydroxide
First 24% of sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24% of
108.97
86.14
0.65
0.50
sodium hydroxide
Total volume
734.65
[0072] Stirring was initialized, under rapid stirring, the temperature of the initial reaction material was maintained at 50° C.-55° C., and then 108.97 g of the aqueous solution of sodium hydroxide (24 wt %) was added within 10 min-15 min, the temperature was maintained for 30 minutes, then waited still for 5 minutes for the reaction mixture to sufficiently separate into a upper layer and a lower layer, 82.94 g of the lower saline water was discharged.
[0073] Stirring was initialized again, under rapid stirring, the upper layer organic phase was obtained by separation and the temperature thereof was maintained at 50° C.-55° C., and then 108.97 g of the aqueous solution of sodium hydroxide (24 wt %) was added within 10 min-15 min, the temperature was maintained for 30 minutes, then waited still for 10 minutes for the reaction mixture to sufficiently separate into a upper layer and a lower layer, 141.93 g of the saline water was discharged.
[0074] Stirring was initialized again, under rapid stirring, the upper layer organic phase was obtained by separation and the temperature thereof was maintained at 50° C.-55° C., CO 2 gas was passed through to adjust the organic phase to pH=7-9, small amount of salt precipitate appeared. The insoluble substances were removed by filtration.
[0075] The obtained clear organic phase was distilled under reduced pressure with rotatory film evaporator. 227.5 g of isopropanol was removed.
[0076] 100 g of water was added to the organic phase remained, stirred for 10 minutes at 50° C.-55° C., waited still for 10 minutes, then 85.68 g of aqueous phase of the layer below was discharged.
[0077] Then 301 g of the obtained upper organic phase was distilled under reduced pressure, 45 mmHg, 90° C.-100° C., dehydration and dried.
[0078] 288 g of glycidyl ester of SHIVA-10 acid with high purity was finally obtained.
[0079] The quality of the glycidylester of tertiary carbonic acid is as follows:
[0080] Epoxy value (EGC): 4212
[0081] Purity: 96.18%
[0082] Hydrolysable chloride: 322 mg/kg
[0083] Color: 15 (Pt/Co)
[0084] The production index of the method is as follows:
[0085] Yield: 96.2% (based on the amount of the SHIVA-10 acid fed)
[0086] Recovery rate of epoxy chloropropane: 97.2%
[0087] Recovery rate of isopropanol: 96.1%
Example 2
[0088] The procedure of example 1 was repeated with different amount of raw materials added, see table below for details.
[0089] In this example, the molar ratio of tertiary carbonic acid to the total amount of water was 1:3.24, wherein, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water produced in acid base reaction=1:2.33:0.7:0.21.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
The preparation of tertiary carbonic chlorinated ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
182.31
154.50
1.97
1.50
Water
55.00
55.00
3.06
2.33
Sum
463.31
457.85
The addition
of catalyst
40% of sodium hydroxide
27.05
18.92
0.27
0.21
The total
476.77
reaction volume
The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
material
Intermediate product
Isopropanol
157.94
202.48
2.63
2.00
Sum
202.48
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
[0000]
Example 2
Quality Index
Epoxy Value (EGC)
4106
Purity %
93.77
Hydrolysable chloride mg/kg
641
Color: (Pt/Co)
20
Production Index
Recovery rate of epoxy
96.7
chloropropane %
Recovery rate of
95
isopropanol %
[0090] The procedure of example 1 was repeated in the following examples 3-6 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the amount of water within the synthesis of tertiary carbonic chlorinated alcohol ester and the amount of isopropanol within the synthesis of glycidylester of tertiary carbonic acid were adjusted under the circumstance, to determine the effect of the amount of water and the amount of isopropanol added to the preparation of glycidylester of tertiary carbonic acid.
Example 3
[0091] The procedure of example 1 was repeated in example 3 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the molar ratio of tertiary carbonic acid: the total amount of water=1:3.24, the molar ratio of the tertiary carbonic acid to water during the synthesis of tertiary carbonic chlorinated alcohol ester=1:2.33. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:2.33:0.7:0.21.
[0092] The molar ratio of tertiary carbonic acid to isopropanol=1:1 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
materials
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
55.00
55.00
3.06
2.33
Sum
524.08
509.35
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
The total
528.27
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The products of (1)
Isopropanol
78.97
101.24
1.31
1.00
Sum
101.24
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Example 4
[0093] The procedure of example 1 was repeated in example 4 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the molar ratio of tertiary carbonic acid: the total amount of water=1:3.24, the molar ratio of the tertiary carbonic acid to water within the synthesis of tertiary carbonic chlorinated alcohol ester=1:2.33. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:2.33:0.7:0.21.
[0094] The molar ratio of tertiary carbonic acid to isopropanol=1:4 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
materials
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
55.00
55.00
3.06
2.33
Sum
524.08
509.35
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
The total
528.27
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Isopropanol
315.87
404.97
5.26
4.00
Sum
404.97
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Example 5
[0095] The procedure of example 1 was repeated in example 5 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the molar ratio of tertiary carbonic acid: the total amount of water=1:10.02, the molar ratio of the tertiary carbonic acid to water within the synthesis of tertiary carbonic chlorinated alcohol ester=1:9.11. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:9.11:0.7:0.21.
[0096] The molar ratio of tertiary carbonic acid to isopropanol=1:1 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
215.41
215.41
11.97
9.11
Sum
684.49
669.77
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
Total
688.68
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Isopropanol
78.73
100.94
1.31
1.00
Sum
100.94
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Example 6
[0097] The procedure of example 1 was repeated in example 6 with the volume of the reactor for preparing glycidylester of tertiary carbonic acid being 2 L and the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the molar ratio of tertiary carbonic acid: the total amount of water=1:10.2, the molar ratio of the tertiary carbonic acid to water within the synthesis of tertiary carbonic chlorinated alcohol ester=1:9.11. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:9.11:0.7:0.21.
[0098] The molar ratio of tertiary carbonic acid to isopropanol=1:4 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
215.41
215.41
11.97
9.11
Sum
684.49
669.77
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
Total
688.68
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Isopropanol
315.87
404.97
5.26
4.00
Sum
404.97
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Initial reaction
491.11
materials
[0099] The comparison between examples 3-6 are shown below:
[0000]
Example 3
Example 4
Example 5
Example 6
Quality Index
Epoxy value ( EGC )
4141
4100
4176
4116
Purity %
94.5
93.6
95.36
94
Hydrogenated chloride
489
524
366
509
Color (Pt/Co)
20
20
20
20
Production Index
Recovering rate of epoxy
96.2
95.8
95.3
96
chloropropane %
Recovering rate of
95.1
94.8
95.8
96.1
Isopropanol
[0100] The procedure of example 1 was repeated in the following examples 7-8 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:20, the amount of water within the synthesis of tertiary carbonic chlorinated alcohol ester was adjusted under the circumstance.
Example 7
[0101] The procedure of example 1 was repeated in example 7 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:20, the molar ratio of tertiary carbonic acid: the total amount of water=1:12.98, the molar ratio of the tertiary carbonic acid to water within the synthesis of tertiary carbonic chlorinated alcohol ester=1:12.07. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:12.07:0.7:0.21.
[0102] The molar ratio of tertiary carbonic acid to isopropanol=1:2 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
56.50
62.09
0.33
1.00
Epoxy chloropropane
607.70
515.00
6.57
20.00
Water
71.36
71.36
3.96
12.07
Sum
735.56
648.45
The addition
of catalyst
40% Sodium hydroxide
6.76
4.73
0.07
0.21
Total
653.18
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Isopropanol
39.66
50.85
0.66
2.01
Sum
50.85
The addition of
sodium hydroxide
First 24% sodium
27.24
21.53
0.16
0.50
hydroxide
Second 24%
27.24
21.53
0.16
0.50
sodium hydroxide
Example 8
[0103] The procedure of example 1 was repeated in example 8 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:20, the molar ratio of tertiary carbonic acid: the total amount of water=1:3.76, the molar ratio of the tertiary carbonic acid to water within the synthesis of tertiary carbonic chlorinated alcohol ester=1:2.85. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:2.85:0.7:0.21.
[0104] The molar ratio of tertiary carbonic acid to isopropanol=1:2 within the synthesis of glycidylester of tertiary carbonic acid.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
75.33
82.78
0.44
1.00
Epoxy chloropropane
810.20
686.61
8.76
20.00
Water
22.50
22.50
1.25
2.85
Sum
908.03
791.89
The addition
of catalyst
40% Sodium hydroxide
9.02
6.31
0.09
0.21
Total
798.20
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Isopropanol
52.88
67.79
0.88
2.01
Sum
67.79
The addition of
sodium hydroxide
First 24% sodium
36.32
28.71
0.22
0.50
hydroxide
Second 24%
36.32
28.71
0.22
0.50
sodium hydroxide
[0105] The comparison of the results of examples 7-8 are shown below:
[0000]
Example 7
Example 8
Quality Index
Epoxy value (EGC)
4185
4191
Purity %
95.6
95.7
Hydrolizable chloride
347
335
Color (Pt/Co)
25
25
Production Index
Recovering rate of epoxy
96.9
96.5
chloropropane %
Recovering rate of
95.4
95.9
isopropanol %
[0106] The procedure of example 1 was repeated in the following examples 9-11 with the molar ratio of tertiary carbonic acid to epoxy chloropropane=1:2, the molar ratio of tertiary carbonic acid: the total amount of water=1:3.24. Specifically, the molar ratio of tertiary carbonic acid:water added: water brought by sodium hydroxide:water generated by acid base reaction=1:2.33:0.7:0.21. The solvent used within the synthesis of glycidylester of tertiary carbonic acid was changed under the circumstance.
Example 9
[0107] The solvent used within the synthesis of glycidylester of tertiary carbonic acid is anhydrous ethanol.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
55.00
55.00
3.06
2.33
Sum
524.08
509.35
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
Total
528.27
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Anhydrous ethanol
157.00
198.99
3.41
2.60
Sum
198.99
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Example 10
[0108] The solvent used within the synthesis of glycidylester of tertiary carbonic acid is toluene.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
55.00
55.00
3.06
2.33
Sum
524.08
509.35
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
Total
528.27
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Toluene
92.00
105.75
1.00
0.76
Sum
105.75
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
Example 11
[0109] The solvent used within the synthesis of glycidylester of tertiary carbonic acid is ethyl acetate.
[0000]
Weight
Volume
Molar
(g)
(mL)
Moles
ratio
(1) The preparation of tertiary carbonic chlorinated alcohol ester
Initial reaction
material
SHINA-10 acid
226.00
248.35
1.31
1.00
Epoxy chloropropane
243.08
206.00
2.63
2.00
Water
55.00
55.00
3.06
2.33
Sum
524.08
509.35
The addition
of catalyst
40% Sodium hydroxide
27.05
18.92
0.27
0.21
Total
528.27
reaction volume
(2) The synthesis of glycidylester of tertiary carbonic acid
Initial reaction
materials
The product of (1)
Ethyl acetate
157.80
177.30
1.79
1.36
Sum
177.30
The addition of
sodium hydroxide
First 24% sodium
108.97
86.14
0.65
0.50
hydroxide
Second 24%
108.97
86.14
0.65
0.50
sodium hydroxide
[0110] The comparison of the results of examples 9-11 are shown below:
[0000]
Quality Index
Example 9
Example 10
Example 11
Epoxy Index (EGC)
3845
2912
2140
Purity %
87.8
66.4
48.8
Color (Pt/Co)
20
25
20
[0111] It can be seen from the results of the examples 9-11, when ethanol was used as solvent, the final product would have better purity and color, while toluene, ethyl acetate were used as solvents, the purity of the product obtained was not very high.
[0112] It should be noted that the examples are only the more advantageous embodiments of the present disclosure, the extent of protection of the present disclosure is not limited thereto, and the specific operation steps of the methods can be modified or replaced by technical equivalents in the present disclosure. Therefore, the modifications of the methods equivalent to the ones described in the description of the present disclosure, or direct or indirect applications of the methods in other related technical fields are all covered in the extent of protection of the present disclosure.
|
The present disclosure provides a preparation method of glycidylester of tertiary carbonic acid. The synthesis is performed in two steps: first, the tertiary carbonic acid reacts with a halo substituted epoxide under a catalyst to produce tertiary carbonic halo substituted alcohol ester; after dehydrohalogenation of the halo substituted alcohol ester of tertiary carbonic acid, the glycidylester of tertiary carbonic acid is formed. In the first step of preparing the halo substituted alcohol ester of tertiary carbonic acid through synthesis, the reaction between the tertiary carbonic acid and the halo substituted epoxide is only performed in the existence of water and the catalyst, and the water comprises water added before the reaction. The present disclosure significantly increases the product output in the unit volume, and is particularly suitable for industrial production of glycidylester of tertiary carbonic acid having the low cost, high purity, low color and stable color.
| 2 |
RELATED APPLICATION
[0001] This application claims the benefit of co-pending U.S. patent application Ser. No. 10/271,334, filed Oct. 15, 2002. This application also claims the benefit of co-pending U.S. Provisional Application Serial No. 60/333,937 filed 28 Nov. 2001.
BACKGROUND OF THE INVENTION
[0002] The invention relates generally to the attachment of a vascular prosthesis to a native vessel, and in particular, to a method and system of devices for the repair of diseased and/or damaged sections of a vessel.
[0003] The weakening of a vessel wall from damage or disease can lead to vessel dilatation and the formation of an aneurysm. Left untreated, an aneurysm can grow in size and may eventually rupture.
[0004] For example, aneurysms of the aorta primarily occur in abdominal region, usually in the infrarenal area between the renal arteries and the aortic bifurcation. Aneurysms can also occur in the thoracic region between the aortic arch and renal arteries. The rupture of an aortic aneurysm results in massive hemorrhaging and has a high rate of mortality.
[0005] Open surgical replacement of a diseased or damaged section of vessel can eliminate the risk of vessel rupture. In this procedure, the diseased or damaged section of vessel is removed and a prosthetic graft, made either in a straight of bifurcated configuration, is installed and then permanently attached and sealed to the ends of the native vessel by suture. The prosthetic grafts for these procedures are usually unsupported woven tubes and are typically made from polyester, ePTFE or other suitable materials. The grafts are longitudinally unsupported so they can accommodate changes in the morphology of the aneurysm and native vessel. However, these procedures require a large surgical incision and have a high rate of morbidity and mortality. In addition, many patients are unsuitable for this type of major surgery due to other co-morbidities.
[0006] Endovascular aneurysm repair has been introduced to overcome the problems associated with open surgical repair. The aneurysm is bridged with a vascular prosthesis, which is placed intraluminally. Typically these prosthetic grafts for aortic aneurysms are delivered collapsed on a catheter through the femoral artery. These grafts are usually designed with a fabric material attached to a metallic scaffolding (stent) structure, which expands or is expanded to contact the internal diameter of the vessel. Unlike open surgical aneurysm repair, intraluminally deployed grafts are not sutured to the native vessel, but rely on either barbs extending from the stent, which penetrate into the native vessel during deployment, or the radial expansion force of the stent itself is utilized to hold the graft in position. These graft attachment means do not provide the same level of attachment when compared to suture and can damage the native vessel upon deployment.
SUMMARY OF THE INVENTION
[0007] The invention provides systems and methods for implanting prostheses in the body. The systems and methods provide permanent attachment of the prosthesis in the body. The prosthesis can comprise, e.g., an endovascular graft, which can be deployed without damaging the native blood vessel in either an arterial or a venous system. The endovascular graft can comprise, e.g., a radially expanding vascular stent and/or a stent-graft. The graft can be placed in the vasculature, e.g., to exclude or bridge an aneurysm, for example, an abdominal aortic aneurysm. The graft desirably adapts to changes in aneurysm morphology and repairs the endovascular aneurysm. The fastening system and methods are deployed through the vasculature and manipulated from outside the body, to deliver a fastener to attach the graft to the vessel wall.
[0008] One aspect of the invention provides a fastener applier for a prosthesis. The applier comprises a drive mechanism sized and configured to be releasably coupled to the fastener to deploy the fastener into the prosthesis. The applier also includes an actuator for the drive mechanism including a sensing mechanism that enables operation of the drive mechanism in response to at least one of (i) a force sensed at or near the fastener, and (ii) contact sensed with a surface at or near the distal end of the fastener body.
[0009] Another aspect of the invention provides a fastener sized and configured for deployment in tissue. The fastener includes a fastener body having a distal end for penetrating tissue in response to a force. The fastener body also has a proximal end for releasably coupling the fastener body to a force applier. The fastener includes a stop structure associated with the proximal end to prevent over-penetration of the fastener body into tissue. In one embodiment, the stop structure couples the fastener body to the force applier, e.g., by a magnetic or mechanical coupling. On one embodiment, the fastener body can comprise, e.g., a helical coil.
[0010] Another aspect of the invention provides a fastener sized and configured for deployment in tissue. The fastener comprises a fastener body having a distal end for penetrating tissue in response to a force. The fastener body also has a proximal end for releasably coupling the fastener body to a force applier. A tracking wire is coupled to the proximal end to guide the force applier into operative contact with the fastener.
[0011] Another aspect of the invention provides a prosthesis comprising a prosthesis body and a fastener assembly integrally carried by the prosthesis body. The fastener assembly includes at least one fastener deployable into tissue in response to force applied by a force applier. A tracking wire is coupled to the fastener to guide the force applier into operative contact with the fastener.
[0012] Another aspect of the invention provides a prosthesis comprising a prosthesis body and a fastener assembly integrally carried by the prosthesis body. The assembly includes at least one fastener deployable into tissue in response to non-rotational force applied by a force applier.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention will be understood from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings, wherein:
[0014] [0014]FIG. 1 is a perspective view of one embodiment of an endovascular graft delivery device shown positioned within an abdominal aortic aneurysm;
[0015] [0015]FIG. 2 is a perspective view of one embodiment the deployment of an endovascular graft within the aneurysm of FIG. 1;
[0016] [0016]FIG. 3 is a perspective view of a fully deployed straight endovascular graft of FIG. 2;
[0017] [0017]FIG. 4 is a perspective view of a fully deployed bifurcated endovascular graft broken away to show an anchoring scaffold at one end;
[0018] [0018]FIG. 5 is a perspective view similar to FIG. 5 showing an alternative scaffold structure;
[0019] [0019]FIG. 6 is a perspective view showing one embodiment of a device for directing the fastener applier;
[0020] [0020]FIG. 7 is a perspective view showing the device of FIG. 6 upon insertion within the deployed endovascular graft of FIG. 3 with both the graft and scaffolding broken away;
[0021] [0021]FIG. 8 is a perspective view of the device of FIG. 6 showing activation of one embodiment of a stabilizing device attached to the directing device;
[0022] [0022]FIG. 9 is a perspective view of the control assembly in FIG. 8 articulating the directing device of FIG. 6;
[0023] [0023]FIG. 10 is a perspective view of an alternative embodiment of the stabilization device of FIG. 8;
[0024] [0024]FIG. 11 is a perspective view showing the activation of the alternative stabilization device of FIG. 10;
[0025] [0025]FIG. 12 is a perspective view showing another embodiment of the stabilization device of FIG. 8;
[0026] [0026]FIG. 13 is a perspective view showing activation of the stabilization device of FIG. 12;
[0027] [0027]FIG. 14 is one embodiment of the fastener applier;
[0028] [0028]FIG. 14A is an enlarged view of the distal end of the fastener applier shown in FIG. 14, showing the details of the fastener drive mechanism;
[0029] [0029]FIG. 14B is a section view of the interior of the handle of the fastener applier shown in FIG. 14;
[0030] [0030]FIG. 15 is a perspective view of the fastener applier of FIG. 14 being positioned within directing device of FIG. 6;
[0031] [0031]FIG. 16 is an enlarged cross-sectional view of one embodiment of the fastener applier of FIG. 14;
[0032] [0032]FIG. 17 is an enlarged cross-sectional view of the attachment applier showing one embodiment of the proximal end of the helical fastener and the drive mechanism;
[0033] [0033]FIG. 18 is a enlarged perspective view of one embodiment of the helical fastener of FIG. 16;
[0034] [0034]FIG. 19 is an enlarged view of the attachment applier showing one embodiment of the control assembly that activates the fastener applier;
[0035] [0035]FIG. 20 is an enlarged view of the attachment applied activated with a fastener implanted into the graft and vessel wall;
[0036] [0036]FIG. 21 is an enlarged view of the completed attachment of the proximal graft of FIG. 3 to the vessel wall with fasteners;
[0037] [0037]FIG. 22 is a perspective view of the graft of FIG. 4 completely attached to the vessel;
[0038] [0038]FIG. 23 is an enlarged section view of the drive mechanism of the fastener applier shown in FIG. 14, showing a contact/force sensing assembly that disables the applier in the absence of desired contact between the fastener and a targeted tissue region;
[0039] [0039]FIG. 24 is an enlarged section view of the drive mechanism of the fastener applier shown in FIG. 14, showing the contact/force sensing assembly enabling use of the applier in response to desired contact between the fastener and the targeted tissue region;
[0040] [0040]FIGS. 25A and 25B are enlarged views of the distal end of a fastener applier showing the details of an alternative embodiment of the fastener drive mechanism;
[0041] [0041]FIG. 26A is an enlarged section view of the drive mechanism of the fastener applier shown in FIGS. 25A and 25B showing a contact/force sensing assembly that disables the applier in the absence of desired contact between the fastener and a targeted tissue region;
[0042] [0042]FIGS. 26B and 26C are enlarged section views of the drive mechanism of the fastener applier shown in FIGS. 25A and 25B, showing the contact/force sensing assembly enabling use of the applier in response to desired contact between the fastener and the targeted tissue region;
[0043] [0043]FIG. 27 is a perspective view of a helical fastener that can be used in association with the fastener applier shown in FIGS. 14, 23, and 24 ;
[0044] [0044]FIG. 28A is a perspective view of a helical fastener that can be used in association with the fastener applier shown in FIGS. 25A and 25B;
[0045] [0045]FIG. 28B is perspective view of a helical fastener that can be used in association with the fastener applier shown in FIGS. 26A to 26 C;
[0046] [0046]FIG. 29 is an enlarged side view, partially in section, of a fastener applier having an angled applicator end that can be used to deploy the helical fastener shown in FIG. 27 without use of a separate directing device;
[0047] [0047]FIG. 30 is an enlarged side view, partially in section, of an alternative embodiment of an angled fastener applier that can be used to deploy the helical fastener shown in FIG. 27 without use of a separate directing device;
[0048] [0048]FIG. 31 is an enlarged side view, partially in section, of an alternative embodiment of an angled fastener applier that can be used to deploy the helical fastener shown in FIG. 27 without use of a separate directing device, the fastener applier having an articulating applicator end;
[0049] [0049]FIG. 32 is a perspective view of an endovascular prosthesis shown positioned within an abdominal aortic aneurysm, the prosthesis including an integrated fastener assembly;
[0050] [0050]FIG. 33 is a perspective view of the endovascular prosthesis shown in FIG. 32, with an intraluminal tool deployed to operatively interact with the integrated fastener assembly, to temporarily or permanently anchor the prosthesis to the wall of the vessel;
[0051] [0051]FIG. 34 is a side view of a fastener that forms a part of the integrated fastener assembly shown in FIG. 33, the fastener having a stem, which is shown in a normally spread-apart condition before its association with the integrated fastener assembly;
[0052] [0052]FIG. 35 is a side view of the fastener shown in FIG. 34, the fastener stem now being shown in a closed condition and housed within a grommet that forms a part of the integrated fastener assembly;
[0053] [0053]FIGS. 36 and 37 are side views showing the use of the intraluminal tool shown in FIG. 33 to apply force to drive the fastener from its position shown in FIG. 35 and through the vessel wall;
[0054] [0054]FIG. 38 is the integrated fastener assembly after deployment to anchor a prosthesis to a vessel wall;
[0055] [0055]FIG. 39 is a side view showing the use of a tracking wire to guide a intraluminal tool into contact with a fastener, so that force can be applied to drive the fastener through the vessel wall;
[0056] [0056]FIG. 40 is an embodiment of a prosthesis delivery catheter for a prostheses in which the stent structure covers only a portion of the prosthesis, the catheter including an array of stabilization struts to help hold the prosthesis in position against the flow of blood;
[0057] [0057]FIG. 41 is another embodiment of a prosthesis delivery catheter for a prostheses in which the stent structure covers only a portion of the prosthesis, the catheter including an array of inverted stabilization struts to help hold the prosthesis in position against the flow of blood; and
[0058] [0058]FIG. 42 is another embodiment of a prosthesis delivery catheter for a prostheses in which the stent structure covers only a portion of the prosthesis, the catheter including a stabilization basket to help hold the prosthesis in position against the flow of blood.
DETAILED DESCRIPTION OF THE INVENTION
[0059] I. Delivering a Prosthesis
[0060] [0060]FIG. 1 depicts an endovascular graft delivery catheter 10 as it is being positioned over a guidewire 12 in a body lumen. The catheter 10 carries a prosthesis 14 (see FIG. 2), which is placed at a targeted site, e.g., by radial expansion of the prosthesis 14 (see FIG. 3). After expansion of the prosthesis 14 , one or more fasteners 28 (see FIGS. 15 and 16) are introduced by a fastener attachment assembly to anchor the prosthesis 14 in place.
[0061] For the purposes of illustration, FIG. 1 shows the targeted site as being within an abdominal aortic aneurysm 11 . The targeted site can be elsewhere in the body. In the illustrated arrangement, the prosthesis 14 takes the form of an endovascular graft.
[0062] [0062]FIG. 2 depicts the initial stage of graft deployment at the targeted site. While the deployment method can vary, in the illustrated embodiment, the delivery catheter 10 has a movable cover 13 , which overlays the graft 14 . When the cover 13 is pulled proximally, the graft 14 is free to radially expand, thereby enlarging to contact the internal walls of the blood vessel. The graft 14 is shown to be self-expanding. Alternatively, the graft 14 can utilize an expanding member, such as a balloon or mechanical expander.
[0063] The process of graft deployment is continued, until the graft 14 is fully deployed within the vessel. The graft 14 can be sized and configured to be either straight or bifurcated form. FIG. 3 depicts a completely deployed straight graft 14 . FIG. 4 depicts a completely deployed bifurcated graft 15 .
[0064] A. The Prosthesis
[0065] The graft 14 desirably incorporates a support frame or scaffold 16 . The scaffold 16 may be elastic, e.g., comprised of a shape memory alloy elastic stainless steel, or the like. For elastic scaffolds, expanding typically comprises releasing the scaffolding from a constraint to permit the scaffold to self-expand at the implantation site. In the illustrated arrangement, the cover 13 serves as a radial constraint. Alternatively, placement of a tubular catheter, delivery sheath, or the like over the scaffold 16 can serve to maintain the scaffold in a radially reduced configuration. In this arrangement, self-expansion of the scaffold 16 is achieved by pulling back on the radial constraining member, to permit the scaffold 16 to assume its larger diameter configuration.
[0066] Alternatively, the scaffold 16 may be constrained in an axially elongated configuration, e.g., by attaching either end of the scaffold to an internal tube, rod, catheter or the like. This maintains the scaffold 16 in the elongated, reduced diameter configuration. The scaffold 16 may then be released from such axial constraint in order to permit self-expansion.
[0067] Alternatively, the scaffold 16 may be formed from a malleable material, such as malleable stainless steel of other metals. Expansion may then comprise applying a radially expansive force within the scaffold to cause expansion, e.g., inflating a scaffold delivery catheter within the scaffold in order to affect the expansion. In this arrangement, the positioning and deployment of the endograft can be accomplished by the use of an expansion means either separate or incorporated into the deployment catheter. This will allow the endograft to be positioned within the vessel and partially deployed while checking relative position within the vessel. The expansion can be accomplished either via a balloon or mechanical expansion device. Additionally, this expansion stabilizes the position of the endograft within the artery by resisting the force of blood on the endograft until the endograft can be fully deployed.
[0068] The graft 14 may have a wide variety of conventional configurations. It can typically comprise a fabric or some other blood semi-impermeable flexible barrier which is supported by the scaffold 16 , which can take the form of a stent structure. The stent structure can have any conventional stent configuration, such as zigzag, serpentine, expanding diamond, or combinations thereof. The stent structure may extend the entire length of the graft, and in some instances can be longer than the fabric components of the graft. Alternatively, the stent structure can cover only a small portion of the prosthesis, e.g., being present at the ends. The stent structure may have three or more ends when it is configured to treat bifurcated vascular regions, such as the treatment of abdominal aortic aneurysms, when the stent graft extends into the iliac arteries. In certain instances, the stent structures can be spaced apart along the entire length, or at least a major portion of the entire length, of the stent-graft, where individual stent structures are not connected to each other directly, but rather connected to the fabric or other flexible component of the graft.
[0069] One illustrative embodiment of the graft scaffold 16 or stent structure is illustrated in the area broke away in FIG. 4. Here, the stent structure is in the form of a simple zigzag pattern, however it is contemplated that the stent design could involve more complex patterns 17 as depicted in FIG. 5. Although only one stent structure within the graft is depicted, in FIGS. 4 and 5, it is contemplated that multiple independent stent structures could be incorporated into the graft, as previously described.
[0070] [0070]FIG. 40 shows an embodiment of a prosthesis delivery catheter 600 for a prostheses 14 in which the stent structure 16 covers only a portion of the prosthesis, e.g., being present only at the ends. As shown in FIG. 40, the prosthesis delivery catheter 600 (which is shown deployed over a guidewire 610 ) includes an array of stabilization struts 612 that are releasably coupled to the stent structure 16 at the end of the prosthesis 14 , e.g., by sutures that can be released by pulling on a drawstring (not shown) that passes through a lumen in the catheter 600 . The stabilization struts 612 hold the self-expanding stent structure 16 in position against the vessel wall 34 , while the remainder of the prosthesis 14 is being deployed (by withdrawal of a delivery sheath 614 ). The struts 612 support the stent structure 16 (and thus the overall prosthesis 14 ) against the force of blood flow through the vessel during prosthesis deployment. The catheter 600 can also include a nose cone 618 at its distal end to diffuse blood flow toward the vessel wall, to aid in supporting the prosthesis 14 during its deployment. Upon, deployment of the prosthesis 14 , the struts 612 can be detached from the stent structure 14 by pulling upon the drawstring to release the sutures, and the catheter 600 is withdrawn over the guidewire 610 through the delivery sheath 614 (the struts 612 , freed from the stent structure 16 , fold back upon the catheter 600 during passage through the delivery sheath 614 ).
[0071] [0071]FIG. 41 shows an alternative embodiment of a prosthesis delivery catheter 700 for a prostheses 14 in which the stent structure 16 covers only a portion of the prosthesis, e.g., being present at the ends. As shown in FIG. 40, the prosthesis delivery catheter 700 (which is also shown deployed over a guidewire 710 ) includes an array of inverted stabilization struts 712 that are releasably coupled to the stent structure 16 at the end of the prosthesis 14 , e.g., by sutures that can be released by pulling on a drawstring (not shown) that passes through a lumen in the catheter 700 . The inverted stabilization struts 712 , like the struts 612 shown in FIG. 40, hold the self-expanding stent structure 16 in position against the vessel wall 34 , while the remainder of the prosthesis 14 is being deployed (by withdrawal of a delivery sheath 714 ). Like the catheter 600 in FIG. 40, the catheter 700 can also include a nose cone 718 at its distal end to diffuse blood flow toward the vessel wall. Upon, deployment of the prosthesis 14 , the struts 712 are detached from the stent structure 14 by pulling upon the drawstring not shown), and the catheter 700 is withdrawn over the guidewire 710 through the delivery sheath 714 (the struts 612 , freed from the stent structure 16 , fold back upon the catheter 600 during passage through the delivery sheath 614 ).
[0072] [0072]FIG. 42 shows another alternative embodiment of a prosthesis delivery catheter 800 for a prostheses 14 in which the stent structure 16 covers only a portion of the prosthesis, e.g., being present at the ends. As shown in FIG. 42, the prosthesis delivery catheter 800 (which is also shown deployed over a guidewire 810 ) includes a self-expanding stabilization basket 812 . The stabilization basket 812 holds the self-expanding stent structure 16 in position against the vessel wall, while the remainder of the prosthesis 14 is being deployed (by withdrawal of a delivery sheath 814 ). Like the catheters 600 and 700 in FIGS. 40 and 41, the catheter 800 can also include a nose cone 818 at its distal end to diffuse blood flow toward the vessel wall. Upon, deployment of the prosthesis 14 , the stabilization basket is placed into a collapsed condition by withdrawal through the delivery sheath 814 , as the catheter 800 is withdrawn over the guidewire 810 .
[0073] In all of the just-described embodiments, the guidewire 610 , 710 , 810 can be subsequently used to deploy a fastener attachment assembly for the prosthesis 14 , as will be described in greater detail next.
[0074] II. Fastening the Prosthesis
[0075] In a desired embodiment, a fastener attachment assembly is provided that makes possible intraluminal fastener attachment. The attachment assembly can be variously constructed.
[0076] A. Two Component Fastener Guide and Attachment Assembly
[0077] In one arrangement, the fastener attachment assembly comprises a fastener guide or directing component 18 and a fastener applier component 27 . The guide component 18 desirably has a steerable or deflectable distal tip, which is initially deployed over the guidewire 12 . In use, the guidewire 12 that is used to deliver and position the prosthesis 14 desirably remains within the vessel for subsequent deployment of the fastener guide component 18 .
[0078] Optionally, the guide component 18 includes a stabilizer for holding, following removal of the guidewire 12 , the deflected tip against a location in the prosthesis 14 , to which a fastener 28 for the prosthesis 14 is to be applied.
[0079] In this arrangement, the applier component 27 is desirably deployed through the guide component 18 . The fastener applier 27 carries at least one fastener 28 and a fastener drive mechanism 100 for advancing the fastener 28 , so that it penetrates the prosthesis 14 and underlying vessel wall, to thereby anchor the prosthesis 14 firmly in place.
[0080] 1. Fastener Directing Component
[0081] [0081]FIG. 6 depicts one embodiment of the directing or guide component 18 that forms a part of the fastener attachment assembly. The component 18 takes the form of a directing device 18 . The device 18 has an obturator 19 positioned within a lumen of the directing device 18 , which extends past the distal of the tip of the directing device. The obturator 19 has a lumen to allow for delivery of the directing device 18 over the guidewire 12 , as shown in FIG. 7.
[0082] The directing device 18 desirably includes an integrated stabilizing device 20 , which aids in maintaining position of the directing device 18 within the vessel upon removal of the guidewire 12 . In one embodiment, the stabilizing device 20 is spring-loaded and is positioned for deployment when the obturator 19 and guidewire 12 are removed (see FIG. 8).
[0083] In the illustrated embodiment (see FIG. 8), the directing device 18 includes a control assembly 21 . In one embodiment the control assembly 21 features a movable wheel or lever 22 , which operate interior steering wires in a conventional fashion to deflect the distal tip 23 of the directing device 18 toward a desired location, as seen in FIG. 9. It is contemplated that the control assembly for the directing device 18 could be activated mechanically, electrically, hydraulically or pneumatically. The control assembly 21 has a through lumen to allow for the passage of the obturator 19 and applier component 27 .
[0084] [0084]FIG. 10 depicts an alternative embodiment, in which the stabilizing device 20 takes the form of a movable strut assembly 24 . The movable strut assembly 24 can be activated, e.g., through a lever 25 on the control assembly (see FIG. 11). In both embodiments (FIGS. 7 and 10) the stabilizing device 20 is distal to the end of the directing device.
[0085] In another alternative embodiment (see FIG. 12), the stabilizing device 20 takes the form of an expandable member 26 adjacent to the distal tip of the directing device. As shown in FIG. 13, the expandable member 26 can be activated, e.g., through a lever 25 on the control assembly 21 . However it also contemplated that this type of stabilizing device 20 could also be inflatable. In all embodiments the stabilizing device could be use to stabilize the directing device 18 either concentrically or eccentrically within the vessel.
[0086] In another embodiment, a separate stabilization device could be used in cooperation with the directing device 18 and to access the vessel. This separate stabilization device could incorporate the forms of the stabilizing devices described above, or some other form of stabilization mechanism.
[0087] 2. Fastener Applier Component
[0088] [0088]FIG. 14 shows one embodiment of the applier component 27 that forms a part of the fastener attachment assembly. The component 27 takes the form of a fastener applier 27 . FIG. 15 depicts the fastener applier 27 being deployed through a lumen of the directing device 18 to the site where a fastener 28 will be installed.
[0089] Located at the distal end of the fastener applier 27 (see FIG. 14) is a fastener drive mechanism 100 . In the illustrated embodiment (see FIG. 14A), the drive mechanism 100 includes a driver 29 that is coupled to a carrier 102 . The coupling between the driver 29 and carrier 102 can take different forms—e.g., magnets, graspers, or other suitable mechanical connection. In the embodiment illustrated in FIG. 14A, the driver 29 and carrier 102 are integrally connected as a single unit.
[0090] The carrier 102 is sized and configured to engage a selected fastener 28 . In FIG. 14A, the fastener takes the form of a helical fastener of the type shown in FIGS. 18 and 27. As best shown in FIG. 27, and as will be described in greater detail later, the helical fastener 28 in FIG. 26 is an open coil 148 with a sharpened leading tip 142 . The proximal end 144 of the fastener 28 includes an L-shaped leg 146 . The L-shape leg 146 desirably bisects the entire interior diameter of the coil 148 ; that is, the L-shaped leg 146 extends completely across the interior diameter of the coil 148 , as FIG. 27 shows. The L-shaped leg 146 serves to engage the carrier 102 of the fastener applier 27 , which rotates the helical fastener to achieve implantation. The L-shaped leg 146 also serves as a stop to prevent the helical fastener from penetrating too far into the tissue.
[0091] The carrier 102 in FIG. 14A includes a slot 180 , which receives the L-shaped leg 146 to couple the fastener 28 for rotation with the carrier 102 . The turns of the coil 148 rest in complementary internal grooves 32 that surround the carrier 102 . The grooves 32 could be positioned along the entire length of the fastener 28 or within a portion of its length.
[0092] The actuation of the drive mechanism 100 can, of course, be accomplished in various ways, e.g., mechanical (i.e., manual or hand-powered), electrical, hydraulic, or pneumatic. In the illustrated embodiment (see FIG. 14B), a drive cable 30 couples the fastener driver 29 to an electric motor 106 carried in the applier handle 108 . The drive cable 30 is desirably made of a suitable material that allows for both bending and rotation. Driven by the motor 106 (which is, in turn, under the control of motor control unit 31 , as will be described later), the drive cable 30 rotates the driver 29 and, with it, the carrier 102 . The carrier 102 imparts rotation and torque to the helical fastener 28 for implantation in tissue.
[0093] [0093]FIG. 16 is an enlarged cross-sectional view of fastener applier 27 and directing device 18 . FIG. 17 is an enlarged cross-sectional view of the fastener applier 27 with a cross-section of the fastener driver 29 depicting the engagement between the fastener driver 29 and helical fastener 28 . FIG. 19 depicts the fastener applier 27 during activation of the fastener drive mechanism 100 . Activation of the drive mechanism 100 rotates, as a unit, the drive shaft 30 , the driver 29 , the carrier 102 , and helical fastener 28 . This rotation causes the helical fastener 28 to travel within the internal grooves 32 of the fastener applier and into the prosthesis 14 and vessel wall 34 (see FIG. 20). FIG. 21 illustrates a completed helical fastener 28 attachment of the graft 14 to the vessel wall 34 .
[0094] In use, the applier 27 is advanced through the directing device 18 and into contact with the prosthesis. The operator actuates the control unit 31 by contacting a control switch 110 (see FIGS. 14 and 14B). This action causes the helical fastener 28 to be rotated off the carrier 102 and through the prosthesis 14 and into the vessel wall 34 . The motor control unit 31 desirably rotates the drive cable 30 a specific number of revolutions with each activation command. This can be accomplished by incorporating a mechanical or electrical counter.
[0095] With the deployment of a fastener 28 , the applier 27 is retrieved through the directing device 18 , and another fastener 28 is loaded into the carrier 102 . The directing device 18 is repositioned and stabilized, and the applier 27 is advanced again through the directing device 18 and into contact with the prosthesis 14 . The operator again actuates the control unit 31 by contacting the control switch 110 to deploy another fastener 28 . This process is repeated at both proximal and/or distal ends of the prosthesis 14 until the prosthesis 14 is suitably attached and sealed to the vessel wall 34 . It is contemplated that from about two to about twelve fasteners 28 may be applied at each end of the prosthesis 14 to affect anchorage. The fasteners 28 can be applied in a single circumferentially space-apart row, or may be applied in more than one row with individual fasteners being axially aligned or circumferentially staggered.
[0096] [0096]FIG. 22 illustrates a perspective view of a graft prosthesis attached to the vessel wall both proximally and distally. It is contemplated that the present invention can be used for graft attachment of both straight and bifurcated grafts within the aorta and other branch vessels.
[0097] An alternative embodiment of the drive mechanism 100 is shown in FIGS. 25A and 25B. In this embodiment, the driver 29 is coupled to a carrier 150 , which forms a part of the helical fastener 28 itself, as also shown in FIG. 28A. As shown in FIG. 28A, the helical fastener 28 is, like the fastener shown in FIG. 27, an open coil 148 with a sharpened leading tip 142 . The proximal end 144 of the fastener 28 includes the carrier 150 .
[0098] The carrier 150 includes a slot 182 . The slot 182 engages a drive flange 184 on the driver 29 (see FIG. 25A) to impart rotation of the driver 29 to rotation of the helical fastener 28 during the implantation process. Like the L-shaped leg of the fastener shown in FIG. 27, the carrier 150 also serves as a stop to prevent the helical fastener from penetrating too far into the tissue.
[0099] The coupling engagement between the carrier 150 and the driver 29 could be accomplished in various ways, e.g., by separate graspers or grippers, a magnetic couple, or any other suitable mechanical connecting means. In the illustrated embodiment, the driver 29 is made of a magnetized material, and the carrier 150 is made from a material that is magnetically attracted toward the magnetized material. Of course, a reverse arrangement of magnetized and magnetically attracted materials could be used.
[0100] In this arrangement, the motor coupling 132 between the drive cable 30 and the motor 106 accommodates axial displacement of the motor cable 30 (left and right in FIGS. 25A and 25B) without interrupting the drive connection with the motor 106 . With the distal tip of the applier device 27 in contact with the prosthesis 14 (see FIG. 25A), the operator actuates the control unit 31 by contacting a control switch 110 . The control unit 31 commands the motor 106 to rotate the drive cable 30 to impart rotation to the driver 29 and the magnetically attached helical fastener 28 . This action causes the magnetically attached helical fastener 28 to be rotated into prosthesis 14 and the vessel wall 34 (see FIG. 25B). Due to the magnetic coupling, as the fastener 28 is deployed to the left in FIG. 25B, the driver 29 moves in tandem with carrier 150 (also to the left in FIG. 25B). Due to the magnetic coupling between the carrier 150 and the driver 29 , the operator must exert a deliberate separation force to decouple the carrier 150 (and, with it, the fastener 28 ) from the driver 29 . This arrangement prevents inadvertent release of a fastener 28 .
[0101] As before described, with the deployment of a fastener 28 , the applier 27 is retrieved through the directing device 18 , and another fastener 28 is magnetically coupled to the driver 29 . The directing device 18 is repositioned and stabilized, and the applier 27 is advanced again through the directing device 18 and into contact with the prosthesis 14 . The operator again actuates the control unit 31 by contacting a control switch 110 to deploy another fastener 28 . This process is repeated at both proximal and/or distal ends of the prosthesis 14 until the prosthesis 14 is suitably attached and sealed to the vessel wall 34 .
[0102] As indicated in the above description, the outer diameter of the applier component 27 is desirably sized and configured to pass through the lumen of the directing component 18 , which can take the form of a suitable steerable guide catheter, to direct the applier component 27 to the desired location. As also above described, the applier component 27 is desirably configured to implant one fastener 28 at a time (a so-called “single fire” approach). This is believed desirable, because it reduces the complexity of the design and accommodates access of the applier 27 through tortuous anatomy. Fastener appliers 27 which carry a single fastener can have a lower profile and may be more effective and less traumatic than fastener appliers which carry multiple fasteners. Still, in alternative embodiments, the applier component 27 may, if desired, be configured to carry multiple fasteners. Moreover, the fastener applier 27 may simultaneously deploy multiple fasteners in the preferred circumferentially spaced-apart space pattern described above.
[0103] a. Prosthesis/Tissue Contact Sensing
[0104] The fastener applier 27 desirably incorporates a function that prevents actuation of the motor 106 until the tip of the applier 27 is in a desired degree of contact with the prosthesis or tissue surface. This prevents inadvertent discharge of a fastener 28 and/or separation of the fastener 28 . This function can be implemented, e.g., using a contact or force sensor, which is either mechanical or electrical in design.
[0105] When the fastener applier 27 is of the type shown in FIGS. 14A. 14 B, and 14 C (see FIGS. 23 and 24), the contact or force sensing function can, e.g., utilize the distal tip 120 of the carrier 102 to transmit a contact force. This force can be transmitted to a force or contact sensing switch 122 located, e.g., within the fastener applier handle 108 . In this arrangement, the switch 122 can be part of the electrical circuit between the actuator switch 110 and the control unit 31 .
[0106] In the illustrated embodiment, the switch 122 includes a stationary switch element 128 (coupled to the interior of the handle 108 ) and a movable switch element 130 (carried by the drive cable 31 ). In this arrangement, the motor coupling 132 between the drive cable 30 and the motor 106 accommodates axial displacement of the motor cable 30 (left and right in FIGS. 23 and 24) without interrupting the drive connection with the motor 106 . The drive cable 30 is coupled by a bearing 134 to the movable switch element 130 , so that the switch element 130 moves in response to movement of the drive cable 30 . The stationary switch element 128 is not coupled to the movable drive cable 30 , which slidably passes through the switch element 130 .
[0107] Due to this arrangement, axial displacement of the drive cable 30 moves the switch element 130 relative to the switch element 128 . More particularly, displacement of the drive cable 30 to the left in FIG. 23 moves the switch element 130 to the left, away from the switch element 128 . Conversely, displacement of the drive cable 30 to the right in FIG. 23 moves the switch element 130 to the right, toward the switch element 128 .
[0108] A spring 126 normally biases the switch elements 128 and 130 apart, comprising an electrically opened condition. In this condition, operation of the actuating switch 110 does not serve to actuate the control unit 31 , as the electrically open switch 122 interrupts conveyance of the actuation signal to the motor control unit 31 . When the switch elements 128 and 130 are in the electrically opened condition, the drive cable 30 is displaced to the left to position the carrier tip 120 beyond the distal tip 124 of the fastener applier 27 . The carrier tip 120 therefore makes contact with the prosthesis 14 or tissue in advance of the applier tip 124 .
[0109] When the carrier tip 120 contacts the surface of the prosthesis or tissue with sufficient force to compress the spring 126 , the drive cable 30 is displaced against the biasing force of the spring to the right in FIG. 23. This moves the switch element 130 to the right. Ultimately, contact between the switch elements 128 and 130 will occur, as shown in FIG. 24. The contact establishes an electrically closed condition. In this condition, operation of the actuating switch 110 serves to actuate the control unit 31 . As shown in FIGS. 23 and 24, a contact screw 136 can be provided to adjust the amount of displacement required to close the switch elements 128 and 130 .
[0110] Upon removal of contact force, or in the absence of sufficient contact force, the spring 126 urges the switch elements 128 and 130 toward the electrically opened condition. The distal tip of the carrier 102 is located distally beyond the distal tip of the applier 27 .
[0111] It should be appreciated that the translation of movement of the carrier tip 120 to the switch 122 need not occur along the entire length of the drive cable 30 . For example, the switch 122 can be located in a translation space between the carrier 102 and the driver 29 . In this arrangement, the driver 29 , coupled to the drive cable 30 need not accommodate axial displacement. Instead, relative movement of the carrier 102 toward the driver 29 in response to contact with the prosthesis 14 will mechanically couple the carrier 10 with the driver 29 (e.g., through a slot and flange connection similar to that shown in FIGS. 25A and 25B), while also closing the switch 122 to energize the circuit between the actuator switch 110 and the motor control unit 31 .
[0112] When the fastener applier 27 is of the type shown in FIGS. 25A and 25B (see FIGS. 26A, 26B, and 26 C), the contact or force sensing function can, e.g., utilize a force sensing rod 190 that slidably passes through a central passage 192 in the carrier 150 ′ (the carrier 150 ′ is shown in FIG. 28B), the driver 29 and the drive cable 30 . The rod 190 is coupled to the movable switch element 130 . In this embodiment, the switch element 130 translates left and right over the drive cable 30 , which rotates on a bearing 134 within the switch element 130 .
[0113] As in the preceding embodiment, the spring 126 normally biases the switch elements 128 and 130 apart, comprising an electrically opened condition. When the switch elements 128 and 130 are in the electrically opened condition, the force sensing rod 190 is displaced to the left beyond the distal tip 124 of the fastener applier 27 . The force sensing rod 190 therefore makes contact with the prosthesis 14 or scaffold structure 16 in advance of the applier tip 124 .
[0114] When the rod 190 contacts the surface of the prosthesis or scaffold structure with sufficient force to compress the spring 126 , the rod 190 is displaced against the biasing force of the spring 126 to the right in FIG. 26A. This moves the switch element 130 to the right. Ultimately, contact between the switch elements 128 and 130 will occur, as shown in FIG. 26B. The contact establishes an electrically closed condition. In this condition, operation of the actuating switch 110 serves to actuate the control unit 31 . This action causes the helical fastener 28 to be rotated into the scaffold structure 16 and into the vessel wall 34 (see FIG. 26C). Due to the magnetic coupling between the driver 29 and carrier 150 ′, the driver 29 is moved in tandem with attached carrier 150 ′ to the left in FIG. 26B, as the fastener 28 is deployed. Also, due to the magnetic coupling between the carrier 150 and the driver 29 , the operator must exert a separation force to decouple the carrier 150 (and, with it, the fastener 28 ) from the driver 29 . As before described, this arrangement prevents inadvertent release of a fastener 28 . A contact screw 136 can be provided to adjust the amount of displacement required to close the switch elements 128 and 130 .
[0115] Upon removal of contact force, or in the absence of sufficient contact force, the spring 126 urges the switch elements 128 and 130 toward the electrically opened condition, moving the tip of the rod 190 out beyond the distal tip 124 of the applier 27 .
[0116] The contact or force sensing arrangements just described can also generate an audible and/or visual output to the operator, to indicate that sufficient contact force between the applier device 27 and the prosthesis or tissue exists.
[0117] B. Angled Component Fastener Guide and Attachment Assembly
[0118] In another arrangement (see FIG. 29), the fastener attachment assembly comprises a unitary, angled fastener guide and applier component 160 . In this arrangement, the component 160 includes a fastener drive mechanism 162 that places the carrier 164 holding the fastener 28 in a perpendicular or near perpendicular position with respect to the prosthesis or tissue. This configuration eliminates the need for a separate steerable guide component 18 for the fastener component 27 , previously described.
[0119] The drive mechanism 162 can vary. In the illustrated embodiment (shown in FIG. 29), the mechanism 162 includes a beveled drive gear 168 coupled to the drive cable 30 . The drive gear 168 operatively meshes with a transfer or pinion gear 170 , which is coupled to the carrier 164 . The axes of rotation of the drive gear 168 and pinion gear 170 are offset about ninety degrees, so that rotation of the drive cable 30 along the axis of the vessel is translated into rotation of the carrier 164 generally perpendicular to the wall of the vessel. The fastener guide and applier component 160 can be positioned and stabilized within the vessel in various ways, e.g., through the use external spring loaded strut or the like (as shown in association with the directing component 18 discussed above), or by use of an expandable member 166 (as FIG. 29 shows). The expansion member 166 can comprise either a balloon or mechanical expansion device. The expansion member 166 stabilizes the position of both the prosthesis and the fastener guide and applier component 160 within the vessel by resisting the force of blood until the prosthesis can be anchored.
[0120] As FIG. 30 shows, the fastener guide and applier component 160 can, if desired, provide an angled deployment between the drive cable 30 and carrier 164 that is somewhat less than ninety-degrees, to aid in intraluminal manipulation of the carrier into perpendicular contact position against the wall of the vessel. As FIG. 31 shows, the fastener guide and applier component 160 can, if desired, be articulated between the drive cable 30 and carrier 164 . In this arrangement, a remote control mechanism is desirable provided to move the carrier 164 from a first, generally straight position (shown in phantom lines in FIG. 31) for deployment to the targeted site, to a second, articulated position (shown in solid lines in FIG. 31) for alignment of the carrier 164 in contact against the vessel wall.
[0121] III. The Fasteners
[0122] As illustrated and described thus far, introduction of the fasteners 28 will typically be affected after the prosthesis 14 has been initially placed. That is, initial placement of the prosthesis 14 will be achieved by self-expansion or balloon expansion, after which the prosthesis 14 is secured or anchored in place by the introduction of a plurality of individual fasteners. The fasteners 28 may be placed only through the fabric of the prosthesis 14 , i.e., avoiding the scaffold structure. Alternately, the fasteners 28 can be introduced into and through portions of the scaffold structure itself. The prosthesis 14 may include preformed receptacles, apertures, or grommets, which are specially configured to receive the fasteners. The fasteners 28 may be introduced both through the fabric and through the scaffold structure. The fasteners can be introduced singly, i.e., one at a time, in a circumferentially spaced-apart pattern over an interior wall of the prosthesis 14 .
[0123] In the exemplary embodiment, the fasteners 28 are helical fasteners, so that they can be rotated and “screwed into” the prosthesis 14 and vessel wall. A desired configuration for the helical fastener 28 (see FIGS. 27, 28A, and 28 B) is an open coil 148 , much like a coil spring. This configuration allows the fastener 28 to capture a large area of tissue, which results in significantly greater holding force than conventional staples, without applying tissue compression, which can lead to tissue necrosis.
[0124] As FIGS. 27, 28A, and 28 B show, the leading tip 142 of the helical fastener 28 is desirable sharp to allow it to penetrate thought the artery wall and/or calcified tissue. This distal tip 142 can be sharpened to cut a helical path through the tissue or it can be sharpened to a point to penetrate the tissue without cutting.
[0125] The proximal end 144 of the fastener serves two design functions. The first function is to engage the carrier 102 of the fastener applier 27 , which rotates the helical fastener during the implantation process. The second function is to act as a stop to prevent the helical fastener from penetrating too far into the tissue.
[0126] In one embodiment (see FIG. 27), the proximal end 144 of the helical fastener 28 includes an L-shaped leg 146 of the coil 148 bisecting the fastener diameter. The leg 146 of the coil 148 comes completely across the diameter to prevent the fastener from being an open coil and to control the depth of penetration into the tissue. In addition, the leg 146 of the coil 148 can be attached to a previous coil to strengthen the entire structure and provide a more stable drive attachment point for the fastener applier. This attachment could be achieved via welding, adhesive or any other suitable means.
[0127] Alternatively (as shown in FIGS. 28A and 28B), the proximal end 144 of the fastener 28 could incorporate a separate cap or carrier 150 or 150 ′ that serves the same function as the leg 146 of the coil 148 in FIG. 27. The carrier 150 or 150 ′ could feature several methods to attach to the fastener applier drive mechanism 100 . These include separate graspers or grippers, a magnetic couple (as previously described), or any other suitable mechanical connecting means. In FIGS. 28A and 28B, the carrier 150 and 150 ′ includes a slot 180 and 182 ′ to mate with a drive flange (as previously described). As also previously described, a magnetic coupling is implemented between the carrier 150 and 150 ′ and the corresponding drive member, to prevent inadvertent separation during use.
[0128] In FIG. 28B, the carrier 150 ′ also includes a passage 152 for holding the contact/force sensing rod 190 shown in FIGS. 26A, 26B, and 26 C.
[0129] The fasteners 28 shown in FIGS. 27, 28A, and 28 B can be made from stainless steel or other types of implantable metal, however it is also envisioned that the fasteners in the above descriptions could be made from implantable polymers or from a biodegradable polymer or combinations of all materials thereof. Desirably, a fastener 28 will have between 2 and 10 turns and will be between 1 mm and 10 mm long. The space between the individual coils will be between 0.25 mm and 3 mm. The diameter of the fastener 28 will be between 1 mm and 6 mm.
[0130] IV. Prosthesis with Integrated Fastener Assembly
[0131] [0131]FIG. 32 shows a prosthesis 500 that includes at least one integrated fastener assembly 502 . FIG. 32 shows the prosthesis 500 deployed in a targeted intraluminal region, in particular, within an abdominal aortic aneurysm 504 . The prosthesis 500 can be deployed elsewhere in the body.
[0132] The prosthesis 500 desirably includes a fabric material or the like carried by a support frame or scaffold 504 , as previously described. The scaffold 504 can be made, e.g., from an elastic material that self-expands radially during deployment from a sheath, or from a malleable material that expands radially in response to a radially expansive force applied within the scaffold by a balloon or a mechanical expansion device.
[0133] Following deployment of the prosthesis 500 in the targeted region, the integrated fastener assembly 502 on the prosthesis 500 is manipulated to anchor the prosthesis 500 to the vessel wall. In the illustrated embodiment, the prosthesis 500 carries two integrated fastener assemblies 502 , one in each end region of the prosthesis 500 .
[0134] In the illustrated embodiment, each fastener assembly 502 is imbedded in a reinforced flange area 506 in the respective end region. Each fastener assembly 502 comprises an array of fasteners 508 circumferentially spaced about the flange 506 . The number of fasteners 508 in the array can vary, e.g., from about two to about twelve fasteners on each flange area 506 . The configuration of the array can also vary, e.g., in the circumferential array, the fasteners 508 can by axially spaced apart as well.
[0135] The fasteners 508 can be formed of a metal or plastic material and can be variously constructed. In the illustrated embodiment, each fastener 508 includes a disc-shaped head 512 and a stem 514 that is bifurcated into two wings 516 and 518 , which are joined by a plastic or memory material hinge region 520 . The material of the hinge region 520 is formed with a resilient memory that biases the wings 516 and 518 to a spread-apart condition (as FIG. 34 shows).
[0136] Each fastener 508 is carried within a grommet 510 on the flange area 506 (see FIG. 35). When the hinge region 520 is confined within the grommet 510 (as FIG. 35 shows), the wings 516 and 518 are retained against the resilient memory in an adjacent, closed condition. In response to the application of a pushing or punching force on the head 512 (see FIG. 35), the wings 516 and 518 are advanced in the closed condition out of the grommet 510 , and into and through the adjacent vessel wall (see FIG. 36). Upon continued advancement, the hinge region 520 is freed from the confines of the grommet 510 (see FIG. 37). As a result, the wings 516 and 518 resiliently spring into their normal spread-apart condition.
[0137] In this arrangement, an intraluminal tool 522 (see FIG. 33) is deployed into the prosthesis 500 to exert a pushing or punching force upon the head 512 of a given fastener 508 . In the illustrated embodiment, the tool 522 comprises a catheter 524 that carries a punch member 526 at its distal end. In a desired arrangement, the distal end of the catheter 524 is steerable, to aid in establishing point contact between the punch member 526 and the head 512 of the given fastener 508 . The head 512 can include a recess 528 to receive and stabilize the tip of the punch member 526 with respect to the head 512 during use (see FIG. 34).
[0138] In use, the punch member 526 is manipulated to apply a pushing or punching force upon the selected fastener head 512 . As FIGS. 35 and 36 show, the application of the pushing force by the punch member 526 forces the wings 516 and 518 against the near side of the vessel wall 34 . The wings 516 and 518 are still in their closed condition, because the hinge region 520 is still confined within the grommet 510 . The closed wings 516 and 518 form an obturator that penetrates tissue as it advances to the far side of the vessel wall. As the hinge region 510 is freed from the grommet 510 (FIG. 37), the wings 516 and 518 resiliently return to their spread-apart condition against the far side of the vessel wall. Upon removal of the punch member 526 (see FIG. 38), the head 512 and spread-apart wings 516 and 518 remain in their mutually opposed condition in the vessel wall, to secure the prosthesis 500 against the vessel wall. In use, the physician locates and manipulates the punch member 526 in succession against each fastener 508 , to complete the anchorage of the prosthesis 500 to the vessel wall.
[0139] In one embodiment (see FIG. 39), each fastener 508 can include a tracking wire 530 that is releasably coupled to the head 512 . The tracking wire 530 extends from the head 512 outside the body for access outside the vessel. In this arrangement, the punch member 526 includes a lumen to accommodate passage of the tracking wire 530 . The tracking wire 530 guides the punch member 526 in an intraluminal path to the respective fastener 508 . After the punch member 526 is manipulated to drive the fastener 508 into the vessel wall, the punch member 526 can be withdrawn over the tracking wire 530 . The tracking wire 530 can be released from the now-secured head 512 , e.g., by applying a moderate pulling force upon the tracking wire 530 . The tracking wire 530 can then be withdrawn. The punch member 526 is sequentially guided over another tracking wire 530 for interaction with another one of the fasteners 508 , until a desired degree of anchorage is achieved.
[0140] In an alternative embodiment, an integrated fastener assembly 502 on the prosthesis 500 can be used to temporarily tack the prosthesis 500 in place while a permanent anchoring technique is carried out. For example, in this arrangement, after using the integrated fastener assembly 502 to temporarily hold the prosthesis 500 in a desired location, the separate helical fasteners 28 are deployed in the manner previously described, to permanently anchor the prosthesis 500 against the vessel wall.
[0141] It will be appreciated that the components and/or features of the preferred embodiments described herein may be used together or separately, while the depicted methods and devices may be combined or modified in whole or in part. It is contemplated that the components of the directing device, fastener applier and helical fastener may be alternately oriented relative to each other, for example, offset, bi-axial, etc. Further, it will be understood that the various embodiments may be used in additional procedures not described herein, such as vascular trauma, arterial dissections, artificial heart valve attachment and attachment of other prosthetic device within the vascular system and generally within the body.
[0142] The preferred embodiments of the invention are described above in detail for the purpose of setting forth a complete disclosure and for the sake of explanation and clarity. Those skilled in the art will envision other modifications within the scope and sprit of the present disclosure.
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Systems and method implant prostheses in the body. The systems and methods provide permanent attachment of the prosthesis in the body. The prosthesis can comprise, e.g., an endovascular graft, which can be deployed without damaging the native blood vessel in either an arterial or a venous system. The endovascular graft can comprise, e.g., a radially expanding vascular stent and/or a stent-graft. The graft can be placed in the vasculature, e.g., to exclude or bridge an aneurysm, for example, an abdominal aortic aneurysms. The graft desirably adapts to changes in aneurysm morphology and repairs the endovascular aneurysm. The fastening systems and methods can be deployed through the vasculature and manipulated from outside the body, to deliver a fastener to attach the graft to the vessel wall.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an apparatus for organic synthesis and reactions and, more particularly, to an apparatus which is used for organic synthesis and reactions and permits analysis of reaction mechanisms and reaction intermediate structures.
[0003] 2. Description of Related Art
[0004] A technique for causing plural substances to mix and react with each other in a quite small space is known as microchip technology or microreactor technology and expected to be put into practical use to provide increased chemical reaction rates and improved efficiencies.
[0005] Microchip reactors for chemical synthesis are often made of glass because of their excellent chemical resistance. Since it is difficult to directly connect a tube, which is used to introduce a synthesis reagent, with a microchannel in a microchip made of glass, it is customary to connect the tube with a holder via a connector after the microchip reactor is held with the holder.
[0006] At tube joints, O-rings are often used to prevent liquid leakage. Therefore, eluates from rubber members and dead volume often present problems. In one available method, a tube is adhesively fixed to the surface of a glass reactor. However, depending on the used solvent, there is the possibility that the adhesive dissolves out. Furthermore, it is possible to machine a threaded structure into a glass material, the structure being used for connection of tubes of liquid chromatographs. Nonetheless, a high level of technique is required to machine the structure, and high cost is necessary.
[0007] Furthermore, a reagent solution having high viscosity may be used depending on the kind of synthesis reaction. The reagent may clog up the channel after introduction of the reagent. Especially, the channel tends to be clogged up near tube joints.
[0008] Microreactor products used for chemical synthesis have already been sold from some manufacturers. The microreactors are chiefly made of glass. A digital representation of a commercially available microreactor for mixing of two reagents is shown in FIG. 7 . The glass microreactor is composed of two plates. A microchannel is formed in one of the plates. A fluid inlet hole and a fluid exit hole are formed in the other. The two plates are bonded together by thermocompression.
[0009] This microreactor is held to a holder. Tubes for introduction of reagents are connected with the microreactor using connectors. The tubes are connected with syringe pumps. Reagent solutions are introduced into the microreactor by the syringe pumps. The introduced reagents are made to meet at the Y-shaped portion of the channel and mixed. The reagents are made to react with each other in the downstream channel, thus producing reaction products.
[0010] A well-known on-line method of detecting reaction products is a thermal lens microscope technique. Where a measurement is performed using a mass spectrometer (MS) or nuclear magnetic resonance spectrometer (NMR) to make structural analysis of reaction products, it is required that the reaction products be collected at the exit of the microreactor and that the sample be introduced into the MS or NMR off-line.
[0011] Vigorous research is now underway to connect a microchip reactor or microreactor having various functions with an MS or NMR having high qualitative analysis capabilities in an on-line manner to perform analyses. See Japanese Utility Model No. S57-75558 and Published Technical Report No. 2004-502547 of the Japan Institute of Invention and Innovation. There are the following research reports:
[0012] (1) Microchip-NMR
[0013] A monograph has been published describing research in which a circular liquid reservoir is formed in a channel within a microchip reactor as shown in FIG. 8 , a microcoil is brought close to the reservoir, and a trace amount of sample is investigated. J. H. Walton et al., Analytical Chemistry, Vol. 75, pp. 5030-5036 (2003). Microcoils or probes dedicated for microchip reactors are at a research stage. There are almost no applications to chemical synthesis.
[0014] (2) Flow NMR
[0015] Reaction reagents are mixed and reacted with each other using a static mixer. The reaction liquid is guided into a probe for flow NMR via a line, and an NMR measurement is performed. This research is at a practical level. The experiment needs a flow NMR probe. Furthermore, there is a drawback that the distance from the reaction portion to the position in the NMR magnet irradiated with an RF magnetic field is long.
[0016] (3) Microchip-MS
[0017] As shown in FIG. 9 , when a microchip reactor is fabricated, a nanoelectrospray nozzle is integrated with the microchip reactor. J. Kameoka et al., Analytical Chemistry, Vol. 74, pp. 5897-5901 (2002). Mass analysis is enabled by applying a high voltage to the nozzle. There are more applications in the biological field than in synthetic chemistry.
[0018] Microchip reactors and microreactors for chemical analysis have the following problems.
[0019] (1) Since the microreactor is of the integrated construction, parts cannot be replaced. Therefore, if the channel or a tube joint is clogged up, the whole microreactor must be replaced. If the microreactor is made of glass, the running cost is high.
[0020] (2) Eluates from the material of the connector and dead volume present problems.
[0021] (3) When reaction products are detected on-line, usable detectors are limited to those using absorption of light.
[0022] (4) When structural analysis of reaction products is performed using an analytical instrument, it is normally necessary to introduce a sample in an off-line manner.
[0023] Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of an NMR is performed, there are the following problems:
[0024] (1) It is necessary to design and develop a dedicated NMR probe. This needs an exorbitant amount of initial investment.
[0025] (2) Since the design of the microchip reactor is dedicated for NMR, it is difficult to connect the reactor directly with other detectors.
[0026] Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of a flow NMR spectrometer is performed, there are the following problems.
[0027] (1) It is necessary to design and develop a dedicated flow probe. This necessitates a huge amount of initial investment.
[0028] (2) It is difficult to place the reaction portion into the probe. Normally, the reaction portion is placed outside the magnet. Consequently, there is a time lag from reaction to detection.
[0029] Where on-line detection using a combination of a microchip reactor and an analytical instrument consisting of an MS is performed, there are the following problems:
[0030] (1) There are only few examples of application to chemical synthesis.
[0031] (2) The design of the microchip reactor is dedicated for MS. It is difficult to connect the microchip reactor directly with other detectors.
SUMMARY OF THE INVENTION
[0032] The present invention has been made in view of the foregoing problems. It is an object of the present invention to provide a microchip reactor which is for use in organic synthesis and which can be used in combination with many analytical instruments.
[0033] This object is achieved in accordance with the teachings of the present invention by an organic synthesis reactor in which fluids are mixed in a very narrow space and reacted in multiple stages. The reactor has an introduction portion for introducing plural reagents from plural channels and a reaction portion disconnectably connected with the introduction portion. Where needed, the introduction portion mixes the introduced reagents and causes them to react with each other. In the reaction portion, a reagent or reaction liquid introduced from the introduction portion is mixed and reacted with other reagents. The introduction portion has an inlet channel for introducing a reagent, introduced from the outside, into the reaction portion and a first discharge channel for discharging the reaction liquid, discharged from the reaction portion, to the outside. The reaction portion has a reaction channel in communication with the inlet channel and a second discharge channel. The reaction channel causes plural reagents sent in from the inlet channel to mix and react. The second discharge channel places the reaction channel into communication with the first discharge channel to return the reaction liquid produced in the reaction channel to the introduction portion.
[0034] In one feature of the present invention, the introduction portion is a microchip having a substrate made of a resin having chemical resistance. The substrate is provided with a microchannel. The reaction portion is a microchip having a substrate made of glass or quartz, the substrate being provided with a microchannel.
[0035] In another feature of the present invention, the introduction portion has an inlet hole for introducing a reagent and a discharge hole for discharging the reaction liquid. The inlet hole and the discharge hole are flush with each other.
[0036] In a further feature of the present invention, the microchannels are formed on both surfaces of the substrate made of glass or quartz by wet etching or drilling. Then, the substrate having the microchannels is sandwiched between two plates of glass or quartz. The substrate and the plates are bonded together by thermocompression, thus completing the reactor.
[0037] In yet another feature of the present invention, the substrate has a thickness of 1 to 5 mm.
[0038] In an additional feature of the present invention, the reaction portion has been finished in a cylindrical or prismatic form having a length of 50 to 300 mm and a maximum width of 2 to 10 mm.
[0039] In still another feature of the present invention, the microchannels have a width and a depth of 50 to 500 μm.
[0040] In yet an additional feature of the present invention, the reaction portion has a detection portion used in combination with an analytical instrument for analyzing the reaction liquid.
[0041] In still a further feature of the present invention, the analytical instrument is at least one of NMR, ESR, and thermal lens microscope.
[0042] In an additional feature of the present invention, an electrospray nozzle for use in combination with a mass spectrometer (MS) for analyzing the reaction liquid is mounted in the discharge hole in the introduction portion for discharging the reaction liquid.
[0043] Because the organic synthesis reactor according to an embodiment of the present invention is designed as described above, the reactor can be fabricated in a microchip form capable of being used in combination with many analytical instruments.
[0044] Other objects and features of the invention will appear in the course of the description thereof, which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] FIGS. 1A, 1B and 1 C schematically show an organic synthesis reactor according to one embodiment of the present invention;
[0046] FIGS. 2A, 2B and 2 C schematically show an organic synthesis reactor according to another embodiment of the present invention;
[0047] FIGS. 3A and 3B schematically show an organic synthesis reactor according to a further embodiment of the present invention;
[0048] FIG. 4 is a cross-sectional view of a thermal lens microscope that embodies an organic synthesis reactor according to an embodiment of the present invention;
[0049] FIG. 5 is a cross-sectional view of an NMR spectrometer that embodies an organic synthesis reactor according to an embodiment of the present invention;
[0050] FIG. 6 is a cross-sectional view of a mass spectrometer that embodies an organic synthesis reactor according to an embodiment of the present invention;
[0051] FIG. 7 shows a commercially available microchip;
[0052] FIG. 8 shows a related-art technique in which a microchip is applied to an NMR spectrometer; and
[0053] FIG. 9 shows another related-art technique in which a microchip is applied to a mass spectrometer.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0054] Embodiments of the present invention are hereinafter described with reference to the accompanying drawings.
FIRST EMBODIMENT
[0055] Referring to FIGS. 1A, 1B and 1 C, there is shown an organic synthesis reactor according to one embodiment of the present invention. The reactor has a reagent introduction-and-reaction portion 2 that is connected at a contact portion 4 with an extensional reaction portion 1 via a connector jig 3 .
[0056] The extensional reaction portion 1 is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate 1 a is provided with a through-hole 12 to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.
[0057] The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.
[0058] The glass substrate having the microchannels are then held between two glass plates. The glass substrate 1 a and glass plates 1 b , 1 c are bonded together by thermocompression. The whole assembly is finished in a cylindrical or prismatic form by a cutting technique. Alternatively, a glass stock may be machined into a semicylindrical form, and microchannels may be formed in this semicylindrical form. Preferably, the length of the extensional reaction portion 1 is 50 to 300 mm. The diameter of the cylindrical form or the maximum width of the prismatic form is 2 to 10 mm.
[0059] Screw holes are formed in the reagent introduction-and-reaction portion 2 to permit connection of tubes. Also, channels are formed in this portion 2 . When the extensional reaction portion 1 and the reagent introduction-and-reaction portion 2 have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels.
[0060] The connector jig 3 has guide portions to facilitate aligning the extensional reaction portion 1 and reagent introduction-and-reaction portion 2 . The contact portion 4 is surface-treated or used in combination with a sealant to prevent liquid leakage.
[0061] Three reagent inlet holes 5 are formed in the reagent introduction-and-reaction portion 2 . Two of the three inlet holes 5 meet each other and are combined into one conduit immediately ahead of a first reaction portion 7 formed within the reagent introduction-and-reaction portion 2 . The conduit passes through the first reaction portion 7 of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit is in communication with a first reaction liquid channel 8 formed in the extensional reaction portion 1 .
[0062] A reagent inlet channel 6 extends from the remaining one of the reagent inlet holes 5 and meets the first reaction liquid channel 8 in a second reaction-and-mixture portion 9 formed in the extensional reaction portion 1 , thus forming one conduit. This conduit is in communication with a second reaction portion 10 of the bent (e.g., serpentine) channel, where a second reaction between the reagents is induced.
[0063] The second reaction portion 10 is in communication with a detection channel 11 of the bent (e.g., serpentine) channel. The second reaction portion 10 passes through a through-hole 12 and reaches the rear side of the extensional reaction portion 1 , the through-hole 12 being formed in the vertical direction. The second reaction portion 10 then passes into the reaction liquid discharge hole 14 through a reaction liquid discharge channel 13 . The three reagent inlet holes 5 and reaction liquid discharge hole 14 are formed in the same side surface of the reagent introduction-and-reaction portion 2 .
[0064] In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent introduction-and-reaction portion 2 and extensional reaction portion 1 . That is, the present embodiment is characterized in that there are two layers of channels.
[0065] Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent introduction-and-reaction portion 2 is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the extensional reaction portion 1 is made of glass or quartz.
[0066] Where viscous reagents are used, the channels inside the reagent introduction-and-reaction portion 2 tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the extensional reaction portion 1 .
SECOND EMBODIMENT
[0067] FIGS. 2A, 2B and 2 C show an organic synthesis reactor according to another embodiment of the present invention. The reactor has a reagent inlet portion 22 that is connected at a contact portion 24 with a reagent reaction portion 21 via a connector jig 23 .
[0068] The reagent reaction portion 21 is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate is provided with a through-hole 33 to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.
[0069] The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.
[0070] The glass substrate having the microchannels is then held between two glass plates. The glass substrate and glass plates are bonded together by thermocompression. The whole assembly is finished in a cylindrical or prismatic form by a cutting technique. Alternatively, a glass stock may be machined into a semicylindrical form, and microchannels may be formed in this semicylindrical form. Preferably, the length of the reagent reaction portion 21 is 50 to 300 mm. The diameter of the cylindrical form or the maximum width of the prismatic form is 2 to 10 mm.
[0071] Screw holes are formed in the reagent inlet portion 22 to permit connection of tubes. Also, channels are formed in the inlet portion 22 . When the reagent reaction portion 21 and the reagent inlet portion 22 have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels.
[0072] The connector jig 23 has guide portions to facilitate aligning the reagent reaction portion 21 and reagent inlet portion 22 . The contact portion 24 is surface-treated or used in combination with a sealant to prevent liquid leakage.
[0073] Three reagent inlet holes 25 are formed in the reagent inlet portion 22 and are in communication with three reaction liquid channels 27 , respectively, formed in the reagent reaction portion 21 .
[0074] Two of the three inlet holes 25 meet each other and are combined into one conduit in the first reaction-and-mixture portion 28 . The conduit is in communication with the first reaction portion 29 of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit then meets another reaction liquid channel 27 in the second reaction-and-mixture portion 30 to form one conduit which is in communication with the second reaction portion 31 of the bent (e.g., serpentine) channel, where a second reaction between the reagents is induced.
[0075] The second reaction portion 31 is in communication with a detection channel 32 of the bent (e.g., serpentine) channel. The detection channel 32 passes through a through-hole 33 and reaches the rear side of the reagent reaction portion 21 , the through-hole 33 being formed in the vertical direction. The second reaction liquid then passes into the reaction liquid discharge hole 35 through a reaction liquid discharge channel 34 . The three reagent inlet holes 25 and reaction liquid discharge hole 35 are formed in the same side surface of the reagent inlet portion 22 .
[0076] In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent inlet portion 22 and reagent reaction portion 21 . That is, the present embodiment is characterized in that there are two layers of channels.
[0077] Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent inlet portion 22 is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the reagent reaction portion 21 is made of glass or quartz.
[0078] Where viscous reagents are used, the channels inside the reagent inlet portion 22 tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the reagent reaction portion 21 .
THIRD EMBODIMENT
[0079] FIGS. 3A and 3B show an organic synthesis reactor according to a further embodiment of the present invention. The reactor has a reagent inlet portion 52 that is connected at a contact portion 54 with a reagent reaction portion 51 via a connector jig 53 and using screws 55 .
[0080] The reagent reaction portion 51 is made of a glass substrate having a thickness of 1 to 5 mm. Microchannels are formed on both surfaces of the glass substrate by wet etching or drilling. The glass substrate is provided with a through-hole 64 to permit a reagent solution to flow from the channel in the front surface to the channel in the rear surface.
[0081] The width and depth of the channels are 50 to 500 μm. The design of the channels and machining method can be modified according to the purpose of use.
[0082] The glass substrate having the microchannels is then held between two glass plates. These glass substrate and glass plates are bonded together by thermocompression. One end portion of the assembly is cut into an elongated T-shaped form. The end portion of the reagent reaction portion 51 is shaped like the letter T to press and join the reagent inlet portion 52 by the connector jig 53 . The T-shaped end portion of the reagent reaction portion 51 is made asymmetrical right and left to prevent the senses of the reagent reaction portion 51 and reagent inlet portion 52 from being confused when they are connected. The connector jig 53 has a structure for recognizing the asymmetrical portion or an asymmetrical fitting portion.
[0083] Screw holes are formed in the reagent inlet portion 52 to permit connection of tubes. Also, channels are formed in the inlet portion 52 . When the reagent reaction portion 51 and the reagent inlet portion 52 have been connected, their channels are aligned. Consequently, a reagent solution can be passed through the channels. The contact portion 54 is surface-treated or used in combination with a sealant to prevent liquid leakage.
[0084] Three reagent inlet holes 56 are formed in the reagent inlet portion 52 and are in communication via three reagent inlet channels 57 , respectively, with three reaction liquid channels 58 , respectively, formed in the reagent reaction portion 51 .
[0085] Two of the three inlet holes 56 meet each other and are combined into one conduit in the first reaction-and-mixture portion 59 . The conduit is in communication with the first reaction portion 60 of the bent (e.g., serpentine) channel, where a first reaction between reagents is produced. The conduit then meets another reaction liquid channel in the second reaction-and-mixture portion 61 to form one conduit which is in communication with the second reaction portion 62 of the bent channel, where a second reaction between the reagents is induced.
[0086] The second reaction portion 62 is in communication with a detection channel 63 of the bent channel. The second reaction liquid passes through a through-hole 64 and reaches the rear side of the second reagent reaction portion 62 , the through-hole 64 being formed in the vertical direction. The second reaction liquid then passes into the reaction liquid discharge hole 66 through a reaction liquid discharge channel 65 . The three reagent inlet holes 56 and reaction liquid discharge hole 66 are formed in the same side surface of the reagent inlet portion 52 .
[0087] In this way, in the present embodiment, the microchannels in the microchip are formed in both top surface side and bottom surface side of the reagent inlet portion 52 and reagent reaction portion 51 . That is, the present embodiment is characterized in that there are two layers of channels.
[0088] Preferably, the material of the organic synthesis reactor is so selected that the reactor can be used in a temperature range from −70° C. to +200° C. To permit mass production using a molding technique, the reagent inlet portion 52 is preferably made of a chemical-resistant resin, such as PEEK (polyetheretherketone), Teflon™, or Diflon. Preferably, the reagent reaction portion 51 is made of glass or quartz.
[0089] Where viscous reagents are used, the channels inside the reagent inlet portion 52 tend to be clogged up especially easily. Consequently, it can be anticipated that the running cost of the reactor in operation will be reduced by designing this portion tending to be clogged up as a replaceable external part attached to the reagent reaction portion 51 .
FOURTH EMBODIMENT
[0090] FIG. 4 shows one embodiment of the present invention in which such an organic synthesis reactor is mounted in various analytical instruments. Liquid delivery modules 36 , 37 , and 38 , such as syringe pumps, are connected with the organic synthesis reactor by tubes, such as capillaries.
[0091] Reagent solutions sent out from the liquid delivery modules 36 and 37 are mixed by a mixing portion 28 where channels intersect. The solutions are reacted in a first reaction portion 29 . The reagent solutions reacted in the first reaction portion are mixed with a reagent introduced from the liquid delivery module 38 in a mixing portion 30 located immediately behind the first reaction portion 29 . Thus, a second stage of reaction is induced in a second reaction portion 31 . Instead of the reagent, a reaction inhibitor or diluting solvent may be introduced from the liquid delivery module 38 . The reaction liquid obtained in the second reaction portion 31 is introduced into a detection channel 32 , where the reaction products are detected by a thermal lens microscope 39 . Then, the reaction liquid is discharged out of the organic synthesis reactor from a reaction liquid discharge hole 35 through a through-hole 33 and through a reaction liquid discharge channel 34 in the rear surface. The liquid is then recovered.
FIFTH EMBODIMENT
[0092] FIG. 5 shows an embodiment of the present invention in which the organic synthesis reactor is mounted in an NMR spectrometer. The organic synthesis reactor can be directly attached to the NMR spectrometer 40 of normal construction. The reactor and liquid delivery modules are connected by tubes, such as capillaries. The reactor is mounted to an NMR sample tube holder having a diameter of 5 mm and to a rotor and inserted into an NMR probe having a diameter of 5 mm (finding the widest use). Under this condition, the reactor is used instead of an NMR sample tube. The organic synthesis reactor may also be combined with an electron spin resonance (ESR) spectrometer by a similar method.
SIXTH EMBODIMENT
[0093] FIG. 6 shows an embodiment of the present invention in which the organic synthesis reactor is mounted in a mass spectrometer (MS). With the organic synthesis reactor, MS detection can be easily performed simply by connecting a nano-electrospray nozzle 41 to a reaction liquid discharge hole 35 . The operation regarding introduction of reagents is the same as in the third and fourth embodiments. In this embodiment, the reaction liquid is discharged from the nano-electrospray nozzle 41 . Mass spectra of the reaction products within the reaction liquid can be measured by electrospray ionization caused by application of a high voltage.
[0094] The present invention can find wide application in research into organic synthesis and reactions.
[0095] Having thus described our invention with the detail and particularity required by the Patent Laws, what is desired protected by Letters Patent is set forth in the following claims.
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An organic synthesis microreactor mixes fluids in a very narrow space and causes the fluids to react in multiple stages. The reactor consists of an introduction portion and a reaction portion disconnectably connected. The introduction portion introduces reagents from channels and, if necessary, mixes and reacts the reagents. The reaction portion accepts a reagent or reaction liquid from the introduction portion and mixes and reacts the reagent or reaction liquid with other reagent.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of plating treatment, particularly to a method of applying partial plating to the surface of a workpiece of such material as metal, ceramic or plastic.
2. Description of the Prior Art
Method are known for forming plated electrically conductive coatings which serve as electrodes or circuit patterns in the production of electronic parts, circuit boards or the like, there is a plating method. There are two plating methods: electroplating and electroless plating. Whether one plating method or the other is employed, a plated coating will be formed on the entire surface of a workpiece unless some measure is taken. However, it is important to form said electrode and circuit patterns on localized portions of the surface of an electronic part or circuit board; therefore, in forming such electrode and circuit patterns, there arises a need for taking measures to ensure localized formation of a plated coating.
Japanese Pat. Application Laid-Open Specification No. 162789/1985 filed by the assignee of this application discloses a method of locally forming a plated coating on the surface of a workpiece by using an elastic member of natural rubber, cork or the like placed in close contact with part of the surface of said workpiece to thereby prevent a plating solution from contacting the area covered by the elastic member. In a typical example of the disclosed method, to form a plated coating on a board having a through-hole except on the inner peripheral surface of said through-hole, said board is subjected to a plating treatment with a plug-like elastic member fitted in the through-hole. According to this technique disclosed in said specification, however, it has been found that the following problems are encountered.
It frequently happens that an elastic member fitted in the through-hole slips out of the through-hole depending on its shape and size, so that plating is applied also to the inner peripheral surface of the through-hole where plating is not desired.
On the other hand, to make it difficult for the elastic member to slip out of the through-hole, an elastic member of relatively large diameter could be used. In this case, however, it becomes difficult to insert the elastic member into the through-hole, so that the operation of insertion is not efficient. Further, if a material of relatively low elasticity is used, the workpiece and/or the elastic member tends to break during insertion into or extraction from the through-hole.
SUMMARY OF THE INVENTION
Accordingly, an object of the invention is to provide a method of forming a plated coating on the surface of a workpiece except on a portion thereof, while solving the problems described above.
A method of plating treatment according to the invention is characterized by the use of a masking member made from water swelling rubber. More specifically, a method of plating treatment according to the invention comprises the steps of preparing a masking member made from water swelling rubber; disposing said masking member in opposed relation to the plating-undesired region of the surface of a workpiece where no plating is desired; imparting water to the masking member to thereby bring about the volumetric self-swelling of the water swelling rubber which constitutes the masking member so as to ensure that the masking member closely contacts the plating-undesired region of the surface of the workpiece; where no plating desired immersing the workpiece in a plating bath with the masking member closely contacted with the plating-undesired region, thereby applying plating to the surface of the workpiece except the region protected by the masking member against entrance of the plating solution.
The types of "water swelling rubber" used in this invention include a first type prepared by specially modifying synthetic rubber so that hydrophilic portions are linked by hydrogen bonds to water molecules thereby to undergo volumetric self-swelling, a second type prepared by mixing a water swelling resin with synthetic rubber, such as chloroprene, and molding and vulcanizing the mixture, and a third type prepared by mixing non-swelling material and swelling material. For example, use may be made of commercially available unvulcanized butyl rubber type sealing material, composite butyl rubber type seal material, vulcanized rubber type seal material, and tar-urethane type seal material.
According to the invention, in the step of disposing the masking member, the masking member is brought into abutment against or in close, proximity to the workpiece, and in the step of imparting water to the masking member, the masking member is immersed in water, for example, to bring about the volumetric water swelling of the water swelling rubber which constitutes the masking member. Such volumetric self-swelling causes the masking member to closely contact the plating-undesired region of the surface of the workpiece where no plating is desired. In this state, when the workpiece is immersed in a plating bath, the masking member prevents the plating solution from entering the region of the workpiece intimately contacted by the masking member. In this manner, a plated coating can be formed only on a limited region of the surface of a workpiece.
As for the method of disposing a masking member in opposed relation to a plating-undesired region of the surface of a workpiece where no plating is desired, various preferable manners may be considered depending on the shape of the workpiece and the location of the plating-undesired region. For example, in the case where plating-undesired regions of a workpiece to be treated where no plating is desired are opposed to each other, the masking member should be disposed so that it is held between these opposed regions, and in this state the masking member should be allowed to undergo volumetric self-swelling so that it is pressed against both of the opposed regions. An example of such opposed regions is at least two opposed regions of the peripheral surface of a hole formed in a workpiece. In the case where the formation of a plated coating on the entire region of the inner peripheral surface of the hole is not desired, the masking member should be inserted into this hole and then allowed to undergo volumetric self-swelling to thereby seal the opening of the hole. Further, in the case where a workpiece has a region on its outwardly directed surface, while using a holding member opposed, to said outwardly directed surface where no plating is desired with a given distance defined therebetween, the masking member should be disposed between said holding member and said outwardly directed surface. In addition, said holding member is preferably formed with through-holes, at least in its area contacted by the masking member, which allow water to pass therethrough.
The step of imparting water to the masking member to cause the water swelling rubber to undergo volumetric self-swelling may be performed in any stage so long as it precedes plating. In the usual plating treatment, prior to the formation of plated coatings, such pre-treatments as degreasing, sensitizing and activating, are performed. The masking member may be immersed in water before or after of any one of these pre-treatments or between adjacent pre-treatments. Water is typically imparted to the masking member is typically effected by immersing it in water. In addition, when an aqueous solution is used in said sensitizing or activating treatment, it is possible to utilize the water contained in such aqueous solution to cause the masking member to undergo volumetric self-swelling. That is, sensitizing or activating treatment can be effected at the same time as the volumetric self-swelling of the masking member.
In addition, to remove the making member upon completion of the formation of the plated coating, though it may be removed in its volumetric self-swelling state, it is preferable that the removal be effected after the masking member has been dried. The reason is that the drying contracts the masking member to allow the latter to be extracted with ease. In addition, in the case where the drying has to be accelerated, the masking member may be heated.
As for the masking member, it is preferable to use one which is superior in both acid and alkali resistances. This is because many of the plating baths are highly acidic or alkaline. This has significance that this prevents the inherent function of the masking member from being degraded during the plating step and, furthermore, this has another significance that this allows the masking member to be used repeatedly and in this respect contributes to decreasing the treating cost. In addition, in the case where the masking member is subjected to such treatments as degreasing, sensitizing and activating, it is preferable that the masking member be superior in resistance to chemicals and to organic solvents as well as superior in acid and alkali resistances.
These objects and other objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of the present invention when taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a sectional view of a workpiece to be treated for explaining an embodiment of the invention showing the stat subsequent to the completion of the plating step;
FIG. 2 is a perspective view of a masking member used in another embodiment of the invention;
FIG. 3 is a sectional view showing the masking member of FIG. 2 disposed in contact with the inner peripheral surface of a cylindrical workpiece to be treated; and
FIG. 4 is a perspective view for explaining a further embodiment of the invention, showing an annular masking member surrounded with by an annular holding member, the annular masking member being placed on the outer peripheral surface of a bar-like workpiece to be treated.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIG. 1, a board 1, such as a circuit board, made of ceramic material, such as alumina, is prepared as a workpiece. This board 1 has a through-hole 2 formed therein. In the board 1, it is the inner peripheral surface of the through-hole 2 that is the region where no plating is desired, and the two main surfaces of the board 1 are formed with plated coatings 3 and 4, respectively. To perform such plating treatment, the following method is adopted.
First, a masking member 5 made of water swelling rubber is prepared, said masking member 5 having a diameter which is equal to or somewhat smaller than the diameter of the through-hole 2. The masking member 5 is intended to be inserted into the through-hole 2, and as a result of the swelling which takes place in the subsequent step, the masking member is pressed against the inner peripheral surface of the through-hole 2, thereby preventing the inner peripheral surface of the through-hole 2 from being formed with a plated coating.
So long as this purpose can be attained, it does not matter whether the cross section of the masking member 5 is circular or otherwise. As for the type of the water swelling rubber constituting the masking member 5, one is used which will swell about 1.2 to 3 times the original volume when it absorbs water. In addition, a resin may be used which limits swelling with respect to the direction of the long axis of the masking member 5.
The masking member 5, in its dry state, is inserted into the through-hole 2, as previously described. Then, the masking member 5, together with the board 1, is immersed in water. As a result, the masking member 5 undergoes volumetric self-swelling to function as a plug for closing the through-hole 2; the masking member 5 is pressed against the inner peripheral surface of the through-hole 2.
Subsequently, the board 1, with the masking member 5 pressed against the inner peripheral surface of the through-hole 2, is immersed in a plating solution and plated coatings 3 and 4 are formed by electroless plating. At this time, since the masking member 5 is pressed against the inner peripheral surface of the through-hole 2, the plating solution is prevented from contacting the inner peripheral surface of the through-hole 2 and hence no plated coating is formed on the inner surface of the through-hole 2.
When the masking member 5, together with the board 1, is dried, the masking member 5 is contracted, so that it can be easily extracted from the through-hole 2.
In the case where a workpiece is in the form of a cylinder having an inner peripheral surface and the plating-undesired region where no plating is desired thereof is an annular region circumferentially extending on said inner peripheral surface, a masking member 11 as shown in FIG. 2 is advantageously used.
Referring to FIG. 2, a base member 12 in the form of a pipe made of relatively rigid plastic is prepared. The masking member 11 is annularly formed on the outer peripheral surface of the base member 12. The masking member 11 is made of water swelling rubber as in the masking member 5 shown in FIG. 1.
Referring to FIG. 3, a cylindrical body 13 which is a workpiece is shown. The cylindrical body 13 has an inner surface 14. The region where no plating is desired in the cylindrical body 13 is an annular region 15 which extends circumferentially on the inner peripheral surface 14. The masking member 11 held on the base member 12 shown in FIG. 2 is inserted along the inner peripheral surface 14 of the cylindrical body 13 until it is positioned in opposition to the annular region 15. In this state of insertion, the outer diameter of the masking member 11 is set so that it is equal to or somewhat smaller than the inner diameter of the cylindrical body 13. With the masking member 11 held opposed to the annular region 15, the masking member 11 together with the cylindrical body 13 and base member 12 is immersed in water. Thereby, the masking member 11 undergoes volumetric self-swelling, with the result that it is pressed against the annular region 15 of the inner peripheral surface 14. In this state, the cylindrical body 13 is immersed in a plating solution, whereby its surface except the annular region 15 is formed with a plated coating.
As shown in FIG. 3, the base member 12 in the form of a pipe preferably has several through-holes 16 to allow passage of water therethrough at least in its portion which contacts the masking member 11. Thereby, water passing through the through-holes 16 contacts the masking member 11 more efficiently, enabling the masking member 11 to swell more quickly.
In addition, the base member 12 shown in FIGS. 2 and 3 has been in the form of a hollow pipe; however, it may be a solid bar.
The masking member 11 held on the outer peripheral surface of the base member 12 may be used in place of the masking member 5 shown in FIG. 1.
Referring to FIG. 4, a cylindrical body 21 which is a workpiece is shown. The cylindrical body 21 has an outer peripheral surface 22. The region where no plating is desired is an annular region 23 which extends circumferentially on the outer peripheral surface 22. A masking member 24 made of water swelling rubber is annularly formed along the inner peripheral surface of an annular holding member 25.
The annularly formed masking member 24 surrounded with the holding member 25 is disposed so that it is opposed to the annular region 23 of the outer peripheral surface 22 of the cylindrical body 21. In this state, the water is supplied to masking member 24, whereupon the masking member 24 undergoes volumetric self-swelling and is thereby pressed against the annular region 23 of the outer peripheral surface 22 of the cylindrical body 21. Therefore, if the cylindrical body 21 is immersed in a plating solution while maintaining this state, it can be formed with a plated coating except on the annular region 23 of the cylindrical body 21.
In addition, in the embodiment shown in FIG. 4, to promote passage of water, the holding member 25 may be formed with through-holes 26 corresponding to the through-holes 16 shown in FIG. 3.
Although the present invention has been described and illustrated in detail, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, the scope of the present invention being limited only by the terms of the appended claims.
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A method of plating treatment for forming a plated coating on the surface of a workpiece except on a region thereof comprises the steps of placing a masking member made of water swelling rubber in abutment against or in close proximity to the region of the workpiece where no plating is desired, immersing, in this state, the masking member in water to cause the water swelling rubber to undergo volumetric self-swelling, and immersing the workpiece in a plating solution with the swelled masking member pressed against the particular region of the workpiece.
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BACKGROUND
[0001] 1. Technical Field
[0002] The present disclosure relates to an electrosurgical forceps and more particularly, the present disclosure relates to an endoscopic bipolar electrosurgical forceps having a shaft rotatable by the selective actuation of a thumb lever.
[0003] 2. Background of Related Art
[0004] Electrosurgical forceps utilize both mechanical clamping action and electrical energy to affect hemostasis by heating the tissue and blood vessels to coagulate, cauterize and/or seal tissue. Many surgical procedures require cutting and/or ligating large blood vessels and large tissue structures. Due to the inherent spatial considerations of the surgical cavity, surgeons often have difficulty suturing vessels or performing other traditional methods of controlling bleeding, e.g., clamping and/or tying-off transfected blood vessels or tissue. By utilizing an elongated electrosurgical forceps, a surgeon can either cauterize, coagulate/desiccate and/or simply reduce or slow bleeding simply by controlling the intensity, frequency and duration of the electrosurgical energy applied through the jaw members to the tissue. Most small blood vessels, i.e., in the range below two millimeters in diameter, can often be closed using standard electrosurgical instruments and techniques. However, larger vessels can be more difficult to close using these standard techniques.
[0005] In order to resolve many of the known issues described above and other issues relevant to cauterization and coagulation, a recently developed technology has been developed by Valleylab, Inc. of Boulder, Colo., a division of Covidien, called vessel or tissue sealing. The process of coagulating vessels is fundamentally different than electrosurgical vessel sealing. For the purposes herein, “coagulation” is defined as a process of desiccating tissue wherein the tissue cells are ruptured and dried. “Vessel sealing” or “tissue sealing” is defined as the process of liquefying the collagen in the tissue so that it reforms into a fused mass with limited demarcation between opposing tissue structures. Coagulation of small vessels is sufficient to permanently close them, while larger vessels and tissue need to be sealed to assure permanent closure.
[0006] In order to effectively seal larger vessels (or tissue) two predominant mechanical parameters are accurately controlled—the pressure applied to the vessel (tissue) and the gap distance between the electrodes—both of which are affected by the thickness of the sealed vessel. More particularly, accurate application of pressure is important to oppose the walls of the vessel; to reduce the tissue impedance to a low enough value that allows enough electrosurgical energy through the tissue; to overcome the forces of expansion during tissue heating; and to contribute to the end tissue thickness which is an indication of a good seal. Various force-actuating assemblies have been developed in the past for providing the appropriate closure forces to affect vessel sealing. For example, one such actuating assembly has been developed by Valleylab, Inc. of Boulder, Colo., a division of Covidien, for use with Valleylab's vessel sealing and dividing instrument for sealing large vessels and tissue structures commonly sold under the trademarks LIGASURE™, LIGASURE 5mm™, LIGASURE ATLAS®. The LIGASURE ATLAS® is presently designed to fit through a 10 mm cannula and includes a bi-lateral jaw closure mechanism and is activated by a foot switch. Co-pending U.S. application Ser. Nos. 10/179,863, 10/116,944, 10/460,926, 10/953,757, and 11/595,194, and PCT Application Serial Nos. PCT/US01/01890 and PCT/7201/11340 describe in detail the operating features of the LIGASURE devices and various methods relating thereto. The contents of each of these applications are hereby incorporated by reference herein.
[0007] During electrosurgical procedures, such as vessel sealing, the particular characteristics of a patient's anatomy may require the surgeon to employ specific surgical techniques. For example, the angle at which a vessel is to be sealed may be dictated by adjacent anatomical structures, as well as the target vessel itself. Anatomical structures may dictate that a surgeon manipulate an electrosurgical instrument in a precise manner in order, for example, to traverse a path to the surgical site. Such manipulations may include varying the attitude of the instrument jaws in order to achieve the desired operative result.
SUMMARY
[0008] The present disclosure is directed to an electrosurgical instrument having a housing that includes a movable thumb handle disposed thereon that is rotatable about a first axis defined by a driveshaft having a first end and a second end. The driveshaft is operably coupled at a first end thereof to the thumb handle and a second handle thereof to a drive assembly. The electrosurgical instrument in accordance with the present disclosure includes a shaft coupled to the housing and rotatable about a second axis defined longitudinally therethrough and having an end effector disposed at a distal end thereof for performing an electrosurgical procedure. In use, a surgeon may rotate the shaft and end effector by manipulating the thumb handle, for example, in a leftward or rightward direction. Advantageously, an instrument in accordance with the present disclosure allows a surgeon to manipulate the instrument, including effectuating the rotation of the shaft, using a single hand.
[0009] The disclosed electrosurgical instrument includes a drive assembly configured to couple the driveshaft and the rotatable shaft, wherein a rotation of the thumb handle and driveshaft is translated into a rotation of the rotatable shaft. In embodiments, the drive assembly includes a driving element operably coupled to a second end of the driveshaft and a driven element operably coupled to a proximal end of the shaft. The driving element and driven element cooperate to translate rotation therebetween. In embodiments, the driving element and/or driven element may be a bevel gear or friction roller configured to cooperate to translate rotational motion therebetween.
[0010] Also disclosed is an electrosurgical system that includes an electrosurgical generator configured to generate electrosurgical energy. The electrosurgical generator may be operatively coupled to the presently disclosed electrosurgical instrument for performing electrosurgical procedures, for example without limitation, cutting, blending, coagulating, ablation, and vessel sealing. In embodiments the electrosurgical generator may supply electrosurgical signals in the radiofrequency range, for example without limitation the 200 kHz-3.3 mHz range, and/or the electrosurgical generator may supply electrosurgical signals in the microwave range, for example without limitation the 900 mHz-2.0 gHz range.
[0011] A method of performing electrosurgery is disclosed herein which includes the steps of providing an electrosurgical module configured to generate electrosurgical energy; providing the electrosurgical instrument described hereinabove; providing a cable assembly configured to operably couple the electrosurgical module and the electrosurgical instrument; actuating the movable thumb handle to rotate the end effector; and applying electrosurgical energy to tissue. In embodiments, the end effector assembly provides two jaw members movable from a first position in spaced relation relative to one another to at least a second position closer to one another for grasping tissue therebetween. In embodiments, the disclosed method includes the step of positioning the jaw members around tissue therebetween and moving the jaw members from a first position in spaced relation relative to one another to at least a second position closer to one another to grasp tissue therebetween.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The above and other aspects, features, and advantages of the present disclosure will become more apparent in light of the following detailed description when taken in conjunction with the accompanying drawings wherein:
[0013] FIG. 1 is an oblique view of an electrosurgical system in accordance with the present disclosure;
[0014] FIG. 2 is a cutaway view of an exemplary electrosurgical instrument having a thumb lever in accordance with the present disclosure;
[0015] FIG. 3A is a perspective view of an exemplary electrosurgical instrument in accordance with the present disclosure having a thumb lever in a center position;
[0016] FIG. 3B is a perspective view of an exemplary electrosurgical instrument in accordance with the present disclosure having a thumb lever in a left position;
[0017] FIG. 3C is a perspective view of an exemplary electrosurgical instrument in accordance with the present disclosure having a thumb lever in a right position;
[0018] FIG. 4A is a perspective view of an electrosurgical instrument in accordance with the present disclosure shown with an end effector in a first position to grasp and seal a tubular vessel or bundle through a cannula;
[0019] FIG. 4B is a perspective view of an electrosurgical instrument in accordance with the present disclosure shown with an end effector in a second position to grasp and seal a tubular vessel or bundle through a cannula;
[0020] FIG. 5A is a view of thumb lever having a thumb saddle in accordance with the present disclosure; and
[0021] FIG. 5B is a view of thumb lever having a thumb paddle in accordance with the present disclosure.
DETAILED DESCRIPTION
[0022] Particular embodiments of the present disclosure will be described hereinbelow with reference to the accompanying drawings; however, it is to be understood that the disclosed embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.
[0023] In the drawings and in the descriptions which follow, the term “proximal,” as is traditional, shall refer to the end of the instrument which is closer to the user, while the term “distal” shall refer to the end which is farther from the user. Relative terms, such as “left”, “right”, “clockwise”, and “counterclockwise” shall be construed from the perspective of the user, i.e., from a proximal viewpoint facing distally.
[0024] The present disclosure includes an electrosurgical apparatus that is adapted to connect to an electrosurgical generator that includes a control module configured for electrosurgical procedures.
[0025] With reference to FIG. 1 , an illustrative embodiment of an electrosurgical system 1 is shown. Electrosurgical system 1 includes a generator 200 that is configured to operatively and selectively couple to electrosurgical instrument 10 for performing an electrosurgical procedure. It is to be understood that an electrosurgical procedure may include without limitation seating, cutting, coagulating, desiccating, and fulgurating tissue, all of which may employ RF energy. Electrosurgical instrument 10 may be a bipolar forceps. Generator 200 may be configured for monopolar and/or bipolar modes of operation.
[0026] With particular respect to the prior disclosure, generator 200 includes a control module 300 that is configured and/or programmed to control the operation of generation of 200 , including without limitation the intensity, duration, and waveshape of the generated electrosurgical energy, and/or accepting input, such as without limitation user input and sensor input. Generator 200 generates electrosurgical energy, which may be RF (radio frequency), microwave, ultrasound, infrared, ultraviolet, laser, thermal energy or other electrosurgical energy. An electrosurgical module 220 generates RF energy and includes a power supply 250 for generating energy and an output stage 252 which modulates the energy that is provided to the delivery device(s), such as an end effector 100 , for delivery of the modulated energy to a patient. Power supply 250 may be a high voltage DC or AC power supply for producing electrosurgical current, where control signals generated by the system 300 adjust parameters of the voltage and current output, such as magnitude and frequency. The output stage 252 may modulate the output energy (e.g., via a waveform generator) based on signals generated by control module 300 to adjust waveform parameters, e.g., waveform shape, pulse width, duty cycle, crest factor, and/or repetition rate. Control module 300 may be coupled to the generator module 220 by connections that may include wired and/or wireless connections for providing the control signals to the generator module 220 .
[0027] As shown in FIG. 1 , electrosurgical instrument 10 also includes an electrosurgical cable 22 which connects the electrosurgical instrument 10 to the generator 200 . Cable 22 is internally divided into cable leads (not explicitly shown) which are designed to transmit electrical potentials through their respective feed paths through the electrosurgical instrument 10 to the end effector 100 . It is contemplated that generators such as those sold by Valleylab, a division of Covidien, located in Boulder, Colo. may be used as a source of electrosurgical energy, e.g., Ligasure™ Generator, FORCE EZ™ Electrosurgical Generator, FORCE FX™ Electrosurgical Generator, FORCE 1C™, FORCE 2™ Generator, SurgiStat™ II or other envisioned generators which may perform different or enhanced functions. One such system is described in commonly-owned U.S. Pat. No. 6,033,399 entitled “ELECTROSURGICAL GENERATOR WITH ADAPTIVE POWER CONTROL”. Other systems have been described in commonly-owned U.S. Pat. No. 6,187,003 entitled “BIPOLAR ELECTROSURGICAL INSTRUMENT FOR SEALING VESSELS”.
[0028] In one embodiment, the generator 200 includes various safety and performance features including isolated output and independent activation of accessories. It is envisioned that the electrosurgical generator includes Valleylab's Instant Response™ technology features which provides an advanced feedback system to sense changes in tissue 200 times per second and adjust voltage and current to maintain appropriate power.
[0029] Electrosurgical instrument 10 can be any type of electrosurgical apparatus known in the available art, including but not limited to electrosurgical apparatuses that can grasp and/or perform any of the above mentioned electrosurgical procedures. One type of electrosurgical apparatus 10 may include bipolar forceps as disclosed in commonly-owned United States Patent Publication No. 2007/0173814 entitled “Vessel Sealer and Divider For Large Tissue Structures”, which is hereby incorporated by reference in its entirety for all purposes herein.
[0030] With reference now to FIGS. 1 and 2 , electrosurgical instrument 10 is shown for use with various electrosurgical procedures and includes a housing 52 having a fixed handle assembly 50 , a movable handle assembly 30 , a trigger assembly 70 , a rotating collar 80 , a thumb lever assembly 90 , a shaft 12 , a jaw drive assembly (not explicitly shown), a shaft drive assembly 102 , and an end effector 100 , which mutually cooperate to grasp, seal and divide large tubular vessels and large vascular tissues. Although the majority of the figure drawings depict an electrosurgical instrument 10 for use in connection with endoscopic surgical procedures, the present disclosure may be used for more traditional open surgical procedures. Shaft 12 includes a distal end 16 dimensioned to mechanically engage the end effector 100 , a central portion 14 which mechanically engages the housing 20 , and a proximal end 18 dimensioned to engage lever drive assembly 102 as further described hereinbelow. Shaft 12 is rotatable approximately 180 degrees about the longitudinal axis A-A thereof and is operatively associated with housing 52 .
[0031] Fixed handle assembly 50 may be integrally associated with housing 52 . Movable handle 30 is movable relative to fixed handle 50 . Fixed handle 50 may be oriented about 30 degrees relative to the longitudinal axis of shaft 12 . Fixed handle 50 and/or movable handle 30 may include one or more ergonomic enhancing elements to facilitate handling, e.g., scallops, protuberances, elastomeric material, etc. In embodiments, movable handle 30 has an opening 40 defined therein which may facilitate grasping by permitting the fingers of a user to pass therethrough, as can be appreciated.
[0032] Thumb lever 90 is operatively associated with housing 52 and is rotatable through an arc of about 180 degrees about the rotational axis “B-B” (See FIG. 1 ). Thumb lever assembly 90 , shaft 12 , and lever drive assembly 102 cooperate to translate the side-to-side motion of thumb lever 90 about the B-B axis thereof into rotational motion of shaft 12 about the A-A axis. Thumb lever 90 includes a hub 93 disposed at the distal end of thumb lever 90 having a driveshaft 94 extending therefrom into housing 52 along axis “B-B”. Driveshaft 94 may be coupled to hub 93 by any suitable means, for example without limitation, by threaded fastener (not explicitly shown), adhesive, or clip. In embodiments, driveshaft 94 may be integrally formed with hub 93 and/or thumb lever 90 . Thumb lever 90 may include a recess 101 configured to improve the rigidity and reduce the material volume thereof. Thumb lever 90 at a proximal end thereof includes a thumb ring 91 defining an opening 92 adapted to accommodate a finger, i.e., thumb, of a user. In other envisioned embodiments best illustrated by FIGS. 5A and 5B , thumb lever 90 at the proximal end may include a thumb saddle 911 or a thumb paddle 921 . Thumb saddle 911 or thumb paddle 921 may additionally include texturing, protrusions, or ribbing 912 , 922 . In embodiments, housing 52 includes a contoured region 55 configured to provide clearance for thumb lever 90 and/or thumb ring 91 .
[0033] Driveshaft 94 is supported within housing 52 by driveshaft sleeve 96 which may be integrally formed with housing 52 . Driveshaft sleeve 96 has an inside diameter dimensioned to allow free rotation of driveshaft 94 within driveshaft sleeve 96 while maintaining alignment of driveshaft 94 with lever drive assembly 102 . In embodiments, driveshaft sleeve 96 may include a bearing (not explicitly shown) such as without limitation ball bearing, roller bearing or friction bearing. In embodiments, the clearance between driveshaft 94 and driveshaft sleeve 96 may be dimensioned to achieve a predetermined amount of friction.
[0034] Lever drive assembly 102 includes bevel gear 98 that is disposed upon the lower end 103 of driveshaft 94 and bevel gear 99 that is disposed upon the proximal end 18 of shaft 12 . Bevel gear 99 engages bevel gear 98 to communicate the side-to-side motion of thumb lever 90 about the B-B (i.e., vertical) axis thereof into rotational motion of shaft 12 about the A-A (i.e., longitudinal) axis. In embodiments, bevel gears 98 and 99 have a unity (1:1) gear ratio. In other envisioned embodiments, bevel gears 98 and 99 have a non-unity gear ratio whereby shaft 12 is driven at a rotational rate greater, or alternatively, less than, that of driveshaft 94 . Bevel gears 98 and 99 may be arranged such that a clockwise rotation of driveshaft 94 imparts a clockwise rotation to shaft 12 , or alternatively, a clockwise rotation of driveshaft 94 imparts a counterclockwise rotation to shaft 12 . In yet other embodiments, the relationship between the rotation of driveshaft 94 and the rotation of shaft 12 is switchably selectable.
[0035] The present disclosure is not limited to the use of bevel gears to translate motion between the driveshaft and shaft. Other envisioned embodiments are disclosed wherein friction rollers, pulley and belts configurations, sprocket and chain configurations, and the like perform the function of lever drive assembly 102 and/or bevel gears 98 and 99 .
[0036] Shaft 12 includes a shaft proximal portion 19 thereof that extends into housing 52 . Shaft proximal portion 19 is supported within housing 52 by shaft sleeve 97 and 97 ′ which may be integrally formed with housing 52 . Shaft sleeve 97 , 97 ′ have an inside diameter dimensioned to allow free rotation of shaft 12 and thus shaft proximal portion 19 within sleeves 97 , 97 ′ while maintaining alignment of shaft 12 and thus shaft proximal portion 19 with lever drive assembly 102 , i.e., maintaining the engagement of bevel gears 98 and 99 . In embodiments, shaft sleeves 97 , 97 ′ may include a bearing (not explicitly shown) such as without limitation ball bearing, roller bearing or friction bearing. In embodiments, the clearance between shaft proximal portion 19 and driveshaft sleeves 97 , 97 ′ may be dimensioned to achieve a predetermined amount of friction.
[0037] In use, electrosurgical instrument 10 may be introduced to the surgical site of patient P through a cannula or trocar port 410 as best illustrated in FIG. 4A whereby end effector 100 may be positioned to grasp and/or seal vessel V. As can be seen, thumb lever 90 has been moved into a left position which, in the illustrated embodiment, has caused end effector 100 to advantageously rotate to a clockwise position that is well-suited for grasping vessel V, while permitting housing 52 to remain in substantially fixed position that may remain well-placed, for example, in the hand of the surgeon. Turning now to FIG. 4B , electrosurgical instrument 10 is positioned to grasp vessel V′ of patient P′, where vessel V′ follows a substantially different path from that of vessel V of FIG. 4A . Thumb lever 90 has accordingly been moved into a right position to cause end effector 100 to rotate to a counterclockwise position well-suited for grasping vessel V′, while permitting housing 52 to remain in substantially fixed position as described hereinabove.
[0038] While several embodiments of the disclosure have been shown in the drawings and/or discussed herein, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. Therefore, the above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
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An electrosurgical instrument and system and method for performing electrosurgery therewith is disclosed. The electrosurgical system includes an electrosurgical generator adapted to supply electrosurgical energy to tissue. The electrosurgical system includes an electrosurgical instrument that provides a shaft, such as a laparoscopic shaft, having at the distal end thereof an end effector. The end effector may include without limitation a pair of movable jaws adapted to perform tissue fusion and/or vessel sealing. The electrosurgical instrument includes a movable thumb lever in operable communication with the shaft to enable the surgeon to rotate the shaft in an ergonomic, single-handed manner.
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FIELD OF THE INVENTION
The present invention generally relates to a composite sandwich structure having outer fiber reinforced composite layers separated by a lightweight core. More particularly, the present invention relates to integrally reinforcing a section of the composite sandwich structure, e.g., by changing the thickness or proportions of one or more layers of the sandwich structure, to provide a stiffened section for a structural interface. The invention has particular advantages for constructing sidewalls of launch vehicles or other aerospace applications.
BACKGROUND OF THE INVENTION
Reinforced composite sandwich structures typically have outer fiber reinforced composite layers separated by a lightweight core made up of metallic or non-metallic honeycomb, structural foams and/or wooden fibers. The outer fiber reinforced composite layers, or face sheets, are generally separated by and connected to the core, which is usually less stiff and less dense than the face sheets. These composite sandwich structures are widely used today in aerospace applications due to their high stiffness-to-weight (i.e., specific stiffness) and strength-to-weight (i.e., specific strength) ratios. The face sheets generally comprise a fiber reinforced resin matrix composite that incorporates strong stiff fibers, such as carbon fiber, into a softer, more ductile resin matrix. The resin matrix material transmits forces to the fibers and provides ductility and toughness while the fibers carry most of the applied force. In the case of composite sandwich structures, the behavior of the face sheets is analogous to the flange of a structural I-beam while the behavior of the core is analogous to the web of the I-beam. In this regard, the face sheets carry the applied loads and the core transfers the load from one face sheet to the other.
Though composite sandwich structures provide increased strength-to-weight ratios compared to, for example, metallic structures, there are several important limitations to use of such composite structures. Composite structures depend primarily on the fiber reinforcement in the resin matrix for their high specific strength and stiffness. These composite structures generally have limited in-plane compressive strength (bearing strength) and may not have the strength to absorb highly localized stress loads, especially when those loads are applied substantially perpendicular to the composite structure. For example at a structural interface a fastener, such as a bolt, passing through the cross sectional area of a composite sandwich structure may provide a localized stress concentration and/or a point load on one or both of the face sheets. In this regard, the composite sandwich structure must provide adequate bearing strength and compressive strength to resist tearing of the face sheets and/or crushing of the core while providing required structural properties to distribute the point load across the structure's surface without failing.
In order to provide the necessary structural integrity necessary at, for example, structural interfaces, additional composite material layers are typically added to the face sheets of the composite sandwich structure. These additional layers, or doublers, provide increased stiffness and bearing strength to the structural interface. Generally, to provide the necessary structural integrity, both face sheets are reinforced with doublers. The additional layers increase the weight of the composite structure, thus reducing the specific strength and stiffness benefits provided by the composite sandwich structure. Therefore, only the region surrounding the structural interface is “doubled”, allowing the rest of the composite structure to maintain its high strength-to-weight and stiffness-to-weight ratios.
In the case of large tubular composite structures, as are used for various components of space launch vehicles, doublers may be applied in one or more ways. For example, the doublers may be co-cured on the outside of composite face sheets, which requires the doublers be applied during the initial composite structure “lay-up.” As will be appreciated, tubular composite structures are generally formed or laid-up on a mandrel that is removed after the structure is cured. In the case of tubular composite sandwich structures, adding doublers during lay-up requires a stepped mandrel having a varied diameter along its length. The stepped mandrel allows a doubling layer to be wound about the mandrel and then the normal face sheet layer wound on top of the doubling layer. As will be appreciated, if the double layer on the inside surface of the tubular structure is in any position other than the end of the mandrel, or if two doubling layers are utilized along the length of the mandrel, the mandrel cannot slide out of the composite sandwich structure upon curing. In this regard, a collapsible mandrel must be used. However, collapsible mandrels increase the cost, weight, and internal structure required of the mandrel, creating difficulties in maintaining mandrel stiffness and tolerances and further creating difficulties in the machinery utilized to apply the materials to the mandrel.
A second method for adding doublers to a section of a tubular composite sandwich structure involves post-bonding the doublers onto a pre-cured structure's face sheets. This allows a mandrel to be removed from a tubular composite structure prior to application of the doublers. However, adding the doublers, especially to the inside surface of a tubular structure, requires extensive tooling and costs. Further, care must be taken to assure the secondary bonding of the doublers to the face sheets provides good mechanical conformance. As will be appreciated, if the doublers do not properly adhere to the surface of the pre-cured face sheets such that, for example, internal voids exist, the entire composite sandwich structure may be irreparably damaged.
Finally, another method for providing a structural interface for a composite sandwich structure is to pan down the ends of the composite sandwich structure such that it transitions from a sandwich construction having two face sheets and an internal core to a monocoque construction where there is no core and the face sheets are now in direct contact. However, this eliminates many of the benefits of utilizing a composite sandwich structure, e.g., I-beam behavior and increased moment of inertia. Further, monocoque transition requires additional tooling and fabrication steps.
All of the above noted methods for providing doublers to stiffen a section of a tubular composite sandwich structure require substantial tooling and manufacturing steps, increasing the cost of the composite structure. Further, each of the above noted methods changes the external geometry of the composite structure (i.e., the spatial envelope within which the structure is contained defined by its exposed surfaces, which may define interior or exterior walls of an aerospace structure) relative to an un-reinforced geometry, which may be problematic in space launch vehicles.
SUMMARY OF THE INVENTION
It is therefore an objective of the present invention to provide an integrally reinforced section in a composite sandwich structure for use as a structural interface.
It is a further objective of the present invention to provide a process to produce an enhanced structural interface in a composite sandwich structure that does not require the use of specialized mandrels or tooling in the lay-up process.
It is a yet further objective of the present invention to provide an enhanced structural interface in a section of composite sandwich structure without altering the exterior dimensions of that composite structure
It is a yet further objective of the present invention to provide a method for allowing selective alteration of the structural properties of a composite sandwich structure for a given exterior geometry limitation.
One or more of the above-noted objectives, as well as additional advantages, are provided by the present invention, which includes a composite sandwich structure having a first face sheet, a second face sheet, and a core sandwiched between the face sheets. More particularly, for a given external geometry, reinforcement of a section of interest is achieved by varying the proportions of the thicknesses of the structural layers. For example, the composite structure may contain at least first and second sections having equal cross-sectional thicknesses measured from the outside surfaces of each face sheet while the relative proportions of the core relative to at least one of the face sheets vary between the first and second sections. As will be appreciated, by varying the relative proportions of the face sheet(s) and core, a composite structure having varying mechanical properties between the first and second sections may be produced while maintaining a predetermined outside profile. Particularly, the relative proportions of the first and/or second face sheet and core may be varied to produce a section within the composite structure that is structurally enhanced (i.e., integrally reinforced) in comparison to other sections of the composite structure. This structurally enhanced section may then be utilized as, for example, a structural interface or joint for attaching the composite structure to other structures.
According to a first aspect of the present invention, a structure for use as a portion of sidewall of space launch vehicle is provided that includes a first face sheet, a second face sheet, and a core sandwiched between the inside surfaces of the first and second face sheets. This core has at least first and second thicknesses at first and second positions along the length of the structure. While the thickness of the core changes between the first and second positions, the distance between the outside surfaces of the first and second face sheets remains substantially equal at the first and second positions. As will be appreciated, in order to maintain the substantially equal distance between the outside surfaces of the face sheets at the first and second positions, the thickness of the first and/or second face sheet generally changes in proportion to the change in the core thickness.
Various refinements exist of the features noted in relation to the subject first aspect of the present invention. Further features may also be incorporated in the subject first aspect of the present invention as well. These refinements and additional features may exist individually or in any combination. For instance, the shape of the composite structure and the locations of the first and second thicknesses of the core may each be varied. In the case of the shape of the structure, a tubular structure may be particularly apt for use as a sidewall in the space launch vehicle. Alternatively, separate curved or flat panels may also be utilized to form the launch vehicle's sidewall. In the case of the core thicknesses, the first and second core thicknesses may be uniform, for example, across the entire width (i.e., about the circumference in a tubular structure) of the composite structure in first and second positions along the length of the structure. Alternatively, the first and second core thicknesses may only extend across a portion of the structure or be formed around regions where altered structural properties of the composite structure are desired.
The face sheets may be any material that provides the structural, thermal, and other properties desired for the sidewall of the launch vehicle. Preferably, at least one of the face sheets has a first thickness in a first position and a second different thickness in a second location to correspond with the first and second core thicknesses. This change in face sheet thickness allows the distance between the outside surfaces of the first and second face sheets to be equal in the first and second positions along the length of the structure without internal gaps or other accommodations in relation to the varying core thickness. As will be appreciated, an increased thickness section of either or both face sheets will generally stiffen the structure and provide greater bearing strength than thinner sections of the face sheets. Therefore, a preferred embodiment for structural interfaces utilizes a reduced core thickness and a corresponding increase in thickness for one, and more preferably both, face sheet(s), providing a section in the composite structure having enhanced stiffness and bearing strength.
In a preferred embodiment, the face sheets are made from one or more layers of a fiber reinforced material. That is, the face sheets may be made of a material that utilizes strong stiff fibers encapsulated in a softer, more ductile resin matrix. The face sheets may be formed from a plurality of layers of carbon fiber reinforced plastic, glass fiber reinforced plastic, aromatic polyamide fiber (such as Kevlar® made by DuPont) reinforced plastic, or any other appropriate material. In this regard, the thickness of each face sheet may be varied by varying the number of fiber reinforced material layers used to form that face sheet. For example, additional fiber reinforced material layers may be added to or removed from one or both face sheets in positions where there is a corresponding reduction, or increase, in core thickness. More particularly, these “augmentation” layers may be applied to or removed from what becomes the inside surface of the face sheets (i.e., the side in contact with the core). By applying and removing the augmentation layers to the inside surfaces of the face sheet(s), the relative proportions of the face sheets and core may be altered without altering the outside dimension of the composite structure.
The structure's core may be any material that provides, in conjunction with the face sheets, the structural, thermal and other properties desired for the sidewall of the launch vehicle. A non-inclusive list of appropriate materials include any light-weight material such as metallic (e.g. aluminum) or non-metallic (e.g. Nomex manufactured by Créations Guillemot Inc. of Beauport, Québec, Canada) honeycomb, structural foam, balsa wood, a metal or metal alloy in an appropriate form, a metal matrix composite in an appropriate form (e.g., a hybrid of a metal/metal alloy and one or more non-metallic materials), or any other appropriate core material and in any appropriate form, including solid materials. As noted, the core has first and second thicknesses in first and second longitudinal positions along the length of the composite structure. In this regard, the core may contain one or more “steps” on one or both of its surfaces. That is, one side may remain substantially planer between the first and second positions while the other side of the core varies the core's thickness between the first and second steps. As will be appreciated, in this situation, the face sheet on the varying side of the core may correspondingly vary in thickness between the first and second positions while the face sheet on the planer side of the core may remain a constant thickness between the first and second positions.
The structural properties of the core may also vary along the length of the structure. For example, core properties at the first longitudinal position may be different than core properties at the second longitudinal position. In one preferred embodiment, the density between the two positions varies with structural requirements. For example, to increase bearing and compressive strength at a reduced thickness core position for use in a structural interface, a core having an increased density may be utilized. The change in density from the first and second position may require using a material having varying properties (i.e., a denser portion along its length) or using two separate materials, such as a solid aluminum block (denser) in a reduced core thickness position having high bearing and compressive strength requirements, and an aluminum honeycomb in core positions having greater thickness and lower bearing and compressive strength requirements. Regardless of the core materials utilized, it is preferred that the first and second sections of these materials are somehow “knitted” together, (i.e., glued, welded, etc.) to increase the structural properties of the resulting structure.
In the case of a tubular structure used in the sidewall of a space launch vehicle, one or more integrally reinforced sections may be utilized. Particularly, the ends of such a structure may be integrally reinforced to provide a structurally sound joint to attach the structure to other components of the launch vehicle. However, it will be appreciated that one or more integrally reinforced sections may be utilized along the length of sidewall.
According to a second aspect of the present invention, a process for making a structure for use as a portion of a space launch vehicle's sidewall is provided. Steps of the process include applying a first face sheet to the outside surface of a mandrel; covering the resulting outside surface of the first face sheet with a core layer having at least a first and second thickness at first and second positions along the length of the mandrel; applying a second face sheet to the resulting outside surface of the core layer; curing the resultant structure and removing the mandrel. Further, at least one of the face sheets will be applied having at least first and second thicknesses such that the combined thickness of face sheets and core (i.e., relative proportions) at each the first and second positions is equal.
Various refinements exist of the features noted in relation to the subject second aspect of the present invention. Further features may also be incorporated in the subject second aspect of the present invention as well. These refinements and additional features may exist individually or in any combination. For instance, a tubular mandrel having a uniform outer surface such as a cylinder may be utilized to form the structure; the mandrel may taper from its first end to its second end; the mandrel may contain steps on its surface to provide for variations in the face sheet formed thereon, etc. The methods of application of the face sheets and/or the core may also vary. For example, the face sheets may comprise strands or filaments that are machine placed (e.g., wound or fiber placed) onto the mandrel, material that is applied by hand, or a combination of the two.
The first and second applying steps, in a preferred embodiment of the present invention, include applying a plurality of fiber reinforced material layers to the outside surface of the mandrel and core, respectively. These fiber reinforced material layers may comprise broad goods (sheets) or filaments. Further these layers will contain a resin that forms the face sheet into a solid laminate structure upon curing. This resin may be a wet resin applied to the fiber reinforced materials after or during placement, or, more preferably, the fiber reinforced materials will be pre-impregnated with the resin material prior to application. As will be appreciated, fiber reinforced materials generally contain an “axis” along which the fibers are oriented. In each applying step, the various fiber reinforced material layers may be applied such that the axes between the layers are orthogonal to produce desired mechanical, thermal and/or other desired properties.
In each of the first and second applying steps, where a plurality of fiber reinforced material layers are utilized, the number of layers may be varied between first and second positions of the face sheet(s) so as to change the thickness of the face sheet in these first and second positions. That is, at least one of the face sheets may have extra fiber reinforced material layers “wound” onto the mandrel or core (or otherwise applied) in positions corresponding with a reduction in thickness of the core along the length of the mandrel. By inserting extra layers onto what becomes the inside surfaces of the face sheets during lay-up, the overall thickness of the composite structure may remain equal in the first and second positions corresponding with the first and second core thicknesses without changing the outside dimensions of the structure.
The step of curing the composite structure generally entails consolidating the composite structure and causing the resin material to harden/set and or dry. Consolidation may utilize any method to provide a compressive force to the face sheet layers such that there is good conformance between the layers upon curing. A non-inclusive list of consolidating method includes, vacuum bagging, pressurized chambers, compaction rollers and squeegees (e.g., for wet resin applications). Curing is preferably done in a autoclave that heats the structure in a pressure chamber having an elevated pressure. Preferably, the composite structure is both vacuum bagged and cured in a pressurized autoclave to provide increased consolidating force for the multi-layered face sheets. The exact temperature and pressure settings as well as the duration of the curing process varies in relation to the materials utilized to form the composite structure.
According to a third aspect of the present invention, a method for designing a multi-layered structure having at least one reinforced portion is provided. The method includes the step of determining a spatial envelope for the structure. That is, determining at least one constraining factor, such as a maximum allowable thickness or length for the multi-layered structure. Next, a portion of the structure is identified for reinforcement. The portion identified for reinforcement may be so identified for any of a plurality of reasons, typically, reinforcement is desired due to the forces that are expected to act upon the structure during its intended use. Based on the constraints of the spatial envelope, at least one of the material properties and/or the dimensions of one or more layers of the multi-layered structure are altered to provide the desired reinforcement at the identified portion. That is the properties/dimensions of the identified portion's layers are altered in comparison with, for example, the layers of non-reinforced portions of the structure. Finally, the reinforcement of the desired portion is designed such that it does not create an external irregularity on a surface of the multi-layered structure.
Various refinements exist of the features noted in relation to the subject third aspect of the present invention. These refinements and additional features may exist individually or in any combination. For example, the step of identifying a portion of the structure for reinforcement may comprise determining one or more required structural properties of the portion to be reinforced, such as tensile strength, compressive strength, bearing strength, stiffness, or any other desired property (.e.g., thermal properties, etc). As will be appreciated, the spatial envelope may also be used to determine the required structural properties of the portion to be reinforced. For example, a planer multi-layered structure having maximum allowable thickness of N (i.e., spatial envelope) and a point load of X may require reinforcement such that the load does not deflect the structure beyond a predetermined maximum value.
As will be appreciated, the method of designing the multilayered structure with one or more reinforced portions requires that the material properties of the various layers be known in order to determine the structure's overall properties. Once the general properties of the structure are known, a material property and/or dimension of one or more of the structure's multiple layers may be altered to reinforce the identified portion. In particular, the material property/dimension of one or more of the layers may be altered in comparison to other (i.e., non-reinforced) portions of the multi-layered structure to produce the desired reinforcement. In a preferred embodiment of the subject aspect of the present invention, one or more layers of the structure are increased in thickness while one or more different layers of the structure are decreased in thickness to provide the desired reinforcement of the identified portion. For example, in the case of a composite structure having first and second face sheets with a core material sandwiched in-between, increasing the thickness of one or both face sheets while correspondingly reducing the thickness of the core may produce a portion of the structure having enhanced stiffness. Further, if the increase of the face sheet's thickness is increased on its inside surface, the structurally enhanced portion will be free of any exterior irregularity associated with the reinforcement. Alternatively, a change in material properties, such as an increased density core or stiffer face sheets at the reinforced portion may be utilized to provide the desired reinforcement while the structure's external surface remains free of any exterior irregularity. Once the materials/dimensions of each layer and the reinforced portion are determined, the structure may be formed by any of a number of methods known to those skilled in the art.
According to a fourth aspect of the present invention a composite structure having variable structural properties is provided. The composite structure comprises a first outermost layer, a second innermost layer and a core layer between the first and second layers creating what is often referred to as a composite sandwich structure. The outermost and innermost surfaces of the outermost and innermost layers, respectively, define the overall thickness of the composite structure at any position on the structure. The composite structure has a variation between a first set of structural properties at a first portion of the structure and a second set of structural properties at a second portion of the structure. This variation in structural properties is at least partially dependent on the relative proportions of the first layer, second layer and core layer at the first and second portions while remaining independent of the composite structure's overall thickness, which may be the same at the first and second portions.
Various refinements exist of the features noted in relation to the subject third aspect of the present invention. These refinements and additional features may exist individually or in any combination. For example, the first and second layers may be made of any materials such as wood or metal. However, in a preferred embodiment the first and second layers comprise a plurality of fiber reinforced material layers such as carbon reinforced plastics, glass fibers, etc.
As noted, the variation in the structural properties of the composite structure between the first and second portions is at least partially related to the relative proportions of the thicknesses of the first layer, second layer, and core in these portions. For example, in a preferred embodiment, the thickness of one of the first and second layers may be increased in relation to the thickness of the core, which may itself be decreased in thickness such that the overall thickness of the structure remains unchanged. As will be appreciated, depending on the material properties (e.g., stiffness, density, etc) of the layers, this may result in a portion of the composite structure having enhanced structural properties in comparison to another portion of the composite structure that has different relative proportions and/or material properties of the layers. In this regard, a composite structure may have an equal overall thickness at a first and second portion while one of these portions provides enhanced or reduced structural properties in comparison to the other portion. For example, the compressive strength or stiffness of a particular portion may be increased or decreased to provide desired structural properties.
The materials utilized to form the layers may also be altered between the first and second portions to produce the variation between the first and second sets of structural properties. For example, where the first and second layer comprise a plurality of fiber reinforced material layers, a first portion may utilize a plurality of glass fibers layer while the second portion may utilize a mixture of glass and stiffer carbon fiber layers. In this regard the second portion may have an increased stiffness in comparison with the first portion. Alternatively, differing core materials may be utilized between the first and second positions having, for example differing densities to produce the variation between the first and second sets of structural properties.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a cross sectional view of a portion of an integrally reinforced composite structure;
FIG. 2 shows a close up view of the integrally reinforced structure of FIG. 1;
FIG. 3 shows a possible orientation of composite fiber plies;
FIG. 4 shows the composite structure of FIG. 1 interfacing with a socket joint;
FIG. 5 shows a cross sectional view of an integrally reinforced composite structure laid up on a mandrel;
FIG. 6 shows a close up view of an externally reinforced end of the structure of FIG. 5 .
FIG. 7 shows a fiber placement machine for winding a composite filament tape onto a mandrel;
FIG. 8 shows a flow chart illustrating one embodiment of a design process for producing an integrally reinforced composite structure; and
FIG. 9 shows a flow chart illustrating a process for producing a tubular composite structure having an integrally reinforced section.
DETAILED DESCRIPTION
The present invention will now be described in relation to the accompanying drawings, which at least assist in illustrating the various pertinent features thereof. By way of initial overview, the present invention relates to an integrally reinforced composite sandwich structure and a method for making the same. One embodiment of such a structure generally contains a first face sheet, a stepped core having two or more thicknesses at two or more “step” locations, and a second face sheet. More particularly, the first, second, or both face sheets also vary in thickness in an inverse relationship with the stepped core to produce a composite sandwich structure that has a constant outside profile between the two “step” locations. That is, the face sheets and the core make up varying relative proportions of the structure's overall thickness at the two locations while the structure maintains a constant outside profile. Accordingly the composite sandwich structure has differing structural properties at the two locations that relate to the varying relative proportions of the face sheets and core. The integral reinforcement of a composite structure will now be described, after which a method for manufacturing the same will be described.
FIG. 1 shows a cross sectional view of one embodiment of a portion of an integrally reinforced composite sandwich structure 140 . As shown, the structure 140 contains a first face sheet 54 , a second face sheet 58 and an internal stepped core 60 . The face sheets 54 , 58 are formed from carbon fiber reinforced plastic, glass fiber reinforced plastic, aromatic polyamide fiber (such as Kevlar® made by DuPont) reinforced plastic, or any other appropriate material. Additionally, the internal stepped core 60 is a light-weight material such as metallic (e.g. aluminum) or non-metallic (e.g. Nomex manufactured by Créations Guillemot Inc. of Beauport, Québec, Canada) honeycomb, structural foam, balsa wood, a metal or metal alloy in an appropriate form, a metal matrix composite in an appropriate form (e.g., a hybrid of a metal/metal alloy and one or more non-metallic materials), or any other appropriate core material and in any appropriate form, including solid materials, for increasing compressive and bearing strengths, as will be discussed herein.
Referring to FIG. 2, a more detailed disposition of the composite sandwich structure 140 of FIG. 1 is shown. The face sheets 54 and 58 each comprise a plurality of fiber reinforced material layers, or plies, 224 - 237 and 210 - 223 , respectively. These plies 224 - 237 and 210 - 223 are formed of a plurality of reinforcing and/or supporting preimpregnated fiber layers. Preimpregnated fiber or “prepregs” are layers of fiber, fiber tape or woven fabric that are preimpregnated with a resin. However, those skilled in the art will appreciate that non-impregnated fibers and a wet resin may also be utilized. Upon curing, the resin forms a solid matrix material that transmits forces to the fibers and provides ductility and toughness while the fibers carry most of the applied force. The fibers may be in any conventional form, such as unidirectional, woven fabric, etc. When unidirectional tape is used, each ply is formed of a plurality of parallel oriented preimpregnated tows that may comprise, for example 6,000 or 12,000 fibers.
The orientation of the tows of each ply is based on the desired directional strength and/or desired thermal properties of the resultant fiber reinforced resin composite. As is conventional, some plies lie parallel to a predetermined direction, which is usually the direction of the major force likely to be applied to the resultant laminate (i.e., cured) structure. Plies whose tows lie in this direction are commonly referred to as 0.degree. plies 300 . (See FIG. 3) Other plies lie at an angle to the 0.degree. plies 300 . That is, the axis of the tows of some plies lie orthogonal to the tow direction of the 0.degree. plies 300 . These plies are commonly referred to as 90.degree. plies 310 . Plies whose tows lie at some other angle with respect to the direction of the tows of the 0.degree. plies 300 are referred to as + and − plies. Most commonly, the tows of these plies form +45.degree. 320 and −45.degree. 330 angles with respect to the direction of the tows of the 0.degree. plies 300 . The number of 0.degree. 300 , 90.degree. 310 , and + and − plies and how they are interleaved is, of course, dependent upon the desired qualities for the resultant composite structure. What is important is that the plies may be oriented to produce desired structural and thermal qualities for the composite structure.
Utilizing a composite sandwich construction provides a composite structure 140 (i.e., specific strength) ratios. However, as noted above, it is desirable to reinforce those sandwich structures at points of concentrated loading such as structural interfaces. For example, FIG. 4 shows the composite structure 140 of FIG. 1 interfacing with a U-shaped socket joint 100 . The socket joint 100 contains a bolt 104 that passes through a first socket joint flange 106 , the composite structure 140 and a second socket joint flange 108 . Upon tightening the bolt 104 , a compressive load may be made on the outside surfaces of the composite structure 140 . Additionally, structural loads (i.e., compressive, tensile, bending moments etc.) may be applied to the composite structure 140 through this structural interface. In order to support the interface loads and spread the force of these loads over a large surface of the composite structure 140 (perpendicular to the plane of the paper) the interfacing section of the composite structure 140 must be reinforced.
Referring again to FIG. 1, it is noted that each face sheet 54 , 58 as well as the core 60 contain first, second, and third sections 62 , 64 , and 66 which have first, second and third differing thicknesses while the outside profile of the composite structure 140 remains unchanged. As will be appreciated, the face sheets 54 , 58 each contain two sections 64 , 66 that are thicker in relation to the section 60 . These thickened face sheet sections 64 , 66 contain various augmentation plies 218 - 223 and 224 - 229 applied to their inside surfaces (See FIG. 2 ). These augmentation plies 218 - 223 and 224 - 229 are generally referred to as “doublers.” The augmented sections 64 and 66 form face sheet sections having greater bearing strength, compressive strength and stiffness in comparison with the non-augmented face sheet section 62 .
As shown in FIG. 2, the core 60 contains two steps 72 , 74 on its bottom surface and two steps 82 , 84 on its top surface. These steps 72 , 74 and 82 , 84 reduce the thickness of the core in an inverse relationship to the augmented sections 64 , 66 of each face sheet 54 , 58 . Moreover, the internally augmented sections of the face sheets in connection with the inversely reduced stepped core 60 produce a composite sandwich section 66 that is stiffer and has greater bearing and compressive properties than the other composite sandwich sections 62 , 64 . This produces a structurally enhanced composite sandwich structure section 66 without altering the outside dimensions of the composite structure 50 . That is, the outside surfaces of each face sheet 54 and 58 remain a constant distance apart notwithstanding the change of the relative dimensions of the thickness of the face sheets 54 and 58 and the stepped core 60 . This provides a composite sandwich structure 140 that is internally or “integrally” reinforced to produce sections having different structural properties.
Integral reinforcement allows the stiffness and bearing strength of the composite structure 140 to be adjusted (i.e., by adding additional doublers to the face sheet inside surfaces) without changing the structure's 140 outside dimensions, allowing for alteration of the composite structure's properties (i.e., post-design changes) without adjusting interfacing hardware, structures or tooling. This is especially important in complex systems such as space launch vehicles where altering one component may require redesigning and/or altering a plurality of secondary components. Further, the internal augmentation allows structural enhancement to a composite sandwich structure 140 while maintaining a uniform outer surface, which may be desirable for aerodynamic purposes or to facilitate mounting ancillary features.
Referring to FIGS. 4 and 2, the section 66 through which the bolt 100 passes contains the augmentation plies 218 - 223 and 224 - 229 and the correspondingly reduced stepped core section 60 . The relative proportions of the face sheets 54 , 58 and core 60 provide the required structural properties for interfacing with the socket joint 100 . The second section 64 provides an intermediate “step” 72 and 82 (See FIG. 2) between the section 66 containing the most plies and the section 62 containing the least. In this regard, the intermediate steps 72 and 82 of section 64 help prevent stress concentrations from forming that may result from a single large increase in plies from one section to the next. As will be appreciated, a plurality of intermediate steps may be used or a tapered core may be utilized along with plies of gradually increasing lengths to prevent stress concentrations.
Referring to FIGS. 2, 5 and 6 , a tubular composite sandwich structure having structurally reinforced sections is described. This tubular composite structure 140 contains the integrally reinforced section described above. Though described in conjunction with a tubular composite sandwich structure for use in space launch vehicle, it is expressly understood that the present invention may be utilized with other composite sandwich structures.
Generally, tubular composite structures are formed on a mandrel or “tool” (See FIG. 5 ). In this regard, one or more plies of a fiber reinforced material are applied to the outside surfaces of a mandrel and cured. The fiber reinforced material plies may be individual fibers, woven fabrics, tows etc., and may be preimpregnated or wet fibers. The fiber reinforced material plies may be hand laid upon the surface of the mandrel or, more preferably, wound onto the mandrel. For example, filament winding may be utilized to place the fibers that make up each ply. Filament winding is a highly automated process utilizing a continuous tow spool (prepreg or wet) of several fiber tows that are wound on a mandrel by a winding machine. For tubular structures, the mandrel is generally a steel or aluminum cylinder with a carefully machined outer diameter. A release agent is applied to the mandrel's surface before winding which enables the composite structure to be removed after curing. The mandrel is then placed under tension in the winding machine which rotates the mandrel while a moving carriage supplies the fiber tows. Typically, these machines are numerically controlled for high repeatability and precision. Regardless of the method utilized to lay-up the various plies, once the plies are laid, the composite structure is subject to some sort of consolidating force and a curing method. The consolidating force provides force to join the plies together and minimize voids in the cured composite structure 140 . Various methods of consolidation include shrink wrapping the pre-cured structure 140 and mandrel, vacuum bagging the pre-cured structure 140 and mandrel and utilizing a pressure chamber pressurized beyond atmospheric pressure. Curing may be done utilizing heat, UV and/or laser. However, as will be appreciated, most large composite structures utilize a vacuum bag to provide the consolidating force and an autoclave to apply heat and pressure while curing the structure.
FIG. 5 shows a cross-sectional view of a cylindrical composite sandwich structure 140 utilized for a portion of a sidewall of a space launch vehicle. As shown, the structure 140 is formed on a generally cylindrical mandrel 160 . FIGS. 2 and 6 show cross-sectional profiles of each end 142 and 144 of the cylindrical composite sandwich structure 140 . FIG. 2 is the same Figure used in the discussion above and contains an integrally reinforced section 66 . As shown in FIG. 5, the right end 162 of the mandrel 160 contains two steps 164 and 166 that each successively reduced the mandrel's diameter. In contrast, the left end 168 of the mandrel 160 maintains a uniform diameter.
FIG. 6 shows the right end 162 of the composite structure on the mandrel 160 . As shown, this section of the composite structure 140 utilizes external augmentation layers and a non-stepped uniform core 60 . The use of the internally augmented reinforced section on the left end 168 of the composite structure 140 allows the composite structure 140 to slide off the mandrel 160 after curing. Alternatively, both ends 162 , 168 of the composite structure 140 may utilize internal augmentation layers to provide a stiffened section for structural interconnections. In this regard, a mandrel having a uniform diameter from the left end 168 to the right end 162 may be utilized.
FIG. 7 shows the lay-up of the fiber reinforced material layers to the outside surface of the mandrel 160 . As shown, a fiber placement apparatus 190 is utilized. Similar to a filament winding machine, the fiber placement apparatus 190 is utilized to place a preimpregnated fiber tape/tow on the outside surface of the mandrel 160 to form the various plies that make up the resultant composite structure 140 . The fiber tape/tow is preferably a carbon fiber reinforced plastic (CFRP). The fiber placement apparatus 190 moves along the longitudinal length of the mandrel 160 on a carriage 195 while the mandrel 160 is rotated. The fiber placement apparatus 190 draws the fiber tape/tow from a spool 194 interconnected to a placement head 192 . As will be appreciated by those skilled in the art, preimpregnated CFRP tape/tow is normally stored in a frozen or refrigerated condition to extend the shelf life of the resin matrix prior to curing. To ensure that the tape/tow adheres to the surface of the mandrel and/or previous plies, the placement head 192 contains a heating element 193 that preheats the tape/tow prior to placement such that it is “tackified”. That is, the resin holding the fibers together is softened (i.e., thawed) to act as a glue that holds the composite structure 140 together prior to curing.
FIG. 8 is a flowchart illustrating one implementation of a design process utilized for producing a composite sandwich structure having at least one integrally reinforced section along its length. Initially, the spatial envelope for the composite structure 140 is determined ( 300 ). That is, a physical constraint such as an allowable thickness of the composite structure at one or more sections is determined. These constraints may be in relation to one or more interfacing structures or forces to be applied to the composite structure. For example, in case of a tubular composite sandwich structure for use as a portion of the sidewall of the space launch vehicle, the end of the composite structure generally interfaces with a metal socket joint (See FIG. 4 ). In this regard, the width of the socket joint mandates the maximum thickness of the composite sandwich structure 140 at the joint. In addition, determination ( 300 ) of the spatial envelope may further entail physical constraints in the lay-up/formation of the composite sandwich structure 140 such as mandrel size, type of mandrel, and/or desired interfacing characteristics, such as a uniform surface for mounting ancillary features, etc.
Once the spatial envelopes are determined ( 300 ) for the composite structure 140 , the structural requirements for one or more sections of the composite structure 140 are calculated ( 310 ). As will be appreciated, this step of calculating ( 310 ) takes into account various loads applied to various sections of the composite structure 140 . For example, a uniform compressive load may be applied over the entire composite structure 140 due to, for example, using the structural composite to interconnect a booster rocket and a payload. In addition, individual sections along the length of the composite structure 140 may be subject to additional individual loads, such as but not limited to, bending moments, compressive forces, tensile forces, etc. Further these forces may be applied-in-plane or out-of-plane with respect to the composite sandwich structure 140 . Based on the calculation(s) ( 310 ), desired stiffness, bearing and compressive strengths are determined ( 320 ) for the various sections of the composite structure 140 .
Based on the determination ( 320 ) of the required strengths of the various composite structure sections, appropriate materials are selected ( 330 ) to form the composite structure 140 . For example, appropriate fiber reinforced materials are selected to form the face sheets and an appropriate spacer material is selected for the core. Once materials are selected ( 330 ), the relative proportions of the first and second face sheet and core are determined ( 340 ) for each section of the composite structure to provide the desired structural characteristics. For example, if a section requires additional stiffness, the core thickness may be reduced while one or both of the face sheets thicknesses is increased, thus, increasing that sections stiffness while maintaining a profile that is the same as the profile at other sections of the composite structure 140 . Accordingly, based on the selection ( 320 ) of materials and determination ( 340 ) of the relative proportions of the face sheets and core, a design layout for the composite structure is produced ( 350 ).
FIG. 9 is a flowchart illustrating one implementation of a process for producing a tubular composite sandwich structure. Initially, a mandrel 160 (See FIGS. 2 and 5) is prepared ( 400 ) for the lay-up of the composite structure 140 . Preparation may entail the sub-step of applying a release agent to the outside surface of the mandrel 160 such that the mandrel may be removed after curing. To form the inside face sheet 58 , the inside ply 210 is applied ( 410 ) to the surface of the mandrel 160 , after which successive plies 211 - 217 are applied ( 410 ) to the outside surface of the preceding ply. As noted above, the directions of the fibers of each ply may be oriented orthogonally in relation to the ply above and/or below it to achieve particular mechanical and/or thermal properties. In this regard, the fiber placement apparatus 190 may be operative to move along the longitudinal length of the mandrel 160 as the mandrel rotates to apply the ply with the desired angle of fiber orientation. Though the lay-up discussed herein refers to a particular number of fiber reinforced material plies, it will be appreciated that the number of these plies may be increased or decreased depending on desired/required mechanical and/or thermal properties. Plies 210 - 217 are applied ( 410 ) across the entire surface of the mandrel 160 . To produce the integrally reinforced section (i.e., sections 64 and 66 of FIG. 2) augmentation plies are applied ( 420 ) to sections of the structure where reinforcement of the inside face sheet 58 is desired. As shown, three augmentation plies 218 - 220 are applied ( 420 ) to sections 64 and 66 on the outside surface of ply 217 . Three additional augmentation plies 221 - 223 are then applied ( 420 ) on the outside surface of ply 220 . These augmentation plies may be applied ( 420 ) utilizing the fiber placement apparatus 190 or manually applied (i.e., hand laid).
Once all the fiber reinforced material plies and augmentation plies that make up the inside face sheet 58 are applied ( 410 and 420 ) to the mandrel 160 , an adhesive is applied to cover ( 430 ) the exposed surface of the inside face sheet 58 . This adhesive is used to secure the core 60 to the mandrel 160 prior to application of the outside face sheet 54 . Accordingly, the core 60 is applied ( 440 ) to the exposed surface of the face sheet 58 . In the illustrated embodiment, a stepped core 60 is utilized that contains two inside steps 72 , 74 that reduce the core's thickness a corresponding amount for each set of augmentation plies 218 - 220 and 221 - 223 . This produces a core 60 that is in direct contact with the outside surface of the inside face sheet 58 across the length of the mandrel 160 . As noted above, the core 60 may be any appropriate homogenous material, however, the core may also utilize different materials for different sections. For example, section 66 may utilize a denser material or even a solid material such as an aluminum block, to increase the bearing and compressive strength of section 66 . Regardless of what material(s) is/are used for the core 60 , sections 62 , 64 and 66 , it is preferred that the various core sections are somehow interconnected to increase the composite structure's post-curing strength and facilitate lay-up.
The core's outside surface also contains two steps 82 and 84 (See FIG. 2) such that the inside and outside surfaces of the core 60 are mirror images. However, it will be appreciated that only one core surface and its contacting face sheet may contain steps and still be within the scope of the invention. In reverse order of the application of the inside face sheet plies 210 - 223 , the outside face sheet's plies 224 - 226 and 227 - 229 are applied ( 450 ) on the outside surface of core section 66 in areas where reinforcement for the outside face sheet 54 is desired. Plies 230 - 237 are then applied ( 460 ) to the outside surface of augmentation ply 229 and the outside surface of the core 60 .
Once all of the outside face sheet plies are laid, the composite structure 140 is consolidated ( 470 ) by enclosing it in a vacuum bag, which is evacuated to reduce the pressure therein by approximately 1 bar. The entire composite structure 140 and mandrel is then placed in an autoclave where heat and pressure are applied to cure ( 480 ) the composite structure 140 . After the composite structure 140 has cured ( 480 ) for a predetermined period, the structure 140 is removed from the autoclave and the mandrel is removed ( 490 ).
Those skilled in the art will now see that certain modifications can be made to the composite structure and method herein disclosed with respect to be illustrated embodiments without departing from the spirit of the instant invention. And while the invention has been described above with respect to the preferred embodiment for use as a sidewall for portion of space launch vehicle, it will be understood that the invention is adaptive to numerous rearrangements, modifications, and alterations that may be utilized for any composite structure and that these rearrangements, modifications, and alterations are intended to be within the scope of the appended claims.
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The present invention generally relates to a multi-layered structure which for a given external geometry a section of interest may be integrally reinforced by varying the relative proportions of the layers in that section. That is, the layers making up the structure may have varying relative proportions to the structure's overall thickness between two or more positions while the structure maintains a constant thickness between the positions. By varying the relative proportions of the structure's layers, the mechanical properties of the structure may be selectively altered from a first position to a second position without altering the structure's external profile. This is especially desirable in composite sandwich structures used in aerospace applications which often require additional reinforcement at structural interfaces. By adjusting the relative proportions of the composite sandwich structure's layers, one or more structurally enhanced sections may be created for structural interfaces without altering the structure's profile.
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FIELD OF THE INVENTION
This invention relates to processes for manufacture of twisted pairs of insulated electrical conductors.
BACKGROUND OF THE INVENTION
A twisted pair is defined in the art of electric cable manufacture as a cable composed of a pair of insulated conductors twisted together around each other without a common covering of insulation. Each conductor is individually insulated separately prior to the twisting process. Twisted pairs are used for the transmission of electrical signals, both analog and digital, and may be used for interconnects driven in a single-ended mode or differential mode.
Signal wiring configured in a single-ended mode uses one conductor to connect the output of one device and the input of another device. If the devices being connected are high speed devices, the conductor should be a controlled impedance interconnection. This can be accomplished by placing ground wires near the signal wire or by providing an overall shield as with a coaxial cable. When a twisted pair is used for single-ended wiring, one of the conductors connects the output while the other conductor provides a return path usually referred to as ground. For this type of interconnect, it is not important that the two conductors of the pair be of equal electrical length.
High performance digital systems frequently use differentially-driven signals. Differential signals provide more precise timing, better noise immunity, and higher signal fidelity. With differential wiring the true signal and its logical complement are sent to the receiving device. The receiving device measures the differential voltage between the two signal lines. As with single-ended systems, if the digital signals are coming from high speed devices the signal wires must be placed in a controlled-impedance environment. There are several advantages to using this type of interconnect. In a twisted pair configuration the signal lines are run in close proximity to each other. Since the signals will be switching directly opposite to one another, the fields generated by these switching signals will cancel out, thereby generating very little electro-magnetic radiation. For the same reason, any radiated electro-magnetic fields impinging on this interconnect system will be sensed equally by both lines, and since the receiving device is only measuring the differential voltage between the two signals, this common-mode noise will be ignored by the receiver. A disadvantage of differentially driven interconnects is that now two conductors are required for each signal. A twisted pair construction is ideally suited to differentially-driven signal transmission. To assure proper operation, each conductor must be well matched for characteristic impedance and time delay.
If the time delays of the two conductors are not well matched, the true signal and logical complement will be received at different times, thereby limiting the useful physical length of interconnect which can be used before signal fidelity is compromised. For the time delays of the two conductors to be well matched, two conditions must be met simultaneously. First, each conductor must have the same dielectric constant, E, since the velocity of propagation (Vp), and hence time delay, of the conductor is determined by the relation: Vp: 1/√E. Secondly, the physical lengths of the two conductors must be matched.
It has been observed that it has become more difficult to meet the requirements needed for high-speed digital differentially-driven systems with twisted pair cables, partly because it is not easy to obtain insulated conductors having exactly equal length and equal signal transmission speed end to end. If one unreels a length of twisted pair cable manufactured by the several methods known in the art and cuts a length of cable from the reel, the signal conductors therein are found to be not of equal length owing to the stresses and movements of the insulated wires as the twisted cable is formed.
The present invention provides a process for preparing twisted pair cables having insulated conductors of equal physical and electrical length.
SUMMARY OF THE INVENTION
The invention comprises a twisted pair of electrical cables formed from insulated conductors having equal physical and electrical length and a process for its manufacture.
The process of manufacture of the cable of the invention comprises passing a pair of adhered insulated electrical conductors of equal length, which have been adhered along their length at the contact line between them, through a closely-fitting die, which rotates about the axis of the pair of insulated conductors passing through the die. The die is attached to a rotating apparatus which holds the entire payoff spool holding the parallel pair of insulated conductors. Since the process starts with conductors of precisely equal physical length, the twisted pair cable formed therefrom by the above process has conductors of equal physical length and therefore equal electrical properties providing that the properties of the conductors and insulation are equal along their length.
The complete process of manufacture varies in some details depending on whether the insulation on the conductors is a thermoplastic polymer or is expanded polytetrafluoroethylene (ePTFE), which is not thermoplastic. Different methods of adhering the two insulated conductors must be used to effect a useful bond between them depending on which type of insulation is used.
Where the insulation is thermoplastic, such as polyester, for example, a preferred way to insulate a conductor is to wrap the conductor with layers of polyester tape having on one side a coating of thermoplastic polyester adhesive. The conductor is wrapped with the tape adhesive side out, which provides easy adherence of two insulated conductors of equal length. Other thermoplastics and adhesives may be used. In the case of thermoplastic insulation on the conductors, after twisting an appropriate solvent is used to remove excess adhesive from the insulated conductors as well as dissolve the bond between them.
Where the insulation is ePTFE, a conductor is tape-wrapped with an ePTFE tape, paired together with another like conductor of equal length over a concave plate or shoe, and the pair passed into a heated medium, such as molten salt bath or hot air oven, the plate or shoe holding the two insulated conductors in contact along their length until a bond is formed between the insulations as they sinter. The preferred ePTFE insulation is that disclosed in U.S. Pat. Nos. 3,953,566, 3,962,153, 4,096,227, 4,187,390, 4,902,423, and 4,478,665 (assigned to W.L. Gore & Associates, Inc.), wherein the ePTFE is characterized as having nodes separated by fibrils of PTFE and a large amount of porosity. An ePTFE insulated bonded pair of conductors breaks apart on passing through a closely-fitting die. The size of the die can be easily and simply changed during simple process testing to select the degree of close-fitting which causes the individual insulated conductors to split apart readily and consistently. Since the individual insulated conductors are bonded up to the point of twisting, their physical lengths are equal. Even if the individual insulated conductors do not split apart, the function of the invention remains the same. The preferred process for adhering ePTFE insulated conductors is fully delineated in U.S. patent application Ser. Nos. 07/574,704 (now abandoned) and 07/747,315 now issued as U.S. Pat. No. 5,245,134, the disclosure which is hereby incorporated by reference.
The conductors of the cable may have interior layers of insulation beneath the ePTFE or thermoplastic insulation and adhesive so long as the outer layers comprise those two insulations as described above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a pair of insulated conductors having two layers of insulation, the outer layers being bonded together.
FIG. 2 is a perspective view of a bonded pair of ePTFE-insulated conductors.
FIG. 3 is a perspective view of a bonded pair of ePTFE insulated conductors having an inner layer of a different insulation.
FIG. 4 is a perspective view of a die through which a bonded pair of insulated conductors is pulled to break them apart as they are being twisted into a twisted pair cable.
FIG. 5 is a schematic view of a process for adhering a pair of ePTFE insulated conductors by passing them across a concave-grooved plate to hold the conductors in contact while sintering occurs in a hot salt bath.
FIG. 6 is a perspective view of a grooved plate or shoe for holding insulated conductors in contact as they move across it together.
FIG. 7 is a perspective view of a pair of parallel adhered insulated conductors passing from a reel over tensioning rollers and bar through a die in a cable twister to break apart the insulated conductors as they are being formed into a twisted pair of equal length conductors.
FIG. 8 is a perspective view of a twisted pair of electrical cables made by the process of the invention from the pair shown in FIG. 2.
DETAILED DESCRIPTION OF THE INVENTION
The invention is now described in terms of the FIGURES to more carefully delineate in more detail the scope, materials, conditions, and processes of the invention.
FIGS. 1, 2, and 3 describe pairs of insulated cables suitable for use in the process of the invention. Two electrical conductors 1 are shown surrounded by a preferably thermoplastic insulation 2 which has coated on the outside a layer of adhesive 3. A conductor 1 is usually wrapped with a polyester tape having coated on at least one side with a heat sealable polyester adhesive. A preferred form of such tape is Milene® tape, obtainable from W.L. Gore & Associates, Inc. Conductor 1 is wrapped, adhesive side out, with layers of tape to form the insulated conductors shown in FIG. 1. A pair of the insulated conductors is passed side by side in contact with each other through a hot air oven to bond the insulations 2 together at bond line 4. The tape-wrap may be helically or cigarette wrapped around the conductor. Other thermoplastic polymers and adhesives may be used instead of the preferred materials. The thermoplastic insulation 2 may also be extruded onto conductor 1 then coated with adhesive 3.
FIG. 2 shows a pair of conductors 1 insulated by ePTFE. The respective ePTFE insulations 6 of a pair of conductors are caused to adhere to each other by passing a pair of the insulated conductors over a grooved shoe or plate to hold them in contact with each other while the insulated conductors are being passed through a molten salt bath at a temperature to cause the ePTFE insulation to sinter and fuse to the adjacent insulation. A hot air oven may be used instead of a salt bath. A temperature in the range of about 325°-350° C. is usually used for sintering ePTFE.
FIG. 3 shows a pair of adhered (along line 5) insulated conductors 1 covered with a thermoplastic insulation 2 and then an outer insulation of ePTFE 6.
FIG. 4 illustrates a die 7 for pulling an adhered pair, such as those shown in FIGS. 1-3, through a closely-fitting groove 8 which matches the dimensions of the pair of insulated conductors. The size of the groove 8 of die 7 may be changed readily by simple testing in order to select the size of groove 8 which will cause the bond 5 between insulations 6 to break as the joined insulated conductors are pulled through die 7. The outside shape and dimensions of die 7 may be varied considerably to suit the engineering needs of the twisting apparatus. In the case of thermoplastic insulations 4 and 3 and adhesive, die 7 is used for twisting only.
FIG. 5 shows a schematic diagram of a suitable process for joining parallel ePTFE insulated conductors along their length. Insulated conductors 12 pass off reels 10 and 11 over guide roll 16 into salt bath 17 over grooved shoes 14 held in the salt bath by supports 13. The sintered bonded together parallel conductor pair is taken up on take-up reel 15.
FIG. 6 describes grooved plate or shoe 14 which has a concave groove 18 formed therein which causes insulated conductors passing over plate 14 to contact each other while they fuse or sinter together to form a bond along the contact line between them or adhere to each other.
FIG. 7 shows a cable twister upon which is mounted a payoff spool 20. Spool 20 contains coiled on it a parallel pair 19 of adhered insulated conductors. The cable twister also comprises a rectangular frame 21 which supports spool 20, a shaft 26 to connect the twister to a mechanism for rotating it, a second frame 24 affixed at generally a right angle to frame 21 and supporting rollers 23 and 28. A spring-loaded roller tension bar 22 is also affixed to and supported by frame 21. An optional addition of frame 27 is shown dotted in, which may supply additional rollers 25 if it is desired to increase the length of parallel pair 19 from spool to die. Die 7, a round alternative version of the die shown in FIG. 4, is attached to and supported by frame 21.
To twist and separate (in the case of ePTFE insulation) parallel pair 19, pair 19 is fed off of spool 20 over one of rollers 23 then over roller tension bar 22 into die 7, from which it passes on to a take-up spool. As parallel pair 19 is being passed over the various rollers and bars and through die 7, the entire cable twister as a unit is being rotated by shaft 26 which results in parallel pair 19 being formed into a twisted pair and in the case of ePTFE insulated conductors, the joining bond between the two insulated conductors usually being broken as they pass through die 7. Where the insulation is thermoplastic, the insulation of the twisted pair remains joined and the pair is later separated by use of an appropriate solvent as mentioned above and residual adhesive coating the surface of the insulation after twisted pair cable formation is also removed at the same time.
An advantage of the process is that it is relatively easy to make parallel adhered pairs of insulated conductors of equal physical length, then twist them into a twisted pair cable, whereas it is more difficult to twist a pair of insulated conductors into a cable, then cut the cable to yield a segment of cable having conductors of equal length. Twisting processes known in the art inherently yield cables having conductors of different physical lengths in the same segment of twisted cable.
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A process for obtaining a twisted pair electrical signal cable having conductors of equal physical length and equal signal transmitting properties by passing a parallel pair of adhered insulated conductors of equal length through a closely-fitting die and twisting the conductors into a twisted pair cable. The process applies to thermopolymer insulated and ePTFE insulated conductors.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable
FEDERALLY SPONSORED RESEARCH
[0002] Not applicable
SEQUENCE LISTING OR PROGRAM
[0003] Not applicable
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] This invention relates to a composition and method for increasing the alertness and arousal of a human being. More specifically, it relates to the oral administration of a dry formulation mixture of the amino acid, taurine, and the stimulant, caffeine, to accomplish the synergistic benefits of these components in combination to increase a person's arousal level. Generally, it provides a convenient, measured, and efficient way to increase arousal without having to imbibe significant amounts of liquid or ingest unnecessary sugar or other carbohydrates, or other active ingredients.
[0006] 2. Related Art
[0007] Caffeine has been used as a stimulant and anti-sleep aid for centuries. While the most common source of caffeine is coffee, it is also found in other natural plant sources such as tea, cola nuts, and mate. Chemically, caffeine is 1,3,7-trimethylxanthine, and related to theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine). It is a bitter, white, water-soluble alkaloid powder.
[0008] Drinking coffee has long been recognized as a way to increase wakefulness and alertness. Many people drink coffee for its caffeine content to become fully awake and alert in the morning. In many work places, coffee is provided throughout the day so that people can operate at peak alertness and efficiency. Students have long appreciated the benefits of coffee to help them study long into the night. An 8 ounce cup of coffee typically contains between 80 mg and 135 mg or more of caffeine. An equal volume of tea delivers between 30 mg and 70 mg of caffeine.
[0009] Caffeine acts as a diuretic and has a stimulatory effect on the central nervous system, the heart, and the respiratory system. Thus, in addition to being a stimulant of the central nervous system, it also has peripheral effects, which, at high doses, can be a problem for some individuals. For example, even moderate amounts of caffeine can cause a rapid heartbeat or palpitations (ectopic heartbeats) in some sensitive people. Other side effects of excessive caffeine can include anxiety, insomnia, diarrhea, diuresis, facial flushing, restlessness, irritability, and trembling. There is a need for a way to achieve the benefits of caffeine while diminishing the possibility of suffering physiologic discomfort.
[0010] Currently, caffeine is available as an “over-the-counter” drug in the form of capsules and tablets. For example, the Bristol-Myers Squibb Company markets caffeine as an alertness aid under the brand name No Doz®. This has caffeine as the active ingredient, available in a variety of doses (the maximum dose is 200 mg per caplet), but also includes inactive ingredients well known in the art. GlaxoSmithKline markets caffeine as an alertness aid under the brand name Vivarin®, available in 200 mg tablets. It also includes inactive ingredients well known in the art. Although these brands are described as being as safe as coffee, there is no active ingredient listed that counteracts potential discomfort resulting from excessive caffeine ingestion. There is a need for such an ingredient.
[0011] Taurine (2-aminoethanesulfonic acid) is a conditionally essential amino acid because it is not incorporated into proteins, but it is found in a free form in many tissues, particularly muscle and nerve tissue. It is water soluble, and available as a fine crystalline powder. It is a neuroinhibitory transmitter and it may help regulate heart and skeletal muscle contractions, osmotic balance, energy levels, and brain neurotransmitter levels. In rats, the LD 50 of taurine is greater than 5,000 mg/kg.
[0012] Taurine appears to have several potentially useful psychological/neurological effects. It has been described as a possible anxiolytic (Chen, SW. et al., Life Sciences 2004 Aug. 6;75(12):1503-11) and an anti-epileptic (El Idrissi A, et al., Adv Exp Med Biol. 2003;526:515-25). It may alleviate visual fatigue (Zhang M, et al. Amino Acids 2004 February;26(1):59-63), attenuate amnesia (Vohra BP and Hui X, Neural Plast. 2000;7(4):245-59), and reduce peripheral sympathetic activity (Chahine R, et al., Arzneimittelforschung. 1994 February;44(2):126-8; Mizushima S, et al., Adv Exp Med Biol. 1996;403:615-22). As a reducer of peripheral sympathetic activity, taurine may counteract the unpleasant effects of caffeine without inhibiting the beneficial stimulating effects of caffeine. Thus, for example, in the “Opinion of the Scientific Committee on Food on Additional information on “energy” drinks” (expressed on 5 Mar. 2003), the view was expressed that “taurine might reduce the cardiovascular effects of caffeine.” (European Commission Health & Consumer Protection Directorate, Brussels Belgium, p. 8, available on the internet at: europa.eu.int/comm./food/fs/sc/scf/out169_en.pdf).
[0013] Taurine is marketed in the U.S. by a number of companies. For example, Twin Laboratories of American Fork, Utah, under its Twinlab® brand, markets Taurine as “Mega Taurine Caps,” which are nutrient capsules containing 1000 mg of taurine. Whole Foods Market of Austin, Tex. markets a “vegetarian” taurine as a dietary supplement available in 500 mg capsules.
[0014] In the last several years, so-called “energy drinks” have become available in the U.S. market. These soft drinks, usually available in 250 ml quantities, are a mix of ingredients usually including at least one stimulant and additional nutrient components such as amino acids, vitamins, and sweeteners. Caffeine is the most common stimulant in these drinks, but other ingredients, such as taurine, glucuronolactone, guarana, ginseng extract, herbal extracts, and vitamins, can also be found in various “energy drinks.” A popular “energy drink” is Red Bull®, which lists as its ingredients: carbonated water, sucrose, glucose, sodium citrate, taurine, glucuronolactone, caffeine, inositol, niacin, D-pantothenol, pyridoxine HCL, vitamin B12, artificial flavors, colors. Red Bull® Sugar Free drink lists as its ingredients: carbonated water, sodium citrate, taurine, glucuronolactone, caffeine, acesulfame k, aspartame, inositol, xanthan gum, niacinamide, calcium pantothenate, pyridoxine HCl, vitamin B12, artificial flavors, colors. Both versions of Red Bulls contain approximately 1000 mg of taurine and approximately 80 mg of caffeine (within the range of the amount of caffeine in a cup of coffee).
[0015] Much of the market success of energy drinks is due to the aura that has been associated with their use by young people in clubs and bars. Despite having a taste that some perceive to be unpleasant and/or artificial, these drinks have acquired a reputation for providing a “legal high” or mild euphoria, and, as a result, have become extremely popular. While the putative feeling of euphoria is likely a myth, enjoyment of these drinks is probably enhanced both by the fun environment in which they tend to be consumed, and the frequent concurrent use of these drinks with alcohol. Although these drinks are expensive, people are willing to buy them because by doing so, they buy into the aura and elan associated with these drinks. Currently, a single can of Red Bull retails for approximately two dollars. This is a lot of money to pay for a drink that delivers 80 mg of caffeine and 1000 mg of taurine. There is a need for a less expensive product that simply delivers caffeine and taurine together, and which is distinct from the psychosocial aura and elan associated with energy drinks.
[0016] There appears to be a psychopharmacologic synergy among the ingredients of these drinks. The caffeine is clearly a stimulant, but its effects, in concert with taurine, are different from what one experiences from caffeine alone, such as consuming a single cup of coffee (one can of Red Bull® provides 80 mg of caffeine, which is less than most cups of coffee). Some studies suggest that taurine mitigates adverse effects such as those caffeine may produce.
[0017] U.S. Pat. No. 6,261,589 discloses a soft drink that is a nutrient dietary supplement with a psychoactive effect. It is a carbonated beverage containing phenylalanine, vitamin B-6, vitamin C, copper, folic acid, taurine, vitamin B-5 (or pro-vitamin B-5), choline, fruit sugar, caffeine, and optionally green tea. This combination of ingredients is disclosed as a means of increasing energy level and general awareness. The inventors claim that taurine helps prevent excessive sensitivity to noradrenaline and that it promotes “a mellow mood without sedation or tranquilization.” Thus, taurine may help one to avoid the discomfort associated with excessive sensitivity to, or intake of, caffeine. The disclosed soft drink also includes additional ingredients such as vitamins, sugar, and other nutrients.
[0018] In Netherlands Patent No. NL1021051C, the inventors disclose a confectionery product based on sugar and/or glucose syrup that includes caffeine and taurine as additives. Although this invention discloses the use of caffeine and taurine for stimulating the central nervous system, respiration, and heart, it is a candy or sweet preparation, and depends upon sugar and/or glucose syrup as important ingredients. In PCT Application No. WO00/62812, the inventor discloses a nutritional composition for improved cognitive performance that comprises caffeine, choline, gamma aminobutyric acid, L-phenylalanine, and taurine in amounts sufficient to improve cognitive performance. In addition to the caffeine and taurine of this invention, several additional ingredients are used beyond what would be needed in a simple alertness aid.
[0019] Health-Tech, Inc. of Totowa, N.J., markets “Health-Tech Energy Strips,” which are thin edible strips containing caffeine, taurine, and other ingredients that dissolve easily on the tongue. Due to size limitations, these novelty strips, sold 24 to package, can only deliver a small amount of active ingredients. Three strips are recommended as providing an initially effective dose followed by 1 or 2 strips taken as needed. The consumer is cautioned not to take more than 24 strips during a 24 hour period. This product is fun to use, but not a serious way to self-administer caffeine and taurine precisely, in target amounts.
[0020] Despite the known combination of caffeine, and taurine with other active ingredients in energy drinks and sweet products, it is curious that no simple, “over-the-counter” dry formulation pharmaceutical product is available for delivering caffeine and taurine orally. The emergence of energy drinks with caffeine and taurine may have led to the development of candies, sweets and other functional foods that also contain caffeine and taurine. This has not, however, led to the combination of caffeine and taurine in a tablet, capsule, caplet or related formulation. Pharmaceutical and nutriceutical manufacturers have failed to appreciate the advantages of combining caffeine and taurine in a tablet, capsule, caplet or similar formulation.
[0021] Accordingly, it is desirable to provide a composition for improving alertness that relies on a combination of ingredients delivered in precise, sufficient amount to operate physiologically to stimulate a person's conscious state without unnecessary discomfort.
SUMMARY OF THE INVENTION
[0022] It is, therefore, an object of the present invention to provide a composition for improving alertness and generally stimulating a person's conscious state, relying on active ingredients that act together to provide a safe, yet higher level of arousal, while minimizing potential discomfort due to untoward side effects.
[0023] It is another object of the present invention to provide a composition for improving alertness comprising caffeine and taurine in amounts sufficient to result in a user feeling more awake, alert, responsive and less fatigued, yet more comfortable than would result from using caffeine without taurine.
[0024] A further object of the present invention is to provide a method of using the composition for precisely administering caffeine in a measured, dry form as a physiologic stimulant yet with a diminished likelihood of the user suffering discomfort due to the caffeine side effects.
[0025] An additional object of the present invention is provide a composition for improving alertness comprising caffeine and taurine without relying on sugar or sweetness to influence product use.
[0026] According to the present invention, the above and other objects are accomplished with a composition and method for causing a higher level of alertness, wakefulness, or arousal in a human being by providing caffeine and taurine combined in a capsule, tablet, pill or other dry form for oral administration in a precisely measured amount.
DRAWINGS
[0027] Not Applicable
DETAILED DESCRIPTION OF THE INVENTION
[0028] Caffeine has long been known in the art as a stimulant useful for increasing a person's level of alertness, wakefulness, or arousal. Because it is found in coffee, tea, cocoa, and other foodstuffs, there is a long history of its use and a thorough understanding of its effects and actions. Unfortunately, caffeine is a broadly acting, non-specific stimulant because it stimulates both the central nervous system and the peripheral nervous system and thus has many physiological effects that can be uncomfortable to the user. For example, it can increase heart rate, diuresis, anxiety, and restlessness.
[0029] Most people receive caffeine by drinking coffee or tea. This means of caffeine administration delivers inconsistent dosages of caffeine either because of differing concentrations of caffeine or different volumes consumed. For example, in brewing coffee there are many uncontrolled variables such as the coffee bean used, the brewing method followed, and the volume consumed. Furthermore, no coffee is available for administering caffeine along with a substance such as taurine that will mitigate the potential side effects of excessive caffeine ingestions.
[0030] Taurine is a non-essential amino acid that has been found to ameliorate some of the uncomfortable effects of caffeine. When caffeine and taurine are taken together, some side effects of caffeine are diminished and the user feels less discomfort, while still benefiting from an increase in alertness.
[0031] Although caffeine and taurine are now available in so-called “energy-drinks,” candy, and “energy-strips,” there is no taurine available in over-the-counter caffeine products such as No Doz® or Vivarin®. These products are serious and effective, they deliver measured doses of caffeine, and they do not rely on sweeteners and hype for marketing. They are not novelty items, but they lack taurine.
[0032] The present invention combines caffeine and taurine in an easily ingestible dry form such as a capsule, tablet, or pill. Other dry forms such as caplets, powders, or granules are also contemplated. More specifically, any pharmaceutically acceptable, dry dosage form is contemplated by the invention. Examples of such dosage forms include, without limitation, compressed tablets, film coated tablets, chewable tablets, quick dissolve tablets, effervescent tablets, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, dispersible granules. The present invention also can be incorporated into a chewing gum as a means of delivery. The preparation of any of the above dosage forms is well known in the art. A user may wish to use water or another liquid to aid in swallowing and ingestion of the present invention.
[0033] It is possible, in the composition of the present invention, for the dosage form to combine various forms of release, which include, without limitation, immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof. Obtaining immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting characteristics and combinations thereof is performed using well known procedures and techniques available to one with ordinary skill in the art. None of these particular techniques or procedures constitutes an inventive aspect of this invention.
[0034] When caffeine and taurine are incorporated into a candy, sweet, or “energy strip,” there is a possible tendency for the user to ingest too much. The user may perceive the product to be sweet, tasty, and/or fun, but these are not desirable perceptions because they may foster inappropriate and potentially harmful use of the active ingredients. This could be a particular problem for children, who might ingest too much of a candy, sweet, soft drink, or “energy-strip” that, along with other ingredients, contains caffeine and taurine. In contrast, the present invention, delivers caffeine and taurine as a capsule, tablet, pill or other familiar oral medicinal vehicle. This will, in no way, be confused as a candy, sweet, or novelty item. Because the present invention is not a candy or sweet, children will not likely be attracted or drawn to the product and, should a child happen to ingest one dose of the caffeine and taurine product, there will be no desire or incentive to take more.
[0035] In the present invention, caffeine and taurine may be ground and mixed together by conventional mixing equipment. The resulting powdered mixture may then be pressed into tablets or placed in gelatin capsules or formulated in another way for oral administration. The product may also contain one or more organic or inorganic additives such as conventional fillers, extenders and excipients. For example, the product may include, but not be limited to, fillers such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, binders such as starches, (e.g., maize starch, wheat starch, rice starch, potato starch) gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. Flow regulating agents and/or lubricants such as silica, talc, calcium stearate, magnesium stearate and/or polyethylene glycol may be added. Stabilizers known in the art also may be used. Disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
[0036] It is contemplated that the present invention can be provided as an oral preparation including but not limited to forms such as a tablet to be swallowed whole, a chewable tablet, a quick dissolved tablet, and effervescent tablet, a hard gelatin capsule, a soft gelatin capsule, a caplet or other well known oral formulation. Although the present invention is intended to be in a dry form, it can be taken with water or another liquid to facilitate swallowing and ingestion.
[0037] It is not the intent of this invention to deliver nutrients, such as vitamins and minerals, etc., in addition to the two listed active ingredients. Doing so would be unnecessary and contribute nothing to the specific aims of the invention.
[0038] The present invention delivers consistent, measured doses of caffeine and taurine. It is provided as a “serious” preparation such as a tablet, capsule, pill, and other forms mentioned herein above. By serious, the inventor means that the invention does not rely on sweetness such as candy preparations and energy drinks, psychosocial marketing “hype,” or novelty formulations such as “energy-strips” to be useful and marketable.
[0039] It is contemplated that, in the preferred embodiment, the caffeine content of a single dose formulation of the present invention is about 200 mg or less. It is further contemplated that, in the preferred embodiment, a single dose formulation of the present invention includes an amount of taurine of about 1000 mg or less. Thus, the unit dosage form of the preferred embodiment of the present invention includes about 200 mg or less of caffeine and 1000 mg or less of taurine. An alternative embodiment of the invention is contemplated to contain between about 50 mg to about 200 mg of caffeine and between about 200 mg to about 2000 mg of taurine.
[0040] The preferred embodiment and various modifications of the concept underlying the present invention have been set forth. Various other embodiments of the present invention, and modifications of the embodiments herein shown and described will occur to those skilled in the art upon becoming familiar with the disclosure herein. It is to be understood, therefore, that the invention may be practiced otherwise than as specifically set forth herein.
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An alertness inducing composition contains the active ingredients caffeine and taurine and various inert substances in a dry formulation. Caffeine and taurine are delivered in an oral formulation that obviates the need for ingesting significant quantities of liquid or sugar.
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BACKGROUND OF THE INVENTION
The present invention relates to a surgical tool for use in knee arthroplasty.
Knee replacement operations have become increasingly common in recent years and are used to provide relief, for example, to patients having painful or debilitating conditions such as rheumatoid arthritis.
In knee arthroplasty, a surgeon cuts bone from the proximal tibia and the distal femur in order to accommodate in the resected joint a knee prosthesis having a femoral and a tibial component. The tibial component typically comprises a polyethylene seat having two wells for receiving the lateral and medial femoral condyles. When the knee is in full extension, it is the distal femoral condyles which are seated in the polyethylene wells. When the knee is in full flexion, the polyethylene wells receive the posterior femoral condyles. The polyethylene seat is usually mounted on a tibial plate made, for example, of titanium, a titanium alloy or a cobalt/chromium alloy which itself is anchored in the tibia.
The femoral component comprises a unitary body having a highly polished distal surface shaped to resemble the articulating surface of the distal femur, the articulating surface comprising lateral and medial pairs of condyles which extend anteriorly, posteriorly and distally. The prosthetic femoral component body is made, for example, of a cobalt/chromium alloy and has a proximal surface shaped to receive a distal femur which has been resected by the surgeon. Optionally, the femoral component is anchored to the femur by means of proximal anchoring stems and cement. The femoral component usually has a substantially uniform thickness over its condyles measured in an anterior-posterior plane.
Of the four or five bone cuts made by the surgeon depending upon the design of the knee implant, three or four are made on the distal femur and one on the proximal tibia. Of these cuts, three are crucial determinants of the gaps formed between the tibia and the femur when the resected knee joint is in flexion and in extension respectively and the collateral ligaments are taut, or at least the medial one thereof is taut.
For the prosthetic knee to be stable both in flexion and in extension, the gap between the resected bone surfaces in flexion ("the flexion gap") should be equal, as nearly as possible, to the gap between the said surfaces in extension ("the extension gap"). This is because the thickness of the femoral component is the same in both the flexion position and the extension position. The thickness of the tibial component remains the same in both positions. Hence the combined thickness of the two components is the same in both positions and should be equivalent in each case to the relevant thickness of the bone that has been resected. The gaps in the resected knee in flexion and extension, when the collateral ligaments are taut, should also be the same. The ligaments will then be equally taut both in flexion and extension when a suitable prosthesis is implanted. This will ensure knee stability and a full range of motion. If the flexion gap exceeds the extension gap and an implant is fitted that fills the flexion gap, the knee will be incapable of full extension. If the extension gap exceeds the flexion gap with a particular implant, then the knee will hyper-extend and will be unstable in full extension. Conversely, if an implant is fitted in this situation that fills the extension gap, there will be similar problems in flexion and risk of dislocation. If the relationship between the flexion and extension gaps is incorrect, the problem cannot be solved by altering the level of the tibial cut or by altering the thickness of the tibial prosthesis. These alterations would affect both the flexion and extension gaps equally. However, adjustment of the level of the distal femoral surface alters only the extension gap. Such adjustment can be made either by cutting bone from the distal femoral condyles or, in the other direction, by packing the surface of the distal femoral condyles with bone cement.
In practice, prosthetic implant thicknesses are chosen to fit in full extension. The surgeon, having cut bone from the proximal tibia and distal femur surfaces, inserts a series of prosthetic tibial implants of increasing thickness into the knee in flexion. He then brings the knee into full extension to check that the knee is stable in extension. If the flexion gap exceeds the extension gap, the distal femur can be progressively cut to allow the knee to extend fully and to be stable in flexion. If the extension gap exceeds the flexion gap then the surgeon can pack the distal femur with cement to close up the extension gap. Inevitably, the position of the cuts and the final choice of the thickness of the implants by the surgeon in these instances are somewhat haphazard because the choice of location of cut or level of pack is no more than an experienced estimate on the part of the surgeon.
In the past, surgeons have used two techniques to try to ensure that the knee is stable in flexion and extension. The more elaborate prior art technique involves the use of a device known as a tensor. This device comprises a fixed distal paddle having lateral and medial flanges and a pair of proximal paddles which are movable with respect to the distal paddle. The arrangement corresponds to a medial paddle pair and a lateral paddle pair. The upper, or proximal, paddles are mounted independently of each other. Movement of the respective proximal paddle is achieved by means of manually operable screw threads. When a winding handle is turned, the threaded portion of the corresponding arm moves up or down. The tensor is equipped with a measuring device for measuring the distance between the proximal and distal paddles recording it for future reference.
In use, the surgeon makes at least two bone cuts before using the tensor. These are to the proximal tibia and to the posterior femoral condyles. Then, with the knee in flexion, the surgeon inserts the tensor paddles, with the proximal and distal paddle pairs close together. Then, by turning the winding handle, he adjusts the proximal/distal paddle distance until it corresponds to the medial flexion gap with the collateral ligament taut. Repeating this process with the lateral paddle pair and having thus established the flexion gap, the surgeon adjusts the position of the recording device to measure the space between the bone cuts. He then locks the measuring device in position to record that distance. The paddles are then brought together to release the tensor from the knee. The knee is then brought into full extension, at which point the tensor is reinserted and anchored within the extension gap by opening the paddles again. The measuring device, still recording the flexion gap distance, is then used as a guide to mark the distal femur at a location where that portion of the bone may then be cut to provide an extension gap of equal magnitude to the flexion gap.
The tensor technique is in practice somewhat elaborate and difficult to use. It is not widely used by surgeons despite having been available since 1976.
The second technique, which is in fact widely used by surgeons, involves the use of simple spacers. These are metal plates of varying thicknesses which the surgeon can insert into the extension gap having already cut the proximal tibia and distal femur. These spacers are used as no more than a convenient checking device to confirm that the surgeon has cut enough bone to accommodate the prosthetic implant and to tell him what size of implant will fit one of the gaps, or perhaps both, without certainty nor control.
Prosthetic implants are manufactured in various sizes to fit various bone sizes. The combined thickness of the femoral and tibial components of such implants is chosen to match the flexion/extension gap which the surgeon has cut. Generally, the femoral prosthetic component is manufactured with a standard thickness of about 9 mm. Tibial components are manufactured in a variety of discrete thicknesses, beginning with about 7 mm and rising in approximately 2.5 mm increments to about 17 mm. Accordingly, the combined thickness of commercially available knee prostheses ranges from about 16 mm up to about 26 mm in approximately 2.5 mm increments.
If insufficient bone has been removed, the surgeon can cut additional bone away. If too much bone has been removed, the surgeon can select a larger prosthesis and then remove more bone if necessary to accommodate the larger thickness. Alternatively, an over-cut bone surface can be packed with an appropriate thickness of bone cement.
This method has the advantage of being simple, if reliable bone landmarks are used to judge the cuts. However, a common practice amongst surgeons is to use such spacers to measure the extension gap and not to go on to check that the flexion gap is of similar magnitude. In part this is due to uncertainty of what corrective action to take if the gaps are unequal. Accordingly, spacers have the disadvantage that, as surgical practice has developed, very little attention is paid to the flexion gap. This results in poor flexion or undue laxity of flexion with consequent risk of dislocation.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide surgeons with a means easily to check the relationship between the flexion and extension gap during knee arthroplasty without the need to become involved with elaborate and complicated techniques. It is a further object of the present invention to provide an operative aid which, during the course of an operation, provides instruction to a surgeon regarding the magnitude of a particular cut or pack which a surgeon should make to stabilise the flexion/extension gap relationship, and to identify the bone from which the cut should be taken or to which the pack should be applied. Yet a further object of the present invention is to provide a tool which assists a surgeon correctly to establish the extramedullar alignment of the leg during a knee replacement operation.
Accordingly, the present invention provides a surgical tool for checking the flexion and extension gaps located between previously resected surfaces of a proximal tibia and corresponding posterior and distal femoral condyles during knee arthroplasty, the tool comprising a central body portion from which extends a handle; a first paddle flange adapted for insertion into a flexion or extension gap, the first paddle flange being mounted on the central body portion; a second paddle flange substantially parallel to the first paddle flange and cooperating therewith in a first position to define, between an upper surface of an upper one of said first and second paddle flanges and a lower surface of a lower one of said first and second paddle flanges, a first distance corresponding to a minimum gap and movable relative to the first paddle flange to define a second distance between the said upper surface and the said lower surface corresponding to a maximum gap; the second paddle flange being mounted so as to be movable relative to the central body portion of the tool to vary the gap defined by the first and second paddle flanges; hand operable means arranged to cause movement of the second paddle flange in a gap-increasing direction to enable determination of the size of the flexion gap or the extension gap; and means providing to a surgeon using the tool indicia comparative of the size of the flexion or extension gap being checked with the size of a flexion or extension gap checked in a previous operation of the tool and/or indicative of any action to be taken to equalize the flexion or extension gap being checked with a flexion or extension gap checked in a previous operation of the tool.
In a particularly preferred form the surgical tool of the invention has the second paddle flange mounted on a racked member so as to be incrementally movable relative to the first paddle flange and wherein a pawl means is arranged to engage the racked member to prevent movement thereof in a gap-decreasing direction, which pawl means is releasable to allow the racked member to move freely between positions corresponding to the minimum and maximum gaps respectively.
Conveniently, the racked member is biased relative to the central body portion towards a position at which a minimum gap is defined between the first and second paddle flanges. In this case, the bias of the racked member may be provided by a coil spring bearing on the central body portion of the tool.
In a preferred embodiment, the racked member is arranged such that successive operation of the hand operable means connected to the member causes the racked member to move incrementally from a first end position corresponding to a minimum gap through a number of intermediate positions corresponding to intermediate gaps to a second end position corresponding to a maximum gap. Preferably, the incremental increase in the gap defined by the first and second paddle flanges upon successive operation of the hand operable means connected to the racked member corresponds to the incremental increase in successive thicknesses of knee prostheses. For example, the increment could be between about 0.5 mm and about 5 mm. The current increment in commercially available prostheses is typically about 2.5 mm.
The hand operable means connected to the racked member conveniently comprises a lever arm pivotally connected to the central body portion and operatively connected to the racked member, whereby pivotal motion of the lever arm relative to the central body portion causes motion of the racked member. In this case, the lever is preferably operable by the extended fingers of one hand, the same hand being used to grip the handle in its palm. The handle may be adapted to receive an extramedullary alignment bar whereby the surgeon, having inserted the tool paddle flanges into a patient's extension gap and having secured the tool in place by operating the hand operable means associated with the racked member to open the first and second paddle flanges to correspond to the patient's extension gap, can align the bar with respect to the handle and, bringing the end of the bar towards the hip, check the valgus angle of the femur with respect to the tibia. A convenient way of achieving this end is to provide a groove in the handle to receive the extramedullary alignment bar.
Visual indicia for indicating, in use, the magnitude of the gap defined by the first and second paddle flanges may be displayed on a member connected to the racked member and movable in association therewith. Preferably, the visual indicia are visible only through a window in an indicia housing section of the tool.
It is preferable if a datum line is visible on the housing section so that indicia displayed in the window align with the datum line to indicate, in use, the magnitude of the gap. More preferably, the indicia housing section carries, above and/or below the window, instructive information with respect to an operation being performed by the surgeon. Even more preferably, the indicia housing carries the instruction "cut" above the window and the instruction "pack" below the window to inform the surgeon, when using the tool to measure a patient's extension gap, having previously used the tool to measure the patient's flexion gap and having aligned a particular visible indicium with the centre of the window during that flexion gap measurement, that if that particular visible indicium is displayed above the centre of the window during extension gap measurement, the surgeon should cut more bone from the distal femur because the extension gap is too small, or that if that particular visible indicium is displayed below the centre of the window during extension gap measurement, the surgeon should pack the distal femur with cement because the extension gap is too large.
The racked member may comprise a racked shaft which extends from the distal paddle flange. Preferably, the racked shaft extends upwardly through the central body portion and into a housing column secured to the central body portion. In this case, the visual indicia may be provided on a sheath connected to the shaft. Preferably this sheath is rotatable relative to the shaft to display a selected one of a number of alternative indicia columns.
The pawl means may comprise teeth on an operating button or pin mounted in the central body portion of the tool, which teeth engage corresponding teeth on the racked member to prevent movement thereof in the direction specified. In this case it is preferred that the operating button or pin is biased into ratchet-type engagement with the racked member, but which engagement is releasable by manually urging the button or pin against its bias.
It can be arranged that each successive operation of the hand operable means associated with the racked member causes the pawl means to click onto the next successive tooth on the racked member, which click is audible, whereby the surgeon knows the magnitude of the flexion or extension gap according to the number of clicks he has heard.
In order that the invention may be properly understood and fully carried into effect, a preferred embodiment will now be described with particular reference to the accompanying drawings, wherein:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a detailed side view of a surgical tool according to the invention;
FIG. 2 shows a cross-sectional drawing through line A--A of FIG. 1 when viewed in the direction indicated by arrow B;
FIG. 3 shows a front end view of a small section of the tool when viewed along arrow C of FIG. 1;
FIG. 4 shows a side sectional view of the portion of the tool depicted in FIG. 3;
FIG. 5 shows a perspective view of a portion of the tool with the central body portion removed for clarity;
FIG. 6 shows a side view of the tool of FIG. 1 being used to determine the flexion gap in a resected knee;
FIG. 7 shows a series of possible views of visible indicia on the tool viewed along arrow D of FIG. 6 during flexion gap measurement;
FIG. 8 shows a similar view of the tool of FIG. 1 being used to determine the extension gap in a resected knee;
FIG. 9 shows a series of possible views of visible indicia on the tool viewed along arrow E of FIG. 8 during extension gap measurement;
FIG. 10 shows a top view of part of the tool depicted in FIGS. 6 and 8;
FIG. 11 shows a developed view of the indicia visible when the tool is viewed along arrow D of FIG. 6 or arrow E of FIG. 8; and
FIG. 12 shows a top plan view of the handle of the tool, indicating the presence of the extra- or intramedullary alignment groove.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, the surgical tool has a first, or proximal, stainless steel paddle flange 1 connected at weld seal 2 to stainless steel central body portion 3 of the tool. Stainless steel arm 4 extends from central body portion 3 and is attached thereto at weld seal 5. Arm 4 terminates in a handle 6 of metal or plastics material, which is secured to arm 4 by pin 7.
A second, or distal, stainless steel paddle flange 8 is mounted on stainless steel shaft 9 and both are movable downwardly to a lower position indicated in ghosted lines and by reference numerals 8' and 9' to show that shaft 9, and hence paddle flange 8, can move between their respective upper positions indicated at 8 and 9 and their respective lower positions 8' and 9' as indicated in FIG. 1. Shaft 9 is only just visible when paddle flange 8 is in its uppermost position. Shaft 9 extends upwardly through bore 10 (FIG. 2) in central body portion 3 into stainless steel column 11. Column 11 is attached to central body portion 3 at weld seal 12. Shaft 9 is movable within central body portion 3 but is biased towards its uppermost position by coil spring 13 (FIG. 2) located inside column 11. Movement of shaft 9, and hence of distal paddle flange 8, is controlled by means of stainless steel lever 14 which is shown in FIG. 1 in two alternative positions 14 and 14'. Lever 14 is pivotally connected to central body portion 3 by pin 15. Lever 14, as shown in solid outline, extends through central body portion 3 and can be seen protruding slightly from the end of central body portion 3 near the junction thereof with proximal paddle flange 1. Proximal paddle flange 1 is provided with recess 16 (FIG. 10) to accommodate the protruding end of lever 14.
Referring to FIGS. 3, 4 and 5, lever 14 has a vertical slot 17 through which shaft 9 extends. The protruding end of lever 14 has a groove 18 which receives a retaining pin 19 mounted on distal paddle flange 8. Retaining pin 19 is of inverted L-shape with a vertical portion 20 extending upwardly from distal paddle flange 8 into the grooved end 18 of lever 14 and a horizontal portion 21 extending towards paddle flanges 1 and 8. The retaining pin 19 receives in its crook a transverse bar 22 mounted within the end groove 18 of lever 14.
Referring again to FIG. 1, on distal paddle flange 8 are mounted two stainless steel guide poles, one of which is designated by reference numeral 23 in FIG. 1. The second guide pole 23' (visible in FIG. 10) is directly behind guide pole 23 as the tool is viewed in FIG. 1. Guide poles 23 and 23' extend upwardly through vertical bores (not shown) in central body portion 3. A snug but slidable fit between each guide pole 23 and its respective bore ensures that movable distal paddle flange 8 always maintains a stable and parallel aspect with respect to fixed proximal paddle flange 1.
Shaft 9 has, within central body portion 3, a ratchet surface 24 (FIG. 2) which engages with pawl teeth 25 (FIG. 2) on stainless steel operating button 26. Button 26 is biased by means of coil spring 27 (FIG. 2) located in a recessed interior portion of central body portion 3. Coil spring 27 biases pawl teeth 25 of operating button 26 into engagement with ratchet surface 24 of shaft 9, thus preventing shaft 9 from moving upwardly to close the gap between paddle flanges 1 and 8. Button 26 can be manually pressed against the bias of coil spring 27 to release the ratchet mechanism and allow shaft 9 to slide freely inside central body portion 3 between limits defined by an upward stop 28 (shown in FIG. 1 as 28' in its lower position) which prevents distal paddle 8 from engaging proximal paddle 1, and defines a gap of 11 mm between the lower (distal) surface of paddle 8 and the upper (proximal) surface of paddle 1, and a downward stop 47 (FIG. 2) located inside column 11.
Column 11 is fixed relative to central body portion 3 and has a window 29 through which visible indicia shown in FIGS. 6 and 8 mounted inside column 11 can be viewed. The visible indicia are provided on stainless steel sheath 30 (FIG. 2) within column 11, which sheath is operatively connected to shaft 9 to move vertically in response to vertical movement of shaft 9 and display different respective indicia in window 29 as a result of such movement. Sheath 30 is also rotatable, rotation being manually effected by means of stainless steel knob 31. Four columns of visible indicia are carried by sheath 30, each respective column being accessible in one of four sheath positions defined by knob 31. Two opposing guide pins 32 and 32' (FIG. 2) are located in knob 31 and retain the knob in position by seating in accommodating recesses 33 and 33' (FIG. 2), of which there are four at 90° intervals, around the top of column 11.
In FIG. 2, the mechanism of the tool inside central body portion 3 and column 11 is more particularly displayed by means of a cross-sectional drawing, which is a cross-section taken through line A--A on FIG. 1 and viewed in the direction of arrow B. Proximal paddle flange 1 is attached to central body portion 3 at weld seal 2. Distal paddle flange 8 is mounted beneath paddle flange 1 and is stably but slidably secured in parallel relation thereto by guide poles 23 and 23' which extend vertically through respective bores (not shown) in central body portion 3. Shaft 9 is secured to paddle flange 8 by threaded screw 34. Reference numeral 14 indicates lever 14 which has a vertical slot 17 (FIG. 5) to receive shaft 9 therethrough. Shaft 9 extends upwardly vertically through central body portion 3 into column 11.
The top of shaft 9 is secured by screw thread 35 to carriage 36, which carriage 36 is vertically movable within housing 37. Carriage 36, and hence shaft 9, are urged towards an uppermost position within housing 37 by coil spring 13. Visible indicia sheath 30 is also mounted on carriage 36 but is rotatable relative thereto by rotation of knob 31. Knob 31 has two guide pins 32 and 32' which are seated in recesses 33 and 33' at the top of column 11. There are four such recesses at 90° intervals around the top of column 11. Resilient washer 38 ensures that guide pins 32 are urged into seating engagement with recesses 33. Shaft 9 has a racked surface 24 which engages teeth 25 on operating button 26. The ratchet engagement can be released by pressing on operating button 26 to urge it into recess 35 within central body portion 3.
In use, referring to FIGS. 6 and 7, a surgeon first presses operating button 26 to release shaft 9 from its ratchet lock whilst being careful to avoid squeezing lever 14 and handle 6 together. Shaft 9 can then move upwardly under the influence of the coil spring 13 within column 11, to which shaft 9 is connected. This movement brings distal paddle flange 8 into its closest possible proximity with proximal paddle flange 1 with stop 28 determining the gap between the two paddle flanges. This gap is predetermined such that the total distance from the proximal (upper) surface of proximal paddle flange 1 to the distal (lower) surface of distal paddle flange 8 is 11 mm. This corresponds to a flexion gap of 5 mm less than that required by the smallest commercially available prosthetic implant, which has a tibial component 7 mm in depth and a femoral component of 9 mm thickness. The prosthesis is thus 16 mm in total depth. Before inserting the tool, the surgeon cuts bone from the proximal tibia and the distal femur in an amount which he estimates will yield an approximately correct gap in flexion and extension for the particular prosthesis he has selected as being suitable for his patient. He then inserts paddle flanges 1 and 8 into the flexion gap, i.e. the gap defined between the proximal tibia resected bone surface 40 and the resected posterior condyles 41 on the distal femur 42 when the knee is in flexion. Then, by squeezing lever 14 towards handle 6 in the direction indicated by arrow F, the surgeon lowers shaft 9, and hence distal paddle flange 8. Gentle pressure on lever 14 causes pawl teeth 25 (FIG. 2) on operating button 26 to click onto the next tooth on racked shaft 9. This click is audible and the number of clicks made thus gives the surgeon a very approximate indication of the magnitude of the flexion gap. The rack is arranged such that each respective click causes the flexion gap defined by the proximal and distal paddle flange surfaces to increase by about 2.5 mm, corresponding to the increments in which prosthetic implants are commercially available. The surgeon continues to squeeze lever 14 until the paddle flanges are open to their fullest extent possible within the flexion gap, with the collateral ligaments 43 taut. One advantage of the present invention is that the surgeon can readily judge the degree of resistance within the joint to any further ratchet click which he may feel it correct to make.
Having thus adjusted proximal and distal paddle flanges 1 and 8 to correspond, between their respective proximal and distal surfaces, to the magnitude of the flexion gap in the resected joint, the surgeon rotates knob 31 in the direction indicated by arrow G until one of seven possible visible indicia is displayed in the centre of window 29 as viewed along arrow D. FIG. 7 shows four of the seven possible indicia. If "T-5" is displayed in window 29 opposite datum line 44 that circumscribes column 11, as shown in FIGS. 7 and 9, the surgeon knows that the flexion gap is too small to allow even the smallest commercially available prosthetic implant to be accommodated therein and that a further 5 mm of bone should be cut to allow the smallest implant to be used. Assuming the surgeon has cut approximately equal amounts of bone from the posterior and distal femur condyles 41 and 45 respectively, the extra 5 mm should be cut from the tibia (hence "T-5"). This is because only a further tibia cut will increase both the flexion and extension gaps simultaneously.
If "T-2.5" is displayed in window 29 opposite datum line 44, the surgeon is informed that he should cut a further 2.5 mm off the proximal tibia in order to use the smallest prosthetic implant.
If "7", "9.5", "12", "14.5", or "17" are displayed in window 29 opposite datum line 44, the surgeon knows that the gap he has cut is wide enough to accommodate an implant having a total depth on its tibia component of 7, 9.5, 12, 14.5 or 17 mm respectively.
When the surgeon is satisfied that the flexion gap is of appropriate magnitude, he releases the tool from the joint by pressing on operating button 26. This action urges the operating button pawl teeth 25 (FIG. 2) into recessed area 39 (FIG. 2) inside central body portion 3, thus releasing the teeth from their ratchet-type engagement with ratchet surface 24 (FIG. 2) of shaft 9. Shaft 9 is then urged, by coil spring 13 (FIG. 2) within column 11, towards its uppermost position, thus bringing distal paddle flange 8 back into its closest possible proximity to paddle flange 1.
The surgeon then releases the tool from the joint whilst leaving knob 31 in the same position at which the flexion gap was displayed in the centre of window 29 during the first measurement. Then, and now referring to FIGS. 8 and 9, after moving the knee into full extension, the surgeon reinserts the tool into the extension gap defined between the resected proximal tibia 40 and distal femur condyles 45. He then squeezes lever 14 towards handle 6 in the direction indicated by arrow H until paddle flanges 1 and 8 separate to correspond to the extension gap. If the same visible indicium is displayed in the centre of window 29 opposite datum line 44 as was displayed during flexion gap measurement ("the flexion indicium"), the surgeon knows that the flexion and extension gaps are approximately equal and he can proceed to implant the prosthesis. If the flexion indicium remains above the centre of window 29, the surgeon knows that the extension gap is too small and he must cut a certain amount of bone off the distal femur condyles. If the flexion indicium falls below the centre of window 29, the surgeon knows that the extension gap is too large and he must pack the distal femur with a certain quantity of bone cement. The indicia can be arranged to display how much bone needs to be removed from, or alternatively, what thickness of bone cement needs to be packed onto the distal femur. Thus, in the embodiment depicted in FIG. 9, the word "cut" is displayed on column 11 above window 29 and the word "pack" is displayed below window 29. The numerals "2.5" are displayed above and below the datum line 44 at the centre of window 29 to indicate that a further 2.5 mm of bone should be cut from the distal femur or, alternatively, that a 2.5 mm layer of bone cement should be packed onto the distal femur prior to implantation of the prosthesis.
FIG. 10 shows a top view of the same embodiment of the invention depicted in FIG. 1. This shows recess 16 in proximal paddle flange 1, which recess accommodates the protruding end of lever 14.
FIG. 11 shows a developed view of visible indicia sheath 30, showing the seven alternative indicia viewable in the particular embodiment of the invention which has been described above.
FIG. 12 shows a top view of handle 6 in which groove 46 for accommodating an intramedullary or extramedullary alignment bar can be seen. Thus, in use, a surgeon may use such a bar to check the valgus angle between his patient's femur and tibia by aligning the bar in groove 46 while the surgical tool of the invention is securely seated in the resected joint with the knee in full extension.
An advantage of the tool of the present invention is that it allows a surgeon to use anterior referencing in the course of the operation. Normally it is necessary for the surgeon to use posterior referencing so that all measurements are made from the back of the knee which is less satisfactory. Because of the variation in physical size of patients they are likely to have differing bone sizes. However, only a limited range of sizes of knee implant is manufactured and sold. Often the gap between different thicknesses can be from about 4 mm to about 5 mm. The surgeon would ideally like to have as much metal as possible at the back of the knee. However, if he uses posterior referencing, any difference between an implant which would be a perfect fit and the next available larger size means that the implant may project somewhat at the front of the knee after implantation. This is currently the best way for the surgeon to achieve correct, or near correct, balance between the flexion gap and the extension gap. Above all the surgeon must avoid resecting the bone so far that he removes a part of the anterior cortex of the femur. If he does then there is a risk of fracture of the femur.
The present invention allows the surgeon to use anterior referencing, using the anterior cortex of the femur as a reference surface.
FIG. 7 illustrates a series of indicia including T-5 and T-2.5. These indications are appropriate only for an implant having a nominal thickness of 7 mm. If the surgeon decides to use a thicker implant, eg 9 mm implant, then he has to do some mental arithmetic to derive the correct information from the tool. If desired the indicia T-5, T-2.5 etc can be replaced by other types of indicia, for example a hatched area having horizontal lines drawn across it with spacings there between corresponding to the nominal increment between different thicknesses of implant in a particular manufacturer's range of implants.
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The present invention relates to a surgical tool for use in knee arthroplasty. The tool is designed to assist a surgeon to implant a knee prosthesis which will be stable when the knee is in flexion and in extension. The tool comprises a parallel pair of paddle flanges adapted for insertion into the flexion or extension gap located between resected surfaces of a proximal tibia and a corresponding distal femur. The paddle flanges are incrementally movable relative to each other to define a range of gaps extending between a minimum gap and a maximum gap between exterior surfaces thereof. The incremental movement is provided by a racked member on which one of the paddle flanges is mounted, the racked member being movable by hand operable means connected thereto and which racked member engages with a pawl to prevent movement thereof in a gap-decreasing direction when the tool is in use.
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CROSS-REFERENCE TO RELATED APPLICATION
This application claims benefit under 35 USC 119(e) to copending U.S. provisional application Ser. No. 61/485,999, filed on May 13, 2011, the entire contents of which are incorporated herein by reference.
BACKGROUND
This application is directed to protective mouthguards for use by athletes to ensure proper placement of the device and jaw alignment, dissipation of detrimental forces during activity, and temporary storage of the mouthguard.
Historically, mouthguard tethering devices consisted of nylon or thermoplastic material that connects the sports guard to the face mask of the helmet. This outdated design is not favored by athletes because it is cumbersome, swings about freely, and places the athlete at risk for head and/or neck injuries when the facemask is incidentally grasped during competition.
Mouthguards are designed to protect the athlete during play by reducing the impact forces to the player during competition. However, failing to wear a mouthguard or wearing an ill fitted device can cause detrimental short term and long term effects such as tooth fracture, tooth avulsion/luxation, condylar and/or mandible fracture, maxillary fracture, jaw fractures, migraines, concussions and TMJ disorders.
Currently, two types of mouthguards exist on the market—custom fit and non-custom fit. Custom fit mouthguards generally provide the best protection for athletes, but are expensive and require a dentist for proper fabrication and fitting. The athlete's molds are made by taking impressions of the maxillary and mandibular teeth. A bite registration is recorded using a wax or elastomeric material. This registers the athlete's jaw position and how the teeth interdigitate. This record is then used to ensure that the upper and lower teeth are properly aligned, and a thermoplastic material is placed over one of the arches to serve as the mouthguard. The prosthesis is then trimmed to ensure proper fit and comfort, and the occlusion is registered by reheating the thermoplastic material to ensure the teeth and condyle are in a protected position. Due to the expense and need for a dental professional to fit custom mouthguards, many athletes do not avail themselves of the added protection and superior performance provided by custom fitting.
So-called “boil and bite” conventional mouthguards are examples of non-custom fit “off the shelf” protective devices widely available on the market. Today's “boil and bite” mouthguards offer little protection to players and are inadequate in various areas including fit, impact strength, proper teeth and jaw positioning, temporary storability, and debonding of the softer layer from the more rigid harder core. Stock mouthguards can be made of rubber, polyvinyl chloride, or a polyvinyl acetate copolymer, and are available in small, medium and large sizes. These conventional mouthguards are not custom molded to fit the individual, and exhibit inadequate support, retention and stability, resulting in common complaints by the user.
Non custom mouthguards such as the “boil and bite” are often ill-fitting and, if not properly seated during the forming phase after heating, can cause injury. One limitation of the “boil and bite” is the inability to provide a uniform thickness around the anterior and posterior teeth for protection. A thickened area of material in one area can cause distortion when cooled, and can become very thin areas in others. These thin areas can lead to inadequate thickness for protection and resulting injury.
Another problem with conventional “boil and bites” is the inability of the user to ensure proper placement of the guard and proper positioning of the jaw during fabrication and fitting. By placing the tray too far anteriorly, posteriorly, or laterally, the teeth are not adequately protected because the guard becomes offset. This creates a bulk of material or thinning of material which may lead to distortion or inadequate protection. Improper seating of the mouthguard during setting can also cause the material to be bulky and more importantly, can lead to improper positioning of the jaw. This may result in harmful effects in the temporal mandibular complex.
Other problems exist in conventional mouthpiece designs. For example, the athlete has no adequate place for storage when the device is temporarily removed during activity. In football, for example, the athlete's mouth guard is sometimes tethered to the helmet via the facemask. This common method of storage results in the mouthguard dangling from the player's helmet. This is often unfavorable to the athletes, and more players are simply holding the mouth guard in their hand or wedging it in the facemask. By wedging the mouth guard, the guard becomes distorted which, in turn, effects the fit and protection. By simply holding the guard, it becomes cumbersome and is often lost or dropped. When dropped, the athlete's mouthguard is soiled with dirt and other harmful bacteria which can lead to numerous problems, including health issues. Another reason athletes find the conventional tethering system unfavorable is that it limits their range of motion as they move their heads in different positions. This conventional tethering of the jaw to the helmet can also cause injury when another player grabs the helmet and the head/neck and jaw is abruptly malpositioned. Conventional approaches do not provide a convenient, safe means of affixing a mouth guard to a player's equipment for storage.
What is needed is a mouthguard that can be easily fitted without the assistance of a dentist, while providing superior protection beyond that available from conventional “boil and bites”. What is further needed is a mouthguard that lowers the risk of severe injury during activity, allows for the proper placement and alignment of the teeth and jaw structures, and which offers safety and sanitization during periods of non-use. What is also needed is an easy and reliable mouthguard storage mechanism that reduces opportunities for contamination or loss during periods of non-use.
SUMMARY
Among other things, this disclosure provides embodiments of a protective mouthguard with improved fit and protection in comparison to conventional “boil and bite” mouthguards, and with less expense and comparable performance to custom mouthguards crafted by a dentist, for example.
In one or more embodiments, alternative innovative clamps, both using a magnetic material design, are disclosed which secure to the face mask and allows the athlete's mouthguard to be temporarily affixed to a helmet, for example, when not being used. In addition, magnetic material can be used in custom mouthguards as well.
In one or more embodiments, the innovative protective mouthguard design of this disclosure addresses concerns identified above with respect to non-professionally fitted mouthguards. For example, embodiments of this disclosure use specially designed built-in guides and scaffolds at experimentally determined angles and/or heights to ensure proper tooth and jaw positioning for protection of a wide population of users. Accordingly, various embodiments of the protective mouthguard of this disclosure address the problems of fit, comfort, speech, and breathability of conventional “boil and bite” mouthguards. In addition, the innovative protective mouthguard design of this disclosure addresses concerns with the expense of custom fitted mouthguards.
In one embodiment, a dual layer protective mouthguard includes an outer layer comprising an exoskeleton having a generally U-shaped tapered base and inner and outer walls adapted to extend into a vestibular area of an oral cavity of a particular person using the protective mouthguard; an inner layer, e.g., a thermo-plastic flowable material, bonded to the inner wall of the outer layer, wherein the exoskeleton comprises front and rear interior scaffold structures having a predetermined height above a bottom of the U-shaped tapered base selected to contact incisor and molar teeth of a selected population of users using the protective mouthguard so as to ensure a uniform thickness of the inner layer material, e,g., a thermo-plastic flowable material, when the protective mouthguard has been fitted to the particular person in the selected population of users, wherein the exoskeleton further comprises interior tapered side bumpers extending from the interior wall of the exoskeleton, said side bumpers arranged to position the mouthguard within the oral cavity and provide a plurality of contact surfaces located at a contour height suitable for contacting teeth of the selected population of users, said plurality of contact surfaces ensuring a desired flow of the inner layer material around each tooth of the particular person when the mouthguard is being fitted to the particular person and thereby provide a desired protective thickness of the thermo-plastic flowable material after being fitted.
In one or more embodiments, a tethering mechanism is included that provides the ability to avoid contamination of the mouthguard during periods of non-use. In one implementation, a magnetic tether is provided, with magnetic or ferromagnetic material embedded in the mouthguard, with a corresponding magnetic or ferromagnetic receiver suitable for holding the mouthguard on a helmet, wristband, or helmet decal, for example.
In one or more embodiments, preventive technologies such as caries prevention utilizing fluoride and/or calcium phosphate and/or medications may be incorporated into the softer inner layer.
In another embodiment, a method of fitting a protective mouthguard to a particular person having physiological parameters encompassed by a selected population of users includes heating the inner layer; placing the protective mouthguard including the heated inner layer in the oral cavity of the particular person using the protective mouthguard; contacting the front and rear interior scaffold structures with incisor and molar teeth of the particular person and thereby ensuring a uniform thickness of the thermo-plastic flowable material; using the interior tapered side bumpers to position the mouthguard within the oral cavity and thereby provide a plurality of contact surfaces and thereby ensuring a desired flow of the thermo-plastic flowable material around each tooth of the particular person; forming the protective mouthguard to oral structures of the particular person, said interior tapered side bumpers and said front and rear interior scaffold structures ensuring a desired protective thickness of the thermo-plastic flowable material after the heated inner layer has cooled, said interior tapered side bumpers ensuring aligning the mouthguard in the oral cavity such that impact forces are directed over a long axis of each tooth of the particular user.
In another embodiment, a method of fitting a protective mouthguard to a particular person having physiological parameters encompassed by the selected population of users includes obtaining a digitally scanned image of oral structures of the particular person; using the digitally scanned image to form a model of the oral structures; heating the inner layer; preforming the protective mouthguard to a shape of the oral structures by using the model, said interior tapered side bumpers and said front and rear interior scaffold structures ensuring a desired protective thickness of the inner layer material after the heated inner layer has cooled, said interior tapered side bumpers ensuring aligning the mouthguard in the oral cavity such that impact forces are directed over a long axis of each tooth of the particular user.
In another embodiment, a method of making a protective mouthguard suitable for providing protection for persons having oral structure properties encompassed by a population of similarly sized but different persons includes obtaining a plurality of oral scan tracings from persons included in the population; overlaying the plurality of oral scan tracings; determining an average centerline of the plurality of oral scan tracings; determining a maximum and a minimum dimension of the protective mouthguard calculated using the plurality of oral scan tracings; and identifying inside bumper locations for plural interior bumpers, said identified locations ensuring contact with all teeth of persons encompassed in the population.
In another embodiment, a mouthguard tethering system includes an external attachment mechanism comprising a clamp mechanism, wherein said clamp mechanism comprises a first clamp half; a second clamp half; a connector arrangement configured to connect the first clamp half to the second clamp half; a ferrous and/or magnetic disc configured to be received in an opening in the second clamp half; and a protective covering arranged to cover the connector arrangement, the ferrous and/or magnetic disc and the opening in the second clamp half.
These and other features and characteristics of the present disclosure, as well as the methods of operation and functions of the related elements of structure and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following description and the appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in the various figures. In various embodiments of this disclosure, the structural components illustrated herein are drawn to scale. It is to be expressly understood, however, that the drawings are for the purpose of illustration and description only and are not intended as a definition of the limits of the inventive concept. As used in the specification and in the claims, the singular form of “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
BRIEF DISCUSSION OF THE DRAWINGS
FIG. 1 illustrates a top view of an exoskeleton or outer shell of a mouthguard of an embodiment;
FIG. 2 illustrates a perspective view of the exoskeleton of FIG. 1 ;
FIG. 3 illustrates a front view of the exoskeleton of FIG. 1 ;
FIG. 4 illustrates a bottom/underside view of the exoskeleton of FIG. 1 ;
FIG. 5 illustrates a rear view of the exoskeleton of FIG. 1 ;
FIG. 6 illustrates a side and partial cutaway sectional view of the exoskeleton of FIG. 1 , taken along the sectional line 6 - 6 of FIG. 2 ;
FIGS. 7A through 7E illustrate a representative sample of five patient scan tracings out of a larger patient population used to demonstrate the differences in tooth and jaw alignment between the patients;
FIG. 8 provides an overlay and evolution of the dimensions of the an embodiment of the exoskeleton of FIG. 1 using the five patient scan tracings of FIGS. 7A-7E ;
FIG. 9 illustrates the overlay of the five patient scan tracings of FIGS. 7A-7E to determine the dimensions of an exemplary exoskeleton of an embodiment;
FIGS. 10A-10H illustrate various perspective views of the layered protective mouthguard of an embodiment and which includes an outer layer/exoskeleton of FIG. 1 and an inner thermoplastic layer;
FIG. 11 illustrates an embodiment of a novel mouthguard clamping mechanism;
FIGS. 12A-12D illustrate an alternative embodiment of a novel mouthguard clamping mechanism; and
FIGS. 13A-13B illustrate an alternative embodiment of a novel mouthguard clamping mechanism.
DETAILED DESCRIPTION
This disclosure provides, in one or more embodiments, a dual layer mouthguard 100 having a U-shaped tapering base with an inner and outer wall extending into the vestibular area of the oral cavity. The outer and inner framework consists of a light weight, shock absorbing material to protect the teeth, surrounding soft tissue and temporal mandibular complex. The liner material may be a thermo-plastic material, e.g., ethyl vinyl acetate (EVA) material, polyurethane, polystyrene, or selected blends thereof, which may be bonded to the harder outer exoskeleton/core, e.g., mechanically coupled and/or chemically bonded. Alternatively, polystyrene may be used, or a nanocarbon material may be used in forming the inner layer or liner material.
With reference to FIGS. 1-5 , advantages of one or more embodiments of new mouthguard design 100 may be found in various features illustrated in the drawings and discussed below. For example, in one embodiment, harder outer core (or exoskeleton) 110 contains front scaffold 120 and rear scaffolds 130 , 131 on interior tray portion 140 made of a semi-rigid material on which the molars and incisor teeth will contact during and after initial fitting to ensure a uniform thickness of the softer, liner material 195 that is placed into interior 140 of exoskeleton 110 to fit mouthguard 100 to a particular user. Liner material 195 may be a flowable material, such as polystyrene, polyurethane, or EVA, and may optionally include a reinforcing nanocarbon fiber material. Exoskeleton 110 may be polystyrene, EVA or a polyurethane/EVA blend, and may include a reinforcing nanocarbon fiber material. The softer liner material 195 is not shown in FIGS. 1-6 to aid in exposition of the arrangement of the constituent parts of exoskeleton 110 . The material used for the inner layer, e.g., flowable liner material 195 is selected to be strong enough to absorb and dissipate forces so as to reduce traumatic injury to the teeth, TMJ, and surrounding oral structures.
In one or more embodiments, mouthguard 100 includes exoskeleton 110 , front internal scaffold 120 , rear internal scaffolds 130 / 131 , interior tray portion 140 , front exterior scaffold 150 , right/left rear outside scaffolds 160 / 161 , exterior bumpers 170 , interior bumpers 171 , facial flanges 180 , buccal flanges 185 , interior lingual flange 190 , and liner material 195 (see FIG. 10A ). The functions and dimensions of these elements will be discussed below.
In an embodiment, the dimensions of rear interior scaffolds 130 , 131 may be 10 mm×5 mm in the posterior, and the dimensions of front interior scaffold 120 may be 9.45 mm×12.5 mm with an incisal flare angle θ 1 =28° in the incisal regions. In addition, front/rear interior scaffolds 120 / 130 / 131 may be raised to have a height of 3 mm above the bottom of interior tray portion 140 to ensure adequate flow of the flowable liner material 195 when mouthguard 100 is fitted to a user. Rear right/left interior scaffolds 130 / 131 may be oriented at rear interior scaffold centerline angle θ 2 =12.5°. These dimensions should be understood to be exemplary in nature, and not limiting, as other dimensions and/or angles may be determined to be more appropriate for other athletes or user populations.
In an embodiment, and as illustrated in the bottom/underside view of FIG. 4 , exoskeleton 110 may contain front outside scaffold 150 , and right/left rear outside scaffolds 160 , 161 . It may be appreciated by one of ordinary skill in the art that the front outside scaffold 150 intrinsically functions as an anterior deprogrammer, configured to open a user's bite by an amount associated with the dimensions of the front outside scaffold 150 . Rear outside scaffolds 160 , 161 may be 1 mm high on the exterior with a determined slant angle θ 5 (see FIGS. 5 and 6 ). This feature allows the condyle to be positioned in a more downward, anterior position to allow better protection of the TMJ joint and allows the muscle to be placed at a more neutral, relaxed position. For a particular population of users, e.g., NFL® athletes, right/left rear outside scaffold slant angle θ 5 =3° mimics the arc of closure to allow less interference and allows the jaw to be more accurately positioned. These parameters may be adapted for a different population of users.
In one embodiment, facial flanges 180 and buccal flanges 185 of exoskeleton 110 were devised based on the average of scanned models of NFL® athletes and information determined by an interactive user interview process so as to be comfortable but yet protective in design. The average height of facial flanges 180 and buccal flanges 185 is 13.5 mm in one embodiment. These flanges have been determined to allow adequate protection of the teeth and supporting bone and soft tissue from impact. Although the embodiment illustrated is directed to a specific population of athletes, i.e., large adult males who play professional football, the inventive concept described herein is equally applicable to other sports and differently sized athletes, e.g., lacrosse, basketball, wrestling, soccer, judo, etc., without departing from the inventive concept described herein. For example, the various angles, heights, and thicknesses of various components may be separately determined on an average basis for each different athlete population.
In one embodiment, interior lingual flange 190 of exoskeleton 110 was devised using the average height that was deemed comfortable and proper fitting to allow airway exchange and speech for NFL® athletes, but which still provided adequate protection. In one embodiment, the average height of interior lingual flange 190 is 11 mm, with interior lingual flange flare angle θ 6 =63.4°. Interior lingual flange 190 allows adequate protection of the teeth and supporting bone and soft tissue from impact. Of course, flare angle θ 6 may (and likely will) be different for a different population of athletes.
In an embodiment, and as illustrated in FIGS. 1 , 2 , and 5 , for example, exterior bumpers 170 and interior bumpers 171 may project 2 mm from the internal walls to provide an adequate thickness of softening layer for protection, as outlined in the standards set forth by the American Academy of Sports Dentistry. The 2 mm bumper is designed such that the contact surface is generally located at the height of contour of the teeth in contact for the particular athlete population. The 2 mm dimension may be modified for athletes with different average sizes. This ensures sufficient flow of the softer thermoplastic inner layer material, i.e., flowable liner material 195 around each tooth for better protection. In an embodiment, the slope of exterior bumper sidewall angle θ 4 , e.g., θ 4 =45° (or θ 4 =135° measured from the vertical sidewall) acts as a guide to properly position mouthguard 100 in the optimally protective position. Mouthguard 100 is centered in order that the impact forces are directed over the long axis of the teeth for better protection. Interior bumpers 171 may be undercut to act as a mechanical lock for flowable liner material 195 to the harder exoskeleton. This reduces the incidence of delamination or separation of the two layers and is an added retention technique in addition to the bond (e.g., chemical and/or mechanical) that joins the two layers of the mouthguard.
In an embodiment, mouthguard 100 may offer advanced dental protection from harmful bacteria by introducing an antimicrobial agent to prevent harmful bacteria from growing inside of the mouthguard. In addition, a Fluoride (F − ) leaching material may be provided in the flowable liner material 195 to reduce the carious rate of teeth from the consumption of high sucrose and carbohydrate drinks or performance enhancers commonly consumed by the athletes. provision of a fluoride leaching agent (e.g., in the form of F − ) into may help reduce the caries rate by providing protection for the outer enamel matrix of the teeth. Further, the thermoplastic materials used in both exoskeleton 110 and flowable liner material 195 are strong enough to absorb and dissipate forces to reduce traumatic injury to the teeth, TMJ, and surrounding oral structures.
In various embodiments, protective mouthguard 100 may be tethered, e.g., conventional straps may be used to tether the mouthguard to a football helmet mask. However, this approach is generally not preferred for the reasons discussed above. In one embodiment, a ferromagnetic material, e.g., stainless steel or other non-corrosive magnetic material may be embedded in the mouthguard. For example, a magnet and/or ferromagnetic material (not shown) may be embedded in either or both the front and rear scaffolds 120 / 130 / 131 / 150 / 160 / 161 of FIG. 1 , or both, or in some other location of the outer layer (exoskeleton) such as facial flanges 180 . A complementary magnet and/or ferromagnetic material adapted to attract the magnet and/or ferromagnetic material embedded in exoskeleton 110 may be provided separately as a wristband, helmet sticker, or in another suitable location to allow temporary stowage and effective retention of the protective mouthguard when not in use. The present mouthguard design thus provides a novel and breakthrough tethering technique which has long been desired by professional athletes.
The initial fitting operation of a protective mouthguard of an embodiment includes, similar to conventional “boil and bites”, heating the protective mouthguard to soften the inner layer, e.g., a thermoplastic layer. The user then places the warmed and softened mouthguard into their mouth, where the tapered and projected side bumpers, acting in cooperation with the front and rear interior scaffolds, and the exterior rear outside scaffolds, ensures proper placement of the mouthguard with respect to the user's teeth, and jaw structure, assuming that the user's pertinent physiological measurements fall within the minimum and maximum averages determined from the measured population.
Such minimum and maximum averages may be determined, for example, from patient populations as represented by the large adult scan tracings of NFL® players in FIG. 7 , which is an exemplary subset of a larger sample size. FIG. 8 , illustrates the superposition of the five samples that allows determination of an approximate centerline of the five models, along with the maximum and minimum outside dimensions for all five models. Finally, FIG. 9 illustrates a further superposition of the five models to determine a final shape and dimensions of the protective mouthguard. As mentioned above, a larger sample size may be used.
FIGS. 10A through 10H provide various perspective views of an unfitted protective mouthguard of an embodiment. In these figures, flowable liner material 195 is depicted in the lighter shading, and the harder exoskeleton outer layer 110 is depicted by the darker shading. In FIG. 10A , for example, bumpers 170 / 171 and scaffolds 130 / 131 / 160 / 161 are illustrated.
FIGS. 10B and 10G illustrate multiple vent holes 145 in a bottom surface of the mouthguard. These vent holes allow the thermoplastic inner layer material, e.g., EVA material, to flow out of the tray portion of the mouthguard when the mouthguard is being fitted over the upper teeth of the user. The inner layer material that flows out the vent holes may aid in cushioning the bottom teeth.
Fitting such a mouthguard to a patient may be accomplished in various ways. For example, the inner layer may be heated and softened, and then placed in contact with the oral structures in the patient's mouth, similar to conventional “boil and bites, with the notable exception of the improved fit and performance achieved by the use of the novel exoskeleton and associated features of this disclosure. Alternatively, with the advent of digital scanning technology, accurate models of the patient's oral structures can be obtained using a digital camera, and a plaster or stone model can be cast based upon the digital image(s). The resulting cast model can be used to preform the mouthguard described above, thus providing valuable customer service by having the ability to fit mouthguards to patients that are not physically present in the dentist's office.
Turning now to FIG. 11 , clamp mechanism 200 includes T-nut 210 , first clamp half 220 , second clamp half 221 , screw 240 , ferrous/magnetic material 250 , ferrous/magnetic material receiver or opening 251 , and protective covering 260 . Ferrous/magnetic material 250 may be ferrous material if mouthguard 100 includes an embedded magnet, or it may be magnetic material if mouthguard 100 includes an embedded piece of ferrous material, or both ferrous/magnetic material 250 and mouthguard 100 may include magnetic material, as long as there is magnetic attraction between the elements to ensure proper retention force and stowage. When assembled, first clamp half 220 and second clamp half 221 clamp around facemask bar 230 , and are retained in position by the interaction between screw 240 and T-nut 210 . As should be appreciated, facemask bar 230 does not form part of the inventive concept, but merely illustrates one environment of use of clamp mechanism 200 .
Turning now to FIGS. 12A-12D , an alternative clamp mechanism 300 includes first clamp half 320 , second clamp half 330 , lock detents 331 / 332 , screw 340 , ferrous/magnetic material 350 , ferrous/magnetic material receiver or opening 355 , protective latching cover 360 , and lock mechanism 361 . Although not shown, alternative clamp mechanism 300 may also include a T-nut to receive screw 340 as in clamp mechanism 200 .
First clamp half 320 and second clamp half 330 of alternative clamp mechanism 300 may assemble around a facemask bar similarly to first clamp half 220 and second clamp half 221 of clamp mechanism 200 , but protective latching cover 360 attaches in a different manner and more securely by the use of lock mechanism 361 in cooperation with lock detents 331 / 332 . Lock detents 331 / 332 are made of a plastic material, and their design allows flexure in an inward direction to engage lock mechanism 361 , as illustrated in FIG. 12D .
Turning now to FIGS. 13A-13B , another alternative clamp mechanism 400 includes T-nut 410 , first clamp half 420 , second clamp half 430 , latches 431 , screw 440 , ferrous/magnetic material 450 , and protective latching ring 460 . Similar to other embodiments, alternative T-nut 410 receives screw 440 to hold clamp mechanism 400 in an assembled condition. In addition, facemask bar groove 470 may be arranged in one or more of first clamp half 420 and second clamp half 430 to receive, for example, a bar of a facemask.
Although similar in some respects to other embodiments, protective latching ring 460 attaches in a different manner by the use of latches 431 around latching ring 460 and which may be made of a plastic material, but which requires less plastic to reduce weight and cost, for example.
It should be noted that the disclosure above mentions various dimensions and angles of various components, but these measurements are not to be construed as limiting, as they merely represent an example of measurements for a particular group and/or type/size of athlete. Other groups, types and/or sizes of athletes may have different dimensions and attributes which may be determined by measuring and averaging techniques.
The above-discussed embodiments and aspects of this disclosure are not intended to be limiting, but have been shown and described for the purposes of illustrating the functional and structural principles of the inventive concept, and are intended to encompass various modifications that would be within the spirit and scope of the following claims.
List of Reference Numbers
Table 1 below lists reference numbers utilized in the specification and drawings:
TABLE 1
Ref. No.
Description
100
mouthguard
110
outer core/exoskeleton
120
front interior scaffold
130
right rear interior scaffold
131
left rear interior scaffold
140
interior tray portion
145
multiple vent holes
150
front outside scaffold
160
right rear outside scaffold
161
left rear outside scaffold
170
exterior bumpers
171
interior bumpers
180
facial flanges
185
buccal flanges
190
interior lingual flange
195
flowable liner material
200
clamp mechanism
210
T-nut
220
first clamp half
221
second clamp half
230
facemask bar
240
screw
250
ferrous/magnetic material
251
ferrous/magnetic material receiver or opening
260
protective covering
300
alternative clamp mechanism
320
first clamp half
330
second clamp half
331
lock detent
332
lock detent
340
screw
350
ferrous/magnetic material
355
ferrous/magnetic material receiver or opening
360
protective latching cover
361
lock mechanism
400
alternative clamp mechanism
410
T-nut
420
first clamp half
430
second clamp half
431
latch
440
screw
450
ferrous/magnetic material
460
protective latching ring
470
facemask bar groove
θ 1
incisal flare angle
θ 2
rear interior scaffold centerline angle
θ 3
rear outside scaffold centerline angle
θ 4
exterior bumper sidewall angle
θ 5
right/left rear outside scaffold slant angle
θ 6
interior lingual flange flare angle
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A dual layer mouthguard with a U-shape polycarbonate/EVA or elastomeric material skeletal base includes channels and ramps to ensure a uniform thickness on the occlusal, buccal and lingual surfaces of the teeth for proper alignment of the jaw and positioning for protection during the placement of the mouthguard. The liner is softer than the base when introduced to heat and remains softer as it is cooled. The base may also include metal/magnetic insertion to serve as a tethering device for temporary storage.
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FIELD OF THE INVENTION
This invention relates to a food glaze composition. More particularly, this invention relates to a glaze composition with vegetable gums for coating food items such as bakery products.
BACKGROUND OF THE INVENTION
Bakers have applied a coating or "wash" to the surface of bakery products to improve the appearance of baked goods. Typically, washes were used prior to baking to impart a shiny, smooth, attractive appearance to the baked products. Initially, these bakery egg washes or sugar washes often contained whole eggs, dried egg white solids, milk protein from a variety of dairy products, oils and fats, starches, sugars, syrups and dextrins derived from various sources. Typically, these washes are not satisfactorily applied after baking, directly to a finished bakery product, or used prior to freezing a bakery product. Also, typically, these washes lack convenience and versatility, as they require immediate use.
For example, the conventional egg wash promotes the growth of microbial organisms, and thus requires constant refrigeration, immediate preparation, and use of brushes and containers which may easily become contaminated with microbial growth. Also, egg washes typically do not bake evenly, often burning or producing streaking and variation in color and shine if the egg wash is not evenly mixed. Moreover, egg washes are not effective in reducing cracking and chipping on baked items, must be applied directly before baking, and cannot be successfully used after baking. Because of the potential health hazards of using egg products on perishable commercial foods, egg washes have been disfavored, and a need for eggless washes exists. Eggless washes typically rely on non-egg white proteins such as sodium or calcium caseinates, soy proteins, whey proteins, yeast proteins and mixtures thereof to impart an acceptable shine. See, e.g., U.S. Pat. No. 4,863,751 to Voss. However, these eggless washes are still susceptible to microbial decomposition. Further, protein-containing washes are not suitable for certain protein-restricted diets (allergens). Accordingly, there is a need for an eggless, protein-free product having desirable baking and stability properties.
The present invention provides a composition that is eggless, protein-free, convenient, versatile and can impart desired properties to food products such as baked or frozen goods.
SUMMARY OF THE INVENTION
The composition of the present invention is a food glaze composition capable of providing food items such as bakery products with an even color and uniform shine. In general, this eggless, protein-free composition includes vegetable gums and other components in an aqueous mixture. Because the composition does not contain egg or milk protein, it is intended for all consumers, including those having dietary or religious (e.g., kosher) restrictions relating to proteins from specific sources. The composition does not require special preparation, and is available in ready-to-use, condensed, or dry formulations. Moreover, the composition can be used in spray-on or brush-on applications. The composition may be applied to a bakery product either before or after baking, as well as to baked or partially baked products prior to freezing. Thus, for example, the composition does not need to be applied at high temperature during baking. The composition can also reduce crust cracking and chipping on baked items, especially pies. Finally, the composition does not require refrigeration, and can be kept at room temperatures for months.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment, the composition of the glaze comprises (in weight %) at least one source of vegetable gum, in a combined amount of from about 0.3 to 15%; at least one source of modified food starch, in a combined amount of from about 1 to 30%; water, in an amount up to about 90%; at least one preservative, in a combined amount of from about 0.01 to 1.00%; and at least one acidulant, in a combined amount of from about 0.1 to 15%. All percents given in the description and claims of this invention are weight percents. The presence of vegetable gum provides the finished gloss to the baking products; it is believed that these gums serve as film-forming gums. Moreover, the use of vegetable gum as a main ingredient for the gloss avoids the need for egg or milk protein in the glazing composition. The modified food starch imparts viscosity and shine to the wash. It is presently understood that the modified food starch and vegetable gums react favorably in the system to improve the properties of the glaze composition. A solubilizing media, such as water, may be added to the system in an amount of up to about 90% by weight of the composition to aid the application of the glaze to the bakery product. Alternatively, the glaze may be prepared in a condensed or concentrated portion with only a portion of the water. The source of acidulation provides the proper pH in the composition for operation of conventional food preservatives, such as sodium benzoate and potassium sorbate.
In other embodiments, the glaze composition of the previous embodiment additionally comprises (in weight %) at least one reducing sugar and/or syrup substrate, in a combined amount of from about 2 to 30%; and/or at least one carrier, in a combined amount of from about 1.5 to 18%. A source of reducing sugars is included in the combined amount of from about 2 to 30% by weight of the composition to enhance the browning of the baked goods. As discussed below, high fructose corn syrup is one such syrup substrate. As further discussed below, carriers or dispersing agents, other than water, may be used as a dispersing media for the vegetable gum, acidulation source and modified food starch.
Thus, in one embodiment, the composition of the invention has the following components: at least one source of vegetable gum, at least one source of modified food starch, water, at least one preservative, at least one food acidulant, at least one source of reducing sugar and/or syrup substrate, and at least one carrier, generally in the following proportions, which includes dry, condensed and ready-to-use formulations of the composition:
______________________________________Ingredient % by Weight______________________________________vegetable gum 0.30-15modified food starch 1-30water 0-90preservative 0.01-1.00food acidulant 0.1-15reducing sugar and/or syrup substrate 2-30carrier 1.5-18 100%______________________________________
Colors, flavorings and pH buffers may also be added to the above glaze compositions, as described below. Of course, the proportion of the main ingredients will vary depending on the amount of such additions to the composition.
In another embodiment of the invention, the composition is ready-to-use, and has the following components, generally in the following proportions, where it is again understood that each component comprises one or more sources of each ingredient:
______________________________________Ingredient % by Weight______________________________________vegetable gum 0.3-2.1modified food starch 1-4water 70-90preservative 0.1-0.5food acidulant 0.1-0.8reducing sugar and/or syrup substrate 2-10carrier 1.5-5.0 100%______________________________________
In one embodiment, as described in Example 1 below, the glaze composition comprises (in weight %), the following ingredients: chelated agar (0.28%); gum arabic (0.28%); microcrystalline cellulose (0.28%); modified corn starch (2.97%); water (90.19%); sodium benzoate (0.05%); potassium sorbate (0.05%); citric acid (0.50%); 42 DE high fructose corn syrup (3.72%); and maltodextrin (1.86%).
A variety of natural or modified vegetable gums may be incorporated into the composition. Any conventional source of the vegetable gums can be used as long as the gum is suitable for use in food products. Combinations of both natural and modified vegetable gums can be used in the glaze composition. In general, natural gums are water-soluble plant products composed of monosaccharide units joined by glycosidic bonds. Natural gums include extracts from vegetable matter; for instance, these include extracts from vegetable and fruit tissues, seeds, roots, beans, plant and tree exudates, and seaweed, as well as gums obtained by microbial fermentation. In general, modified vegetable gums include derivatives of natural vegetable gum and particular synthetic gums. Modified vegetable gums can be prepared by chemical or physical reactions such as polymerization, or by mechanical alterations such as agglomeration, for example.
Suitable natural vegetable gums include, but are not limited to the following: gum arabic (acacia gum), guar gum (guar flour), agar (agar-agar), carrageenan gum (alpha, kappa and all other types), karaya gum (sterculia gum; India tragacanth, kadaya gum), gum ghatti, locust agar, algin, pectin, xanthan gum, locust bean gum, gum tragacanth, tamarind gum, and combinations thereof. Suitable modified vegetable gums include, but are not limited to the following: chelated agar; pectin derivatives including both low- and high-methoxyl pectin; alginates such as propylene glycol alginate; cellulose derivatives such as microcrystalline cellulose, methylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium hydroxymethyl cellulose; carboxymethyl locust bean gum; gellan gum; carboxymethyl guar gum; and combinations thereof.
Typically, the combined amount of the suitable natural and/or vegetable gums present in the composition is from about 0.3% to 15% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of vegetable gums is from about 0.3% to 2.1% by weight of the composition. In one ready-to-use formulation, the amount (in weight %) of the vegetable gums was as follows: chelated agar (chelated agar (D), Bunge Foods), 0.28%; gum arabic (Sethness-Greenleaf Company), 0.28%; and microcrystalline cellulose (RC591F, FMC Corporation), 0.28%. It should be noted that the suppliers of various ingredients used in this composition are provided as one source of these ingredients; other comparable commercial sources of these ingredients may, of course, also be used.
A commercial modified food starch is used in the composition to impart additional viscosity and shine to the wash. The starch may be derived from any vegetable source, and include water-soluble polymers derived from a corn, potato, tapioca, wheat, rice, sago, sorghum or starch by, for example, acetylation, chlorination, acid hydrolysis, or enzymatic action. Typically, the combined amount of one or more such modified food starches is from about 1% to 30% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of modified food starch is from about 1% to 4% by weight of the composition. In one particular ready-to-use formulation, the amount of modified corn starch (Polar gel #13, American Maize-Products Co.) used was 2.97% by weight of the composition.
The water used in the present invention may be, for example, tap, bottled or treated water having a pH of from about 6 to 7. Typically, the amount of water present in the composition is up to 90% by weight of the composition. In a ready-to-use formulation, for example, the amount of water present in the composition is from about 70% to 90% by weight of the composition. In one particular ready-to-use formulation, the amount of water was 90.19% by weight of the composition. It may be desirable to condense the vegetable gum composition or to delete a portion of the water from the formulation to produce a concentrated formulation. In the case of a dry formulation, water can be added to the product to reconstitute the vegetable gum composition.
Reducing sugars and/or syrup substrates may be included to enhance the browning of the baked products. It is believed that these sugars react with the protein in flour to form a brown coloration. Suitable sugar components include, for example, fructose (levulose) such as high fructose corn syrup, glucose (dextrose), galactose, maltose (malt sugar; maltobiose), and combinations thereof. Typically, the combined amount of such reducing sugars and/or syrup substrates is from about 2% to 30% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of reducing sugars and/or syrup substrates is from about 2 to 10% by weight of the composition. In one particular ready-to-use formulation, the amount of high fructose corn syrup (ISO 42 DE, Chicago Sweeteners) used was 3.72% by weight of the composition
A small amount of an edible acid (e.g., food acidulant) may be included in the composition of this invention to lower the pH of the composition to below about 4.5. Typically, the combined amount of such food acidulant is from about 0.1% to 15% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of acidulant is from about 0.1% to 0.8% by weight of the composition. It is believed that the lowered pH may increase the effectiveness of preservatives such as potassium sorbate and sodium benzoate. Suitable edible acids include citric acid (2-hydroxy-1,2,3-propane tricarboxylic acid), adipic acid (hexanedioic acid; 1,4-butanedicarboxylic acid), malic acid (hydroxysuccinic acid; apple acid), and the like. In one particular ready-to-use formulation, the amount of citric acid (Gadot Biochemical Industries) used was 0.50% by weight of the composition.
A carrier, diluent, or dispersing agent such as maltodextrin or dextrin may be used in the present composition. Typically, the combined amount of such carrier is from about 1.5% to 18% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of carrier is from about 1.5% to 5.0% by weight of the composition. In one particular ready-to-use formulation, maltodextrin (M-100 Maltrin®, Grain Processing Corporation, Muscatine, Iowa), was used at the amount of 1.86% by weight of the composition.
A relatively low amount of a chemical preservative or spoilage inhibitor may be included in the composition. These preservatives may, for example, aid in controlling growth of mold, yeast and bacteria. Typically, the combined amount of such preservative is from about 0.01% to 1.00% by weight of the composition. In a ready-to-use formulation, for example, the combined amount of preservatives is from about 0.1% to 0.5% by weight of the composition. Suitable preservatives include, for example, potassium sorbate, sodium benzoate, propylene glycol, and combinations thereof. In one particular ready-to-use formulation, potassium sorbate (powder, Ashland Chemical) was present at 0.05% by weight of the composition; and potassium sorbate (powder, Ashland Chemical) was present at 0.05% by weight of the composition.
In addition, for example, food coloring agents and flavoring agents, either natural or artificial or both, antioxidants, and pH buffers may be incorporated into the composition. Flavoring agents include any substance that is, for example, sweet, sour, salty, savory, herbal or spicy to the taste, and variations thereof. For example, it may be desirable to include sugarless sweeteners including sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, sucralose, aspartame, salts of acesulfame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, and combinations thereof. Coloring agents include, for example, annatto, caramel, tumeric, carotene, or other artificial or natural yellow "egg" coloring agents and combinations thereof. Antioxidants include, for example, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, citric acid, or the like. Also, it may be desirable to include any suitable commercial pH buffer in the composition.
Those skilled in the art to which the invention pertains may make modifications and other embodiments employing the principles of this invention without departing from its spirit or essential characteristics particularly upon considering the foregoing teachings. The described embodiments, as well as the Examples below, are to be considered in all respects only as illustrative and not restrictive and the scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description Consequently, while the invention has been described with reference to particular embodiments and Examples, modifications would be apparent to those skilled in the art, yet still fall within the scope of the invention.
EXAMPLE 1
A ready-to-use formulation of the composition was formed from the following ingredients:
______________________________________Ingredient % by Weight______________________________________chelated agar 0.28gum arabic 0.28microcrystalline cellulose 0.28modified corn starch 2.97water 90.19sodium benzoate 0.05potassium sorbate 0.05citric acid 0.50high fructose corn syrup (42 DE) 3.72maltodextrin 1.86 100.00______________________________________
This ready-to-use composition was prepared by adding water to a cooking kettle equipped with high shear and scraped surface mixers. All ingredients except the citric acid were first added to the high shear mixer, and mixed until all the ingredients were suspended in the wash. In this example, the ingredients were obtained from the following suppliers: chelated agar (chelated agar (D), Bunge Foods); gum arabic (Sethness-Greenleaf Company); microcrystalline cellulose (RC591F, FMC Corporation); modified corn starch (Polar gel #13, American Maize-Products Co.); potassium sorbate (powder, Ashland Chemical); sodium benzoate (powder, Ashland Chemical); citric acid (Gadot Biochemical Industries); high fructose corn syrup (ISO 42 DE, Chicago Sweeteners); and maltodextrin (Maltrin M-100, Grain Processing Corporation). The scrape surface mixing blades were then be employed as the mixture was heated to 190° F., and held at that temperature and continually mixed for five minutes. The mixture was cooled to 180° F., and citric acid was then added. The composition was then packed in 1 gallon plastic jars at 170-175° F. for storage.
EXAMPLE 2
A ready-to-use composition was prepared as described in Example 1, and was sprayed or brushed onto various food items, before and/or after baking, before and/or after freezing. The composition imparted an even color and shine to various food items, including fruit and savory (e.g., turkey pot pie, other meat pies) pies, danish pastries, coffee cakes, puff pastry (e.g., turnovers), hard crust breads and rolls, partially-baked hard crust breads and rolls, and oven-baked bagels. In the case of oven-baked bagels, use of the composition eliminated the need of boiling or steaming the bagels, for shine, prior to baking. Also, use of the composition reduced the amount of cracks and chips on baked items such as the pie crust of the fruit and savory pies.
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A food glaze composition for coating food items including bakery products. The glaze composition includes one or more natural or modified vegetable gums and is eggless and protein-free. The composition imparts a shine, aids in browning, retards moisture loss from the glazed product, and can be applied to food products before and/or after baking and freezing. The glaze composition is also effective in controlling the development of mold, yeast and bacteria.
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CROSS-REFERENCE TO A RELATED APPLICATION
[0001] The invention described and claimed hereinbelow is also described in German Patent Application DE 10 2013 110452A, filed on Sep. 24, 2013. The German Patent Application, the subject matters of which is incorporated herein by reference, provides the basis for a claim of priority of invention under 35 U.S.C. 119(a)-(d).
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a separating device. Known separating devices can be designed as axial separating rotors of a combine harvester, which are used to separate crop picked up by the combine harvester into the different components thereof, and to separate and remove said components. The crop is separated by the separating device into a grain component and a non-grain component, such as straw and chaff, by a treatment process, which physically acts on the crop.
[0003] Document EP 2 298 063 A2 makes known a separating device, which is designed as an axial threshing-separating rotor. This axial threshing-separating rotor has the task of collecting grain contained in the crop in a first step via threshing, wherein the grain is separated from non-grain components. The grain is threshed and largely separated out in threshing section adjoining an inflow region of the axial threshing-separating rotor. Parts of the threshed-out grain reach the subsequent separating region of the axial threshing-separating rotor along with the non-grain components. The remaining grain is separated from the non-grain components in the separating region. The threshing section of the axial threshing-separating rotor comprises crop-treatment elements embodied as grates, which extend substantially transversely to the rotational direction of the axial threshing-separating rotor. The grates are directly engaged with the crop, which exerts a highly abrasive effect on the grates.
[0004] According to EP 2 298 063 A2, the grates have a circular cross-section in order to reduce grain damage. The grates are disposed on a ramp-shaped support element, which extends downward in the rotational direction of the axial threshing-separating rotor and extends into the crop stream. The ramp-shaped support element has a front side having a right-angled cross section in order to achieve a level of aggressiveness that is required for the threshing. The wear that occurs on the sharp-edged front edge of the ramp-shaped support element is correspondingly high, which is due to the high bearing pressure in this region. The high bearing pressure is exerted by the crop onto the support element, in particular onto the front edge facing the crop stream. A coating on the surface of the element, which is applied as protection against wear, is also worn off by the crop, thereby making it necessary to replace the support element and grates located thereon at regular, short intervals of time.
SUMMARY OF THE INVENTION
[0005] The present invention overcomes the shortcomings of known arts, such as those mentioned above.
[0006] To that end, the present invention provides a separating device designed in a way that longer service lives of the crop-treatment elements that are particularly exposed to wear can be achieved.
[0007] In an embodiment, the at least one crop-treatment element, which has a substantially cuboid cross-section, has a front edge, which faces the direction of rotation and away from a conveyance direction of the crop and has a curved shape that is optimized in terms of flow. The front edge, which extends in the axial direction of the crop-treatment element, forms a transition from a substantially perpendicular section of the crop-treatment element to a substantially horizontal section. In this manner, the bearing pressure of the section of the crop-treatment element that first comes into contact with the crop-treatment element is reduced, thereby reducing wear.
[0008] The level of aggression required for the threshing process and which is exerted onto the crop is substantially determined by the cuboid cross-section. In particular, the course that is optimized in terms of flow results in an approximately constant bearing pressure, which is applied by the crop stream onto the front edge of the crop-treatment element. The bearing pressure applied by the crop is varied by the course of the front edge. In particular, the curved course of the front edge is adapted to different types of crop. It is thereby possible to account for the different wear behavior associated with the particular crop type.
[0009] Preferably, the course of the front edge can be convex. It is thereby possible to achieve a gentle deflection of crop in the region of the front edge. In contrast thereto, a concavely embodied front edge could result in a hollowing-out of the crop-treatment element, which would result in greater wear.
[0010] Advantageously, the front edge is provided, at least in sections, with a coating in order to increase the wear-resistance. The service life of the crop-treatment element is additionally increased as a result. The resistance of the coating itself also is increased by the curved front edge of the crop-treatment element, which has been optimized in terms of flow. The crop-treatment element is made of a material having relatively low hardness. The front edge, which has been optimized in terms of flow and is most exposed to the abrasive effect of the crop stream, is provided with a coating having great hardness. The coating, at least in sections, is applied depending on the expected bearing pressure that is exerted by the crop onto the crop-treatment element.
[0011] Preferably, a material reserve is applied in highly-stressed regions of the crop-treatment element during the production thereof. This material reserve is used as a wear reserve. The build-up of the material reserve is achieved by suitable production methods such as casting, forging, or hot forming.
[0012] The radius of curvature of the front edge of the crop-treatment element is variable depending on the material of which the coating is made. The radius of curvature can be reduced as the material hardness of the coating applied onto the front edge increases. The coating can be applied by common coating methods, such as thermal spraying, build-up welding, sintering, laser coating, chemical vapor deposition, physical vapor deposition, or seal-in alloys that are applied in a liquid state and are hard-material cured.
[0013] As an alternative or, in addition thereto, the at least one crop-treatment element is made of a wear-resistant material. Curable steel materials are options for use as the basic material for a crop-treatment element, which continuously comprises a wear-resistant material and has a front edge that has been optimized in terms of flow. These steel materials can be case-hardened after shaping. These steel materials also can be inductively or conductively cured after shaping. In addition, press quenching can be utilized for curable steel materials. The crop-treatment element is curved entirely or only in regions directly after being shaped in a tool.
[0014] The radius of curvature of the front edge of the crop-treatment element can vary depending on the material of which the crop-treatment element is made. As the hardness of the material used for the crop-treatment element increases, the radius of curvature can be selected to be smaller in order to approximate a sharp-edged shape of the front edge. The reduction of the radius of curvature is limited by the exponentially increasing wear resulting from the increasing bearing pressure.
[0015] Preferably, the at least one crop-treatment element is disposed in the inflow region of a separating device designed as an axial separating rotor. The axial separating rotor is designed as an axial threshing-separating rotor, the threshing elements of which are embodied in the shape of grates. The axial separating rotor is disposed downstream of a tangentially operating threshing device, which comprises crop-treatment elements embodied as grates in the inflow region and are designed as guidance and conveyance elements for the crop.
[0016] In this inflow region, the at least one grate is impacted by non-grain components as well as grain, which has a greater abrasive effect than non-grain components. The effect of this on the wear behavior of the at least one grate can be reduced by the measured described herein. The inflow region of the axial separating rotor is adjoined by a central region, in which the remaining grain is separated from the developing straw mat and is separated out by separating grates. Crop-treatment elements, which are embodied as so-called fingers and loosen the straw mat, are disposed in this central region. These fingers also can be embodied accordingly with a front edge that is optimized in terms of flow.
[0017] The at least one crop-treatment element also can be disposed in the outflow region of a separating device designed as an axial separating rotor, i.e., embodied as a so-called paddle.
[0018] In addition, the at least one crop-treatment element also can be embodied as a beating arm, which is disposed coaxially to a drum of a separating device embodied as a threshing device, on the periphery thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Further features and advantages of the invention will become apparent from the description of embodiments that follows, with reference to the attached figures, wherein:
[0020] FIG. 1 shows a schematic view of a combine harvester;
[0021] FIG. 2 shows an exploded view of a separating rotor; and
[0022] FIG. 3 shows a detailed view III of a grate according to FIG. 2 ; and
[0023] FIG. 4 shows the grate 30 in its entirety.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] The following is a detailed description of example embodiments of the invention depicted in the accompanying drawings. The example embodiments are presented in such detail as to clearly communicate the invention and are designed to make such embodiments obvious to a person of ordinary skill in the art. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention, as defined by the appended claims.
[0025] The combine harvester 1 depicted schematically in FIG. 1 comprises an axial separator 2 , a header 3 , a threshing unit 4 , a cleaning unit 5 , a grain tank 6 , a driver's cab 7 and a further-handling device 8 for the residual crop flow, which is disposed downstream of the axial separator 2 , and a straw chopper and/or a spreader
[0026] The crop 9 cut by the header 3 travels through a feeder housing 10 to the thresher unit 4 operating according to the tangential principle. The thresher unit comprises a cylinder 11 and an assigned concave 12 . The crop components separated out on the concave 12 are conveyed by way of a grain pan 13 to the cleaning unit 5 , which comprises a fan 14 and an upper and lower sieve 15 , 16 . The grain-short straw mixture that emerges from the concave 12 in the tangential direction is conveyed into the axial separator 2 . The conveying process is supported by a rotating impeller 11 disposed parallel to the cylinder 11 .
[0027] The axial separator 2 is disposed in the longitudinal direction of the combine harvester 1 and substantially comprises a stationary, cylindrical housing 18 which rises in the conveyance direction FR, and in which a rotatably driven separating rotor 19 is supported. The housing 18 has a lower region having separating grates 20 and a closed, upper concave cover 21 having guidance devices disposed on the inner side for supporting the conveyance motion of the crop. The separating rotor 19 is equipped with crop-treatment elements on the periphery thereof, as viewed in the axial direction. The crop-treatment elements have various designs and are, for example, grates 30 , fingers 31 , or paddles 32 , which partially have the function of intensifying the separating procedure. All the crop-treatment elements have a cuboid cross-sectional shape and, due to the function thereof, have constant contact with the crop, which is conveyed by the separating rotor 19 , and all have an abrasive effect.
[0028] The grains contained in the crop mixture and portions of short straw and chaff are separated out on the separating grates 20 and are conveyed to the cleaning unit 5 by way of the return pan 22 located thereunder. The cleaned grains travel by way of a conveyor auger 23 and an elevator 24 into the grain tank 6 . Inside the axial separator 2 , the straw and chaff forming the crop residue are conveyed in the direction of the transfer region 25 and, from there, travel by way of an outlet width 26 and, in a distributed manner, reach the further-handling unit 8 , which is attached to a frame underneath a straw outflow hood 27 transversely to the direction of travel.
[0029] FIG. 2 shows the separating rotor 19 of the axial separator 2 . The separating rotor 19 substantially comprises an inflow region 33 , a central region 34 , and an outflow region 35 . The inflow region 33 is used to receive the crop 9 , which substantially comprises straw and grain conveyed therewith after the threshing process. In the central region 34 of the separating rotor 19 , the fingers 31 act on the crop mat forming between the separating rotor 19 and the separating grates 20 and the concave cover 21 in order to remove the remaining grain from the straw and remove the grain through the separating grates 20 . In the outflow region 35 , the straw is transferred to the further-handling device 8 .
[0030] As mentioned above, the separating rotor 19 comprises different crop-treatment elements in the respective regions 33 , 34 , 35 , which are detachably fastened on the separating rotor 19 by holders 36 provided thereon for this purpose. The crop-treatment elements are detachably attached due to the wear to which the crop-treatment elements are exposed during the processing of the crop. The wear behavior is influenced by the material of which the crop-treatment elements are made and by the geometric shape of the various crop-treatment elements. In addition, the type of crop to be processed has a considerable influence on the service life of the crop-treatment elements, since, for example, the requirements for wear-resistance in the case of processing rice as the crop are particularly high.
[0031] As is evident from the exploded view according to FIG. 2 , the grates 30 embodied as crop-treatment elements have a substantially cuboid cross-section, as viewed in the radial direction, although these also can have a spiral shape as viewed in the axial direction. The fingers 31 and the paddles 32 also have a substantially cuboid cross-section. The grates 30 , the fingers 31 , and the paddles 32 are arranged, as viewed in the rotational direction R of the separating rotor 19 , such that these come into contact with the crop first.
[0032] FIG. 3 shows an enlarged detailed sectional view III according to FIG. 2 of a grate 30 , where FIG. 4 shows the grate 30 in its entirety. The illustration shows the upper section of the grate, the front edge 40 of which, facing the rotational direction of the separating rotor 19 , comes into contact with the crop first. The front edge 40 of the grate 30 , which forms between a substantially vertical section 37 and a substantially horizontal section 38 adjacent thereto has a curved course that is optimized in terms of flow. Due to the curved course of the front edge 40 , the bearing pressure induced by the impacting crop is reduced in this region. The wear of the surface of the front edge 40 is therefore markedly reduced.
[0033] The course of the convex front edge 40 is described by the radius of curvature KR thereof. The radius of curvature KR varies depending on the hardness of the material of which the crop-treatment elements such as the grate 30 , the finger 31 , or the paddle 32 are made. As the hardness of the material of which the crop-treatment element is made increases, the radius of curvature KR can be selected to be smaller.
[0034] Since the basic material of which the crop-treatment element is made generally does not have very great hardness, for reasons of processability, a wear-protection layer is applied onto the front edge 40 in the form of a coating 39 .
[0035] The material used for the coating 39 has a markedly greater hardness than the basis material of the crop-treatment element. In the coating of the front edge 40 as well, there is a dependence between the hardness of the material used for the coating 39 and the radius of curvature KR that describes the course of the front edge 40 . The curved course of the front edge 40 , which is optimized in terms of flow, is also advantageous in terms of the application of a coating 39 , since, due to the reduced bearing pressure, the coating 39 is not stressed or worn off to the extent that is the case with a sharp-edged course of the front edge according to the prior art.
LIST OF REFERENCE SIGNS
[0036] 1 combine harvester
[0037] 2 axial separating device
[0038] 3 header
[0039] 4 threshing unit
[0040] 5 cleaning mechanism
[0041] 6 grain tank
[0042] 7 driver's cab
[0043] 8 further-handling unit
[0044] 9 crop
[0045] 10 feeder housing
[0046] 11 cylinder
[0047] 12 concave
[0048] 13 grain pan
[0049] 14 fan
[0050] 15 lower sieve
[0051] 16 upper sieve
[0052] 17 impeller
[0053] 18 housing
[0054] 19 separating rotor
[0055] 20 separating grate
[0056] 21 concave cover
[0057] 22 return pan
[0058] 23 conveyor auger
[0059] 24 elevator
[0060] 25 transfer region
[0061] 26 outlet width
[0062] 27 straw outflow hood
[0063] 30 grate
[0064] 31 finger
[0065] 32 paddle
[0066] 33 inflow region
[0067] 34 central region
[0068] 35 outflow region
[0069] 36 holders
[0070] 37 vertical section
[0071] 38 horizontal section
[0072] 39 coating
[0073] 40 front edge
[0074] R rotational direction
[0075] KR radius of curvature
[0076] FR conveyance direction
[0077] As will be evident to persons skilled in the art, the foregoing detailed description and figures are presented as examples of the invention, and that variations are contemplated that do not depart from the fair scope of the teachings and descriptions set forth in this disclosure. The foregoing is not intended to limit what has been invented, except to the extent that the following claims so limit that.
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A separating device formed with rotationally driven components and stationary components has at least one crop-treatment element for processing crop. The crop-treatment element extends transversely to the rotational direction (R) of the components, at least in sections. The crop-treatment element has a substantially cuboid cross-section and a front edge with a curved course optimized in terms of flow, and which faces a rotational direction (R) and away from a conveyance direction (FR) of the crop.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is continuation of co-pending U.S. application Ser. No. 10/202,739, which was filed Jul. 25, 2002, and is incorporated herein in its entirety by express reference thereto.
FIELD OF THE INVENTION
[0002] The present invention relates generally to golf balls. More specifically, the present invention relates to methods for heating golf ball components.
BACKGROUND OF THE INVENTION
[0003] Solid golf balls are usually two or more piece constructions. Two-piece golf balls include a single-piece core and a cover. The core forms a golf ball component that the cover surrounds. Multi-piece golf balls include one or more core layers, an intermediate layer, and a cover. In such balls, the core and intermediate layer form the golf ball component that the cover surrounds.
[0004] For a preferred cover, one material is a thermosetting composition. One method of making golf balls with a thermoset cover includes disposing the golf ball component into a cover mold and casting the cover thereon. During casting, heat is generated by an exothermic reaction of the thermoset processes. As a result of this heat, the ball component tends to undergo volumetric thermal expansion. The thermal expansion of the component can force the cover mold open and cause the component to shift in the mold so that the cover is uneven and has excessive flash. Also, the thermal expansion makes it difficult to maintain size accuracy in the finished ball. This can result in an unplayable ball.
[0005] Prior solid golf balls having cast urethane covers were made using a method that includes preheating the golf ball component to a predetermined elevated temperature. Preheating the component is done to the extent that causes the component to undergo volumetric thermal expansion. Thereafter, the cover is cast onto the component. For example, see U.S. Pat. No. 6,096,255, which is incorporated herein in its entirety.
[0006] It is well known in the art that preheating golf ball components decreases the total temperature change the component is exposed to and minimizes the thermal expansion of the component in the cover mold. Heating methods that have been utilized in the prior art are convection heating, whether it be a batch process or a continuous conveyor system. It is not unusual to require 34 hours of convection heating to raise the temperature of a golf ball core from 68° F. to 125° F. This length of time can be a production bottleneck and consume a large amount of energy.
[0007] Therefore, what is desired is a method of heating golf ball components by a much faster and energy efficient means.
SUMMARY OF THE INVENTION
[0008] The invention provides a method for heating a golf ball component, whether it be a core, core having multiple core layers, or a core with additional intermediate layer(s) thereon. The heating is preferably completed prior to the component having a layer or cover applied. The method comprises heating the ball components by radio frequency (RF). The golf ball components travel into a RF field between a series of electrodes. The electrodes are located at the top and bottom of a conveyor system for a predetermined RF exposure. A RF generator provides the energy for pre-heating. Ball components pass through a RF applicator and RF attenuation tunnels at both the feed and discharge ends. Energy levels are controlled based on the load requirements calculated by specific heat and desired change in temperature. A custom automation system moves a high volume of product in and out of the RF tunnel for a desired length of time to heat the component to a predetermined temperature. One embodiment adds supplemental convection heating to enhance consistent temperature on the component surface.
[0009] Preferably, a tight temperature gradient is achieved across the cross-section of each ball component as well as a low deviation in temperature between each ball component.
[0010] An increase in energy efficiency is achieved as only that energy which directly heats the ball components is necessary and expended.
[0011] The present invention provides for a ball component exhibiting a greater consistency as RF heats the product from the center to the outside.
[0012] An embodiment of the invention provides for a post cure of a polybutadiene core to reduce the time of the molding cycle.
[0013] The present invention provides for a rapid curing of urethane golf ball covers.
[0014] The present invention provides for pre-heating the golf ball prior to spray painting and for providing RF heat to cure the paint.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is an elevational partially cut-out front view of a conveyor feed of product into and out of an RF heater.
[0016] FIG. 2 is a top view of the system shown in FIG. 1 .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The present invention relates generally to the heating of golf ball components by radio frequency (RF). The components can include a core, a center and at least one core layer, or a core, and a combination of at least one core layer and/or at least one intermediate layer. RF heating can also be employed to post-cure golf ball polybutadiene cores, cure urethane castings and cure the spray paint on a finished golf ball. The golf balls may also be pre-heated by RF waves prior to the application of the paint.
[0018] A golf ball component experiences a dramatic increase of heat when a core layer or especially an intermediate layer or cover layer is cast to it. The volumetric expansion of the ball component during this process often causes manufacturing difficulties. One problem area is that the thermal expansion of the component can force the cover mold open and cause the component to shift in the mold so that the cover is uneven and has excessive flash. This can result in an unplayable ball. To alleviate and counteract excessive thermal expansion during the casting process, manufacturers may preheat the ball component to a predetermined elevated temperature, usually between about 100° F. to about 160° F. and up to 300° F. when used for post curing of polybutadiene cores. The pre-heated ball component is therefore not exposed to the dramatic volumetric thermal expansion as would an unheated component. It is well known in the art that preheating the golf ball components decreases total temperature change the component is exposed to and therein minimizes the thermal expansion of the component while in the cover mold. Thus, manufacturers may preheat the golf ball components prior to casting over them with another layer. Methods that have been utilized in the prior art are primarily two types of convection heating; a batch process and a continuous conveyor process. It is not unusual with the batch process to require about 3-4 hours of convection heating to raise the temperature of a golf ball core from 68° F. to 125° F. In a continuous conveyor process this time can be reduced to about 45 to 60 minutes. This length of time can be a production bottleneck in both space and energy costs.
[0019] The present invention utilizes a method of heating the golf ball component by means of radio frequency (RF) waves. This as accomplished by feeding golf ball components into the system by automatic conveyor feed system and subsequently into an RF generated field, where the temperature rise in a golf ball component from about 68° F. to 125° F. can be achieved in 30 to 60 seconds. (Chart I below) It is to be appreciated that while the method as described herein utilizes a conveyor feed system, the present invention may also be employed utilizing a batch process.
COMPARISON OF GOLF BALL SUBASSEMBLY PRE-HEATING METHODS INITIAL CORE TEMP. FINAL CORE TEMP. TEMPERATURE RISE (PRIOR TO HEATING) (AFTER HEATING) (Δ T) PROCESS TIME HEATING METHOD (DEG. F.) (DEG. F.) (DEG. F.) (HRS: MINS; SECS;) CONVECTION HEAT 68 125 57 3-4 HRS. BATCH PROCESS CONVECTION HEAT 68 125 57 45-60 MINS. CONTINUOUS CONVEYOR RADIO FREQUENCY 68 125 57 30-60 SECS. CONTINUOUS CONVEYOR
[0020] The present invention provides for a product with a greater consistency as RF waves heat the golf ball component from the center to the outside. The heating occurs instantly and uniformly throughout all three dimensions. No temperature differential is required to force heat by conduction from the surface to the center as in surface heating processes. An increase in energy efficiency is achieved as only energy is used that directly heats the product. No long warm-up or cooling time is required. Power is consumed only when the load is present and only in proportion to the load.
[0021] In a radio frequency heating system, the RF generator creates an alternating electric field between two electrodes. The component to be heated is conveyed between the electrodes where the alternating energy caused polar molecules in the product material to continuously reorient themselves to face opposite poles much like the way bar magnets behave in an alternating magnetic field. The friction resulting from molecular movement causes the material to rapidly heat throughout its entire mass. The amount of heat generated in the component is determined by the frequency, the square of the applied voltage, dimensions of the component and the dielectric loss factor of the material which is essentially a measure of the ease with which the material can be heated by RF waves.
[0022] The process of the present invention is shown on FIGS. 1 and 2 . A continuous conveyor 11 accepts a continuous supply of golf ball components 12 and transports them into and through a RF generator 13 where a pair of electrodes, a ground electrode 14 and a plate electrode 15 , create a RF field 16 therebetween. The golf ball components 12 are passed through the RF field 16 by a custom automation system at such a rate to cause an increase in golf ball temperature from room temperature (about 68° F.) to about 100° F. to 160° F. The rate of speed in which the golf ball components 12 are moved within the RF waves is a function of the energy that is required to raise the temperature of the components to the predetermined temperature. The time is preferably between 30 to 60 seconds. Energy levels are controlled based on the load requirements calculated by specific heat and desired temperature change. The time is a function of the energy level capacity of the machine 10 and the number, size and composition of the components 12 moving through the field 16 at any given time. The present invention employs a conveyor feed system that handles rows of multiple golf ball components. As the components pass through the field 16 , the conveyor has means to constantly rotate them, thereby allowing for a more uniform heating of each component. Although the drawings show rows having 9 components across, this number is merely a convenience item that relates directly to the size of each component and the RF equipment. Preferably the number of ball components in a row is greater than 3 and between 6 to 12.
[0023] In another embodiment of the invention, supplemental convection heating is added to enhance a consistent temperature across the surface of the component.
[0024] The definition of a golf ball component 12 includes a single layer core; a core of a center and at least one outer core layer; and a core of one or more layers covered by at least one intermediate layer. The method of the present invention is intended to heat the golf ball component 12 prior to casting a subsequent core, intermediate layer or cover layer thereon, and if further core or intermediate layers are desired they are preferably subsequently cast prior to the ball component cooling down.
[0025] The type of preheating equipment used to generate the RF waves is preferably a Macrowave™ Model L-200 such as supplied by the Radio Frequency Company, Millis, Mass.
[0026] The core composition can be made from any suitable core materials including thermoset polymers, such as natural rubber, ethylene propylene rubber or epdiene monomer, polybutadiene (PBD), polyisoprene, styrene-butadiene or styrene-propylene-diene rubber, and thermoplastics such as ionomer resins, polyamides, polyesters, or a thermoplastic elastomer. Suitable thermoplastic elastomers include Pebax®, which is believed to comprise polyether amide copolymers, Hytrel®, which is believed to comprise polyether ester from Elf-Atochem, E.I. Du Pont de Nemours and Company, various manufacturers, and Shell Chemical Company, respectively. The core materials can also be formed from a castable material. Suitable castable materials include those comprising a urethane, polyurea, epoxy, silicone, IPN's, etc.
[0027] The polybutadiene rubber composition preferably includes between about 2.2 parts and about 5 parts of a halogenated organosulfur compound. The halogenated conventional materials for such cores include core compositions having a base rubber, a cross-linking agent, filler and a co-cross-linking agent. The base rubber typically includes natural or synthetic rubbers. A preferred base rubber is 1,4-polybutadiene having a cis-structure of at least 40%. Natural rubber, polyisoprene rubber and/or styrene-butadiene rubber may be optionally added to the 1,4-polybutadiene. The initiator included in the core composition can be any known polymerization initiator that decomposes during the cure cycle. The cross-linking agent includes a metal salt of an unsaturated fatty acid such as a zinc salt or a magnesium salt of an unsaturated fatty acid having 3 to 8 carbon atoms such as acrylic or methacrylic acid. The filler typically includes materials such as tungsten, zinc oxide, barium sulfate, silica, calcium carbonate, zinc carbonate and the like. The polybutadiene rubber composition preferably includes between about 2.2 parts and about 5 parts of a halogenated organosulfur compound. The halogenated organo-sulfur compound may include pentafluorothiophenol; 2-fluorothiophenol; 3-fluorothiophenol; 4-fluorothiophenol; 2,3-fluorothiophenol; 2,4-fluorothiophenol; 3,4-fluorothiophenol; 3,5-fluorothiophenol 2,3,4-fluorothiophenol; 3,4,5-fluorothiophenol; 2,3,4,5-tetrafluorothiophenol; 2,3,5,6-tetrafluorothiophenol; 4-chlorotetrafluorothiophenol; pentachlorothiophenol; 2-chlorothiophenol; 3-chlorothiophenol; 4-chlorothiophenol; 2,3-chlorothiophenol; 2,4-chlorothiophenol; 3,4-chlorothiophenol; 3,5-chlorothiophenol; 2,3,4-chlorothiophenol; 3,4,5-chlorothiophenol; 2,3,4,5-tetrachlorothiophenol; 2,3,5,6-tetrachlorothiophenol; tetrafluorothiophenol; 4-chlorotetrafluorothiophenol; pentachlorothiophenol; 2-chlorothiophenol; 3-chlorothiophenol; 4-chlorothiophenol; 2,3-chlorothiophenol; 2,4-chlorothiophenol; 3,4-chlorothiophenol; 3,5-chlorothiophenol; 2,3,4-chlorothiophenol; 3,4,5-chlorothiophenol; 2,3,4,5-tetrachlorothiophenol; 2,3,5,6-tetrachlorothiophenol; pentabromothiophenol; 2-bromothiophenol; 3-bromothiophenol; 4-bromothiophenol; 2,3-bromothiophenol; 2,4-bromothiophenol; 3,4-bromothiophenol; 3,5-bromothiophenol; 2,3,4-bromothiophenol; 3,4,5-bromothiophenol; 2,3,4,5-tetrabromothiophenol; 2,3,5,6-tetrabromothiophenol; pentaiodothiophenol; 2-iodothiophenol; 3-iodothiophenol; 4-iodothiophenol; 2,3-iodothiophenol; 2,4-iodothiophenol; 3,4-iodothiophenol; 3,5-iodothiophenol; 2,3,4-iodothiophenol; 3,4,5-iodothiophenol; 2,3,4,5-tetraiodothiophenol; 2,3,5,6-tetraiodothiophenoland; and their zinc salts, the metal salts thereof, and mixtures thereof, but is preferably pentachlorothiophenol or the metal salt thereof. The metal salt may be zinc, calcium, potassium, magnesium, sodium, and lithium, but is preferably zinc.
[0028] Additionally, suitable core materials may also include cast or reaction injection molded polyurethane or polyurea, including those versions referred to as nucleated, where a gas, typically nitrogen, is incorporated via intensive agitation or mixing into at least one component of the polyurethane. (Typically, the pre-polymer, prior to component injection into a closed mold where essentially full reaction takes place resulting in a cured polymer having reduced specific gravity.) These materials are referred to as reaction injection molded (RIM) materials. Alternatively, the core may have a liquid center.
[0029] The core preferably has a compression in the range between about 30 to 110. For a core that is relaively soft the compression should be about 40 to 80, and for a relatively hard core, the compression should be about 90 to 110. The core preferably has a Coefficient of Restitution greater than 0.80.
[0030] The intermediate layer, if desired, can be formed by joining two hemispherical cups of material in a compression mold or by injection molding, as known by one of ordinary skill in the art. The intermediate layer may be a thermoplastic or a thermoset material. For example, a recommended ionomer resin material is SURLYN® and a recommended thermoplastic copolyetherester is Hytrel®, which are commercially available from DuPont. Blends of these materials can also be used. Another example of a suitable intermediate layer material is a thermoplastic elastomer, such as described in U.S. Pat. Nos. 6,315,680 and 5,688,191, which are both incorporated herein by reference in their entireties.
[0031] The intermediate layer may be formulated wherein vulcanized PP/EPDM. Santoprene® 203-40 is an example of a preferred intermediate layer comprises of dynamically vulcanized thermoplastic elastomer, functionalized styrene-butadiene elastomer, thermoplastic polyurethane or metallocene polymer or blends thereof. Suitable dynamically vulcanized thermoplastic elastomers include Santoprene®, Sarlink®, Vyram®, Dytron® and Vistaflex®. Santoprene® is the trademark for a dynamically Santoprene® and is commercially available from Advanced Elastomer Systems. Examples of suitable functionalized styrene-butadiene elastomers include Kraton FG-1901× and FG-1921×, which is available from the Shell Corporation. Examples of suitable thermoplastic polyurethanes include Estane® 58133, Estane® 58134 and Estane® 58144, which are commercially available from the B. F. Goodrich Company. Suitable metallocene polymers whose melting points are higher than the cover materials can also be employed in the mantle layer of the present invention. Further, the materials for the intermediate layer described above may be in the form of a foamed polymeric material. For example, suitable metallocene polymers include foams of thermoplastic elastomers based on metallocene single-site catalyst-based foams. Such metallocene-based foam resins are commercially available from Sentinel Products of Hyannis, Mass. Suitable thermoplastic polyetheresters include Hytrel® 3078, Hytrel® 3548, Hytrel® 4078, Hytrel® 4069, Hytrel® 6356, Hytrel® 7246, and Hytrel® 8238 which are commercially available from DuPont. Suitable thermoplastic polyetheramides include Pebax® 2533, Pebax® 3533, Pebax® 4033, Pebax® 5533, Pebax® 6333, and Pebax® 7033 which are available from Elf-Atochem. Suitable thermoplastic ionomer resins include any number of olefinic based ionomers including SURLYN® and lotek®, which are commercially available from DuPont and Exxon, respectively. The flexural moduli for these ionomers is about 1000 psi to about 200,000 psi. Suitable thermoplastic polyesters include polybutylene terephthalate. Likewise, the dynamically vulcanized thermoplastic elastomers, functionalized styrene-butadiene elastomers, thermoplastic polyurethane or metallocene polymers identified above are also useful as the second thermoplastic in such blends. Further, the materials of the second thermoplastic described above may be in the form of a foamed polymeric material.
[0032] Such thermoplastic blends comprise about 1% to about 99% by weight of a first thermoplastic and about 99% to about 1% by weight of a second thermoplastic. Preferably the thermoplastic blend comprises about 5% to about 95% by weight of a first thermoplastic and about 5% to about 95% by weight of a second thermoplastic. In a preferred embodiment of the present invention, the first thermoplastic material of the blend is a thermoplastic polyetherester, such as Hytrel®.
[0033] The present invention includes urethane/polyurea intermediate layer having a Shore D hardness less than 60, and for a soft layer a Shore D of less than 50, and a flexural modulus between 500 and 30,000 psi.
[0034] The present invention also includes the use of a variety of non-conventional cover materials. In particular, the covers of the present invention may comprise thermoplastic or engineering plastics such as ethylene or propylene based homopolymers and copolymers including functional monomers such as acrylic and methacrylic acid and fully or partially neutralized ionomers and their blends, methyl acrylate, methyl methacrylate homopolymers and copolymers, imidized, amino group containing polymers, polycarbonate, reinforced polyamides, polyphenylene oxide, high impact polystyrene, polyether ketone, polysulfone, poly(phenylene sulfide), reinforced engineering plastics, acrylonitrile-butadiene, acrylic-styrene-acrylonitrile, poly(ethylene terephthalate), poly(butylene terephthalate), poly(ethylene-vinyl alcohol), poly(tetrafluoroethylene) and their copolymers including functional comonomers and blends thereof. These polymers or copolymers can be further reinforced by blending with a wide range of fillers and glass fibers or spheres or wood pulp.
[0035] Additional preferred cover materials include thermoplastic or thermosetting polyurethane, such as those disclosed in U.S. Pat. Nos. 6,371,870; 6,210,294; 6,193,619; and 5,484,870; and metallocene or other single site catalyzed polymers such as those disclosed in U.S. Pat. Nos. 5,824,746; and 5,981,658.
[0036] While it is apparent that the illustrative embodiments of the invention disclosed herein fulfill the objectives stated above, it is appreciated that numerous modifications and other embodiments may be devised by those skilled in the art. Therefore, it will be understood that the appended claims are intended to cover all such modifications and embodiments which would come within the spirit and scope of the present invention.
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A method of heating a golf ball component by using radio frequency waves to reduce the thermal expansion experienced by a golf ball component such as a core, core and at least one core layer or a core and a combination of core and/or intermediate layers. The component is heated prior to having a layer applied in order to reduce the dramatic temperature increase the component experiences upon an intermediate layer being applied. The preheating reduces the amount of thermal expansion the component undergoes in the casting process.
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CROSS-REFERENCE TO RELATED APPLICATION
This application is a 371 of PCT/IB2010/056024, filed Dec. 22, 2010, the contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to a therapeutic approach, either viral vector-mediated gene therapy or by administration of modified sulfatases, in particular the sulfamidase enzyme, to cross the blood-brain barrier and treat the CNS pathology in Mucopolysaccharidoses (MPS), in particular MPS type IIIA.
BACKGROUND OF THE INVENTION
Mucopolysaccharidosis type IIIA (MPS-IIIA) is an inherited disease caused by the deficiency of sulfamidase (SGSH), an enzyme involved in the stepwise degradation of large macromolecules called heparan sulfates. As a consequence, undegraded substrates accumulate in the cells and tissues of the affected patients causing cell damage. The central nervous system (CNS) is the predominant target of damage and in fact, MPS-IIIA patients show severe mental retardation and neuropathological decline that ultimately leads to death (often<20 years). Clinical symptoms include hyperactivity, aggressive behaviour and sleep disturbance (1).
A naturally occurring mouse model of MPS-IIIA has been identified with pathophysiology and symptoms that resemble the human condition (2-4). These mice represent an ideal model to study the physiopathology of this disorder and to test new therapeutic protocols.
The treatment of brain lesions represents the principal goal of any therapeutic approach for MPS-IIIA. A route to reach the brain consists in the direct injection of a therapeutic molecule directly into the brain. A number of different enzyme replacement therapy (ERT) protocols have been tested. In these protocols, a recombinant sulfamidase enzyme was administered through the direct injection into the brain of MPSIIIA mice. These strategies are able to delay the appearance of neurodegenerative changes when sulfamidase is administered in the younger mice (5, 6). In addiction, a Gene Therapy protocol based on the intracerebral injection of the SGSH gene via AAV vectors was successfully developed by the authors of the invention (7). Although these direct brain-targeting approaches have been shown to be clinically effective they represent highly invasive approaches for human therapeutic applicability.
Since every neuron in the brain is perfused by its own blood vessel, an effective alternative low-invasive route to reach the brain is the intravenous administration of the therapeutic molecule (8). However, this very dense network of microvasculature, which forms the Blood-Brain Barrier (BBB), is not permeable to all the molecules and might impede effective delivery of therapeutic agents (9). Indeed, intravenous administration of lysosomal enzymes has produced a therapeutic effect on the somatic pathology of many LSDs but it has no or little effect on the CNS pathology due to the impermeability of the BBB to large molecules (10). In MPS-IIIA, it has been demonstrated that intravenous injection of sulfamidase does not alter the pathology or behavioural process occurring in the MPS-IIIA mouse brain when the enzyme is supplied after the BBB has been formed (11).
Importantly, a recent study by Urayama et al. demonstrated that sulfamidase is transported across the BBB in neonatal mice throughout the mannose 6-phosphate receptor-mediated transport but the influx into adult brain was negligible (12).
It is clear that in such context the real challenge for the therapy of MPS-IIIA and in general for all LSDs involving the CNS is to develop CNS systemic treatment strategies that can overcome the major obstacle represented by BBB. An effective strategy to cross the BBB is the targeting of proteins to the CNS via receptor-mediated transcytosis (13). Well-characterized BBB receptors include: low density lipoprotein receptor (LDLR), the transferrin receptor (TfR), and the insulin-like growth factor receptor (IGF-R). The LDLR family represents a group of cell surface receptors that binds apolipoprotein (Apo) complexes (lipid carriers) for the internalizing into the lysosomes (14-16). On the surface of the BBB, LDLR binding to Apo results in the transcytosis to the luminal side of the BBB, where the apolipoprotein is released to be uptaken by neurons and astrocytes. A recent study has demonstrated that fusing the LDLR-binding domain of Apo to a lysosome enzyme results in an efficient delivery of the chimeric enzyme to the CNS (17).
WO2004108071 refers to a chimeric CNS targeting polypeptide comprising a BBB-receptor binding domain, such as the Apolipoprotein B binding domain, for therapeutic use in lysosomal storage diseases.
WO2004064750 refers to nucleic acids encoding a chimeric lysosomal polypeptide (specifically the lysosomal acid glucosidase GAA implicated in the lysosomal storage disorder Glycogen storage disease type II) comprising a secretory signal sequence (i.e. Vi-antitrypsin and alpha-l-antitrypsin) and the related AAV vectors.
WO2005002515 refers to a compound comprising a megalin-binding moiety conjugated to an agent of interest for receptor mediated drug delivery, particularly by transcytosis, across the blood-brain barrier. Moreover the document refers to a method of treating a lysosomal storage disease based on the administration of a composition comprising a megalin-binding moiety. Apolipoprotein B and Mucopolysaccharidosis IIIA are mentioned.
WO2009131698 refers to a therapy based on a chimeric NaGlu enzyme characterized by an Apolipoprotein B binding domain and directed specifically to Mucopolysaccharidosis IIIB.
Cardone et al. (Hum Mol Gen, 2006 15(7):1225) describes the correction of Hunter syndrome (the lysosomal storage disease Mucopolysaccharidosis Type II) in the MPSII mouse model by liver-directed AAV2/8-TBG-mediated gene delivery.
WO2007092563 refers to a method and compositions for tolerizing a mammal's brain to exogenously administered acid sphingomyelinase polypeptide by first delivering an effective amount of a transgene encoding the polypeptide to the mammal's hepatic tissue and then administering an effective amount of the transgene to the mammal's central nervous system (CNS). The therapeutic approach is directed to Niemann-Pick disease, a lysosomal storage disease. Liver- specific promoters and AAV type 8 are mentioned.
WO2009075815 refers to methods of treating Pompe disease (a lysosomal storage disease) which involves the administration of an AAV vector in the context of enzyme replacement therapy. Liver-specific promoter (thyroid hormone-binding globulin promoter) and AAV type 8 are mentioned.
None of the above prior art cited documents disclose or even suggest the modified sufamidase enzyme of the instant invention and that it may have a therapeutic effect for the treatment of MPS type IIIA.
SUMMARY OF THE INVENTION
As disclosed in the background art, brain pathology is the most common feature in lysosomal storage disorders. Therefore, the treatment of brain lesions represents the principal goal of any effective therapy for these disorders.
The major obstacle to efficiently treat the brain by systemic delivery of a therapeutic agent is the blood brain barrier (BBB).
Authors developed a new non-invasive therapeutic approach to treat the brain pathology in the mucopolysaccharidosis type IIIA (MPS-IIIA), a lysosomal storage disorder with a severe central nervous system involvement. This strategy is based on the construction of a chimeric sulfamidase (the sulfatase enzyme which is deficient in MPS-IIIA), optimized with two amino-acid sequences (one to the N-terminus and the other to the C-terminus of the protein) which confer to the modified sulfamidase the capability to be highly secreted and efficiently targeted to the brain by crossing the blood brain barrier (BBB). The modified enzyme is expressed by adeno-associated virus (AAV) serotype 8 which specifically target the liver and make it like a factory organ of the therapeutic enzyme.
The modified sulfamidase may be effectively used for both gene therapy and for enzyme replacement therapy (ERT).
The modification approach may be used for other lysosomal enzymes which are deficient in other mucopolisaccharidoses with severe CNS involvement.
Therefore it is an object of the instant invention a nucleotide sequence encoding for a chimeric sulfatase, said chimeric sulfatase essentially consisting in the N-terminal-C-terminal sequence order of: a) a signal peptide derived by either the human α-antitrypsin (hAAT) amino acid sequence or the human Iduronate-2-sulfatase (IDS) amino acid sequence; b) a human sulfatase derived amino acid sequence deprived of its signal peptide; c) the ApoB LDLR-binding domain.
In a preferred embodiment the encoded signal peptide has a sequence belonging to the following group: MPSSVSWGILLLAGLCCLVPVSLA (SEQ ID No. 2) or MPPPRTGRGLLWLGLVLSSVCVALG (SEQ ID No. 4 or 6).
In a preferred embodiment the nucleotide the human sulfatase is the human sulfamidase, more preferably the encoded human sulfamidase derived amino acid sequence has essentially the sequence:
(SEQ ID No. 8) MSCPVPACCALLLVLGLCRARPRNALLLLADDGGFESGAYNNSAIATPHL DALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDVHHFNS FDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSVLQVGR NITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCEKFGNG ESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGRMDQGV GLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLLVSSPE HPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTGRSLLP ALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMPFPIDQ DFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDPHETQN LATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQCQPLHN EL.
Such sequence is encoded by SEQ ID No. 7 nt sequence:
5′-
ATGAGCTGCCCCGTGCCCGCCTGCTGCGCGCTGCTGCTAGTCCTGGGGCT
CTGCCGGGCGCGTCCCCGGAACGCACTGCTGCTCCTCGCGGATGACGGAG
GCTTTGAGAGTGGCGCGTACAACAACAGCGCCATCGCCACCCCGCACCTG
GACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAATGCCTTCACCTCGGT
CAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCACTGGCCTGCCCCAGC
ATCAGAATGGGATGTACGGGCTGCACCAGGACGTGCACCACTTCAACTCC
TTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAGCCAAGCTGGTGTGCG
CACAGGCATCATCGGGAAGAAGCACGTGGGGCCGGAGACCGTGTACCCGT
TTGACTTTGCGTACACGGAGGAGAATGGCTCCGTCCTCCAGGTGGGGCGG
AACATCACTAGAATTAAGCTGCTCGTCCGGAAATTCCTGCAGACTCAGGA
TGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACGACCCCCACCGCTGTG
GGCACTCCCAGCCCCAGTACGGAACCTTCTGTGAGAAGTTTGGCAACGGA
GAGAGCGGCATGGGTCGTATCCCAGACTGGACCCCCCAGGCCTACGACCC
ACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACACCCCGGCAGCCCGAG
CCGACCTGGCCGCTCAGTACACCACCGTCGGCCGCATGGACCAAGGAGTT
GGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGTCCTGAACGACACACT
GGTGATCTTCACGTCCGACAACGGGATCCCCTTCCCCAGCGGCAGGACCA
ACCTGTACTGGCCGGGCACTGCTGAACCCTTACTGGTGTCATCCCCGGAG
CACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTACGTGAGCCTCCTAGA
CCTCACGCCCACCATCTTGGATTGGTTCTCGATCCCGTACCCCAGCTACG
CCATCTTTGGCTCGAAGACCATCCACCTCACTGGCCGGTCCCTCCTGCCG
GCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTTTGGCAGCCAGAGCCA
CCACGAGGTCACCATGTCCTACCCCATGCGCTCCGTGCAGCACCGGCACT
TCCGCCTCGTGCACAACCTCAACTTCAAGATGCCCTTTCCCATCGACCAG
GACTTCTACGTCTCACCCACCTTCCAGGACCTCCTGAACCGCACCACAGC
TGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTCATTACTACTACCGGG
CGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCCCACGAGACCCAGAAC
CTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGAGATGCTTCGGGACCA
GCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCTGGGTGTGCGCCCCCG
ACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGCCAGCCCCTCCACAAT
GAGCTGTGA-3′.
In a preferred embodiment the encoded ApoB LDLR-binding domain has essentially the sequence:
(SEQ ID No. 10)
SVIDALQYKLEGTTRLTRKRGLKLATALSLSNKFVEGS.
In a preferred embodiment the nucleotide sequence has essentially the sequence belonging to the following group:
SEQUENCES WITH FLAG (expert shall easily substi-
tute the flag sequence with any other suitable
spacer sequence):
a) Assembly hAATsp-SGSH-3xflag cassette (1611).
(SEQ ID No. 11)
5′-
ATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTG
CCTGGTCCCTGTCTCCCTGGCTCGTCCCCGGAACGCACTGCTGCTCCTCG
CGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATCGCC
ACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAATGC
CTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCACTG
GCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTGCAC
CACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAGCCA
AGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGGAGA
CCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTCCTC
CAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATTCCT
GCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACGACC
CCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAGAAG
TTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCCCCA
GGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACACCC
CGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGCATG
GACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGTCCT
GAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCCCCA
GCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTGGTG
TCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTACGT
GAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCCCGT
ACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGCCGG
TCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTTTGG
CAGCCAGAGCCACCACGAGGTCACCATGTCCTACCCCATGCGCTCCGTGC
AGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCCTTT
CCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCTGAA
CCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTCATT
ACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCCCAC
GAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGAGAT
GCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCTGGG
TGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGCCAG
CCCCTCCACAATGAGCTGTCATCTAGAGGATCCCGGGCTGACTACAAAGA
CCATGACGGTGATTATAAAGATCATGACATCGACTACAAGGATGACGATG
ACAAGTAGTGA-3′
b) Assembly hIDSsp-SGSH-3xflag cassette (1614 bp).
(SEQ ID No. 13)
5′-
ATGCCCCCGCCCCGCACCGGCCGCGGCCTGCTGTGGCTGGGCCTGGTGCT
GAGCAGCGTGTGCGTGGCCCTGGGCCGTCCCCGGAACGCACTGCTGCTCC
TCGCGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATC
GCCACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAA
TGCCTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCA
CTGGCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTG
CACCACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAG
CCAAGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGG
AGACCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTC
CTCCAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATT
CCTGCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACG
ACCCCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAG
AAGTTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCC
CCAGGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACA
CCCCGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGC
ATGGACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGT
CCTGAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCC
CCAGCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTG
GTGTCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTA
CGTGAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCC
CGTACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGC
CGGTCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTT
TGGCAGCCAGAGCCACCACGAGGTCACCATGTCCTACCCCATGCGCTCCG
TGCAGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCC
TTTCCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCT
GAACCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTC
ATTACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCC
CACGAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGA
GATGCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCT
GGGTGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGC
CAGCCCCTACACAATGAGCTCTCATCTAGAGGATCCCGGGCTGACTACAA
AGACCATGACGGTGATTATAAAGATCATGACATCGACTACAAGGATGACG
ATGACAAGTAGTGA-3′
c) Assembly hAATsp-SGSH-3xflag-ApoB cassette (1734
bp).
(SEQ ID No. 15)
5′-
ATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTG
CCTGGTCCCTGTCTCCCTGGCTCGTCCCCGGAACGCACTGCTGCTCCTCG
CGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATCGCC
ACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAATGC
CTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCACTG
GCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTGCAC
CACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAGCCA
AGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGGAGA
CCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTCCTC
CAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATTCCT
GCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACGACC
CCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAGAAG
TTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCCCCA
GGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACACCC
CGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGCATG
GACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGTCCT
GAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCCCCA
GCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTGGTG
TCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTACGT
GAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCCCGT
ACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGCCGG
TCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTTTGG
CAGCCAGAGCCACCACGAGGTCACCATGTCTTACCCCATGCGCTCCGTGC
AGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCCTTT
CCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCTGAA
CCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTCATT
ACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCCCAC
GAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGAGAT
GCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCTGGG
TGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGCCAG
CCCCTCCACAATGAGCTGTCATCTAGAGGATCCCGGGCTGACTACAAAGA
CCATGACGGTGATTATAAAGATCATGACATCGACTACAAGGATGACGATG
ACAAGATCTCTGTCATTGATGCACTGCAGTACAAATTAGAGGGCACCACA
AGATTGACAAGAAAAAGGGGATTGAAGTTAGCCACAGCTCTGTCTCTGAG
CAACAAATTTGTGGAGGGTAGTAGATCTTAGTGA-3′
d) Assembly hIDSsp-SGSH-3xflag-ApoB cassette (1737
bp).
(SEQ ID No. 17)
5′-
ATGCCCCCGCCCCGCACCGGCCGCGGCCTGCTGTGGCTGGGCCTGGTGCT
GAGCAGCGTGTGCGTGGCCCTGGGCCGTCCCCGGAACGCACTGCTGCTCC
TCGCGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATC
GCCACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAA
TGCCTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCA
CTGGCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTG
CACCACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAG
CCAAGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGG
AGACCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTC
CTCCAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATT
CCTGCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACG
ACCCCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAG
AAGTTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCC
CCAGGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACA
CCCCGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGC
ATGGACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGT
CCTGAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCC
CCAGCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTG
GTGTCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTA
CGTGAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCC
CGTACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGC
CGGTCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTT
TGGCAGCCAGAGCCACCACGAGGTCACCATGTCCTACCCCATGCGCTCCG
TGCAGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCC
TTTCCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCT
GAACCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTC
ATTACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCC
CACGAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGA
GATGCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCT
GGGTGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGC
CAGCCCCTACACAATGAGCTCTCATCTAGAGGATCCCGGGCTGACTACAA
AGACCATGACGGTGATTATAAAGATCATGACATCGACTACAAGGATGACG
ATGACAAGATCTCTGTCATTGATGCACTGCAGTACAAATTAGAGGGCACC
ACAAGATTGACAAGAAAAAGGGGATTGAAGTTAGCCACAGCTCTGTCTCT
GAGCAACAAATTTGTGGAGGGTAGTAGATCTTAGTGA-3′
SEQUENCES WITHOUT FLAG:
e) Assembly hAATsp-SGSH cassette.
(SEQ ID No. 19)
5′-
ATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTG
CCTGGTCCCTGTCTCCCTGGCTCGTCCCCGGAACGCACTGCTGCTCCTCG
CGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATCGCC
ACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAATGC
CTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCACTG
GCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTGCAC
CACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAGCCA
AGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGGAGA
CCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTCCTC
CAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATTCCT
GCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACGACC
CCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAGAAG
TTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCCCCA
GGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACACCC
CGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGCATG
GACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGTCCT
GAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCCCCA
GCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTGGTG
TCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTACGT
GAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCCCGT
ACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGCCGG
TCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTTTGG
CAGCCAGAGCCACCACGAGGTCACCATGTCCTACCCCATGCGCTCCGTGC
AGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCCTTT
CCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCTGAA
CCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTCATT
ACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCCCAC
GAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGAGAT
GCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCTGGG
TGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGCCAG
CCCCTCCACAATGAGCTGTGA-3′
f) Assembly hIDSsp-SGSH cassette.
(SEQ ID No. 21)
5′-
ATGCCCCCGCCCCGCACCGGCCGCGGCCTGCTGTGGCTGGGCCTGGTGCT
GAGCAGCGTGTGCGTGGCCCTGGGCCGTCCCCGGAACGCACTGCTGCTCC
TCGCGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATC
GCCACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAA
TGCCTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCA
CTGGCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTG
CACCACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAG
CCAAGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGG
AGACCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTC
CTCCAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATT
CCTGCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACG
ACCCCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAG
AAGTTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCC
CCAGGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACA
CCCCGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGC
ATGGACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGT
CCTGAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCC
CCAGCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTG
GTGTCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTA
CGTGAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCC
CGTACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGC
CGGTCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTT
TGGCAGCCAGAGCCACCACGAGGTCACCATGTCCTACCCCATGCGCTCCG
TGCAGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCC
TTTCCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCT
GAACCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTC
ATTACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCC
CACGAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGA
GATGCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCT
GGGTGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGC
CAGCCCCTACACAATGAGCTCTGA-3′
g) Assembly hAATsp-SGSH-ApoB cassette.
(SEQ ID No. 23)
5′-
ATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTGCTG
CCTGGTCCCTGTCTCCCTGGCTCGTCCCCGGAACGCACTGCTGCTCCTCG
CGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATCGCC
ACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAATGC
CTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCACTG
GCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTGCAC
CACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAGCCA
AGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGGAGA
CCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTCCTC
CAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATTCCT
GCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACGACC
CCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAGAAG
TTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCCCCA
GGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACACCC
CGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGCATG
GACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGTCCT
GAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCCCCA
GCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTGGTG
TCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTACGT
GAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCCCGT
ACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGCCGG
TCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTTTGG
CAGCCAGAGCCACCACGAGGTCACCATGTCTTACCCCATGCGCTCCGTGC
AGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCCTTT
CCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCTGAA
CCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTCATT
ACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCCCAC
GAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGAGAT
GCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCTGGG
TGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGCCAG
CCCCTCCACAATGAGCTGTCATCTAGATCTGTCATTGATGCACTGCAGTA
CAAATTAGAGGGCACCACAAGATTGACAAGAAAAAGGGGATTGAAGTTAG
CCACAGCTCTGTCTCTGAGCAACAAATTTGTGGAGGGTAGTAGATCTTAG
TGA-3′
h) Assembly hIDSsp-SGSH-ApoB cassette.
(SEQ ID No. 25)
5′-
ATGCCCCCGCCCCGCACCGGCCGCGGCCTGCTGTGGCTGGGCCTGGTGCT
GAGCAGCGTGTGCGTGGCCCTGGGCCGTCCCCGGAACGCACTGCTGCTCC
TCGCGGATGACGGAGGCTTTGAGAGTGGCGCGTACAACAACAGCGCCATC
GCCACCCCGCACCTGGACGCCTTGGCCCGCCGCAGCCTCCTCTTTCGCAA
TGCCTTCACCTCGGTCAGCAGCTGCTCTCCCAGCCGCGCCAGCCTCCTCA
CTGGCCTGCCCCAGCATCAGAATGGGATGTACGGGCTGCACCAGGACGTG
CACCACTTCAACTCCTTCGACAAGGTGCGGAGCCTGCCGCTGCTGCTCAG
CCAAGCTGGTGTGCGCACAGGCATCATCGGGAAGAAGCACGTGGGGCCGG
AGACCGTGTACCCGTTTGACTTTGCGTACACGGAGGAGAATGGCTCCGTC
CTCCAGGTGGGGCGGAACATCACTAGAATTAAGCTGCTCGTCCGGAAATT
CCTGCAGACTCAGGATGACCGGCCTTTCTTCCTCTACGTCGCCTTCCACG
ACCCCCACCGCTGTGGGCACTCCCAACCCCAGTACGGAACCTTCTGTGAG
AAGTTTGGCAACGGAGAGAGCGGCATGGGTCGTATCCCAGACTGGACCCC
CCAGGCCTACGACCCACTGGACGTGCTGGTGCCTTACTTCGTCCCCAACA
CCCCGGCAGCCCGAGCCGACCTGGCCGCTCAGTACACCACCGTCGGCCGC
ATGGACCAAGGAGTTGGACTGGTGCTCCAGGAGCTGCGTGACGCCGGTGT
CCTGAACGACACACTGGTGATCTTCACGTCCGACAACGGGATCCCCTTCC
CCAGCGGCAGGACCAACCTGTACTGGCCGGGCACTGCTGAACCCTTACTG
GTGTCATCCCCGGAGCACCCAAAACGCTGGGGCCAAGTCAGCGAGGCCTA
CGTGAGCCTCCTAGACCTCACGCCCACCATCTTGGATTGGTTCTCGATCC
CGTACCCCAGCTACGCCATCTTTGGCTCGAAGACCATCCACCTCACTGGC
CGGTCCCTCCTGCCGGCGCTGGAGGCCGAGCCCCTCTGGGCCACCGTCTT
TGGCAGCCAGAGCCACCACGAGGTCACCATGTCTTACCCCATGCGCTCCG
TGCAGCACCGGCACTTCCGCCTCGTGCACAACCTCAACTTCAAGATGCCC
TTTCCCATCGACCAGGACTTCTACGTCTCACCCACCTTCCAGGACCTCCT
GAACCGCACCACAGCTGGTCAGCCCACGGGCTGGTACAAGGACCTCCGTC
ATTACTACTACCGGGCGCGCTGGGAGCTCTACGACCGGAGCCGGGACCCC
CACGAGACCCAGAACCTGGCCACCGACCCGCGCTTTGCTCAGCTTCTGGA
GATGCTTCGGGACCAGCTGGCCAAGTGGCAGTGGGAGACCCACGACCCCT
GGGTGTGCGCCCCCGACGGCGTCCTGGAGGAGAAGCTCTCTCCCCAGTGC
CAGCCCCTCCACAATGAGCTGTCATCTAGATCTGTCATTGATGCACTGCA
GTACAAATTAGAGGGCACCACAAGATTGACAAGAAAAAGGGGATTGAAGT
TAGCCACAGCTCTGTCTCTGAGCAACAAATTTGTGGAGGGTAGTAGATCT
TAGTGA-3′.
It is a further object of the invention a recombinant plasmid suitable for gene therapy of MPS comprising the nucleotide sequence as above disclosed under the control of a liver specific promoter, preferably the liver specific promoter is the human thyroid hormone-globulin (TBG) promoter, more preferably the human thyroid hormone-globulin (TBG) promoter has essentially the sequence:
(SEQ ID No. 27)
5′-GCTAGCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGTGGCCCT
TGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAGGAGCAC
AAACATTCCAGATCCAGGTTAATTTTTAAAAAGCAGTCAAAAGTCCAAGT
GGCCCTTGGCAGCATTTACTCTCTCTGTTTGCTCTGGTTAATAATCTCAG
GAGCACAAACATTCCAGATCCGGCGCGCCAGGGCTGGAAGCTACCTTTGA
CATCATTTCCTCTGCGAATGCATGTATAATTTCTACAGAACCTATTAGAA
AGGATCACCCAGCCTCTGCTTTTGTACAACTTTCCCTTAAAAAACTGCCA
ATTCCACTGCTGTTTGGCCCAATAGTGAGAACTTTTTCCTGCTGCCTCTT
GGTGCTTTTGCCTATGGCCCCTATTCTGCCTGCTGAAGACACTCTTGCCA
GCATGGACTTAAACCCCTCCAGCTCTGACAATCCTCTTTCTCTTTTGTTT
TACATGAAGGGTCTGGCAGCCAAAGCAATCACTCAAAGTTCAAACCTTAT
CATTTTTTGCTTTGTTCCTCTTGGCCTTGGTTTTGTACATCAGCTTTGAA
AATACCATCCCAGGGTTAATGCTGGGGTTAATTTATAACTAAGAGTGCTC
TAGTTTTGCAATACAGGACATGCTATAAAAATGGAAAGATGTTGCTTTCT
GAGAGACTGCAG-3′.
The expert in the field will realize that the recombinant plasmid of the invention has to be assembled in a viral vector for gene therapy of lysosomal disorders, and select the most suitable one. Such viral vectors may belong to the group of: lentiviral vectors, helper-dependent adenoviral vectors or AAV vectors. As example lentiviral vectors for gene therapy of lysosomal storage disorders is described in Naldini, L., Blomer, U., Gage, F. H., Trono, D., and Verma, I. M. (1996a). In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272(5259), 263-7; Consiglio A, Quattrini A, Martino S, Bensadoun J C, Dolcetta D, Trojani A, Benaglia G, Marchesini S, Cestari V, Oliverio A, Bordignon C, Naldini. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice L. Nat Med. 2001 March; 7(3):310-6; Follenzi A, Naldini L. HIV-based vectors. Preparation and use. Methods Mol Med. 2002;69:259-74. As a further example helper-dependent adenoviral vectors are described in Brunetti-Pierri N, Ng P. Progress towards liver and lung-directed gene therapy with helper-dependent adenoviral vectors. Curr Gene Ther. 2009 October; 9(5):329-40.
In a preferred embodiment the recombinant plasmid derives from the plasmid vector AAV2.1 and is suitable for AAV viral vectors, preferably AAV serotype 8.
Then it is a further object of the invention a viral vector for gene therapy of lysosomal disorders comprising any of the recombinant nucleic acid vectors as above disclosed. Preferably the lysosomal disorder is MPS, more preferably MPS type IIIA.
It is a further object of the invention a pharmaceutical composition comprising the viral vector as above disclosed, preferably for systemic administration.
It is a further object of the invention a chimeric sulfatase essentially consisting in the N-terminal-C-terminal sequence order of a) a signal peptide derived by either the human a-antitrypsin (hAAT) amino acid sequence or the human Iduronate-2-sulfatase (IDS) amino acid sequence; b) an human sulfatase derived amino acid sequence deprived of its signal peptide; c) the ApoB LDLR-binding domain.
In a preferred embodiment the chimeric sulfatase has a signal peptide having a sequence belonging to the following group: (SEQ ID No. 2) or (SEQ ID No. 4).
In a preferred embodiment the chimeric sulfatase has a human sulfamidase derived sequence, preferably (SEQ ID No. 8).
In a preferred embodiment the chimeric sulfatase comprises an encoded ApoB LDLR-binding domain having essentially the sequence of (SEQ ID No. 10).
In a preferred embodiment the chimeric sulfatase has essentially the sequence belonging to the following group:
SEQUENCE WITH FLAG (expert shall easily substi-
tute the flag sequence with any other suitable
spacer sequence):
a) hAATsp-SGSH-3xflag aminoacid sequence (* =
stop).
(SEQ ID No. 12)
MPSSVSWGILLLAGLCCLVPVSLARPRNALLLLADDGGFESGAYNNSAIA
TPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDVH
HFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSVL
QVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCEK
FGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGRM
DQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLLV
SSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTGR
SLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMPF
PIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDPH
ETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQCQ
PLHNELSSRGSRADYKDHDGDYKDHDIDYKDDDDK**
b) hIDSsp-SGSH-3xflag aminoacid sequence (* =
stop)
(SEQ ID No. 14)
MPPPRTGRGLLWLGLVLSSVCVALGRPRNALLLLADDGGFESGAYNNSAI
ATPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDV
HHFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSV
LQVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCE
KFGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGR
MDQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLL
VSSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTG
RSLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMP
FPIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDP
HETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQC
QPLHNELSSRGSRADYKDHDGDYKDHDIDYKDDDDK**
c) hAATsp-SGSH-3xflag-ApoB aminoacid sequence
(* = stop)
(SEQ ID No. 16)
MPSSVSWGILLLAGLCCLVPVSLARPRNALLLLADDGGFESGAYNNSAIA
TPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDVH
HFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSVL
QVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCEK
FGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGRM
DQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLLV
SSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTGR
SLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMPF
PIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDPH
ETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQCQ
PLHNELSSRGSRADYKDHDGDYKDHDIDYKDDDDKISVIDALQYKLEGTT
RLTRKRGLKLATALSLSNKFVEGSRS**
d) hIDSsp-SGSH-3xflag-ApoB aminoacid sequence
(* = stop)
(SEQ ID No. 18)
MPPPRTGRGLLWLGLVLSSVCVALGRPRNALLLLADDGGFESGAYNNSAI
ATPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDV
HHFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSV
LQVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCE
KFGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGR
MDQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLL
VSSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTG
RSLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMP
FPIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDP
HETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQC
QPLHNELSSRGSRADYKDHDGDYKDHDIDYKDDDDKISVIDALQYKLEGT
TRLTRKRGLKLATALSLSNKFVEGSRS**,
SEQUENCES WITHOUT FLAG:
e) hAATsp-SGSH aminoacid sequence (* = stop)
(SEQ ID No. 20)
MPSSVSWGILLLAGLCCLVPVSLARPRNALLLLADDGGFESGAYNNSAIA
TPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDVH
HFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSVL
QVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCEK
FGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGRM
DQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLLV
SSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTGR
SLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMPF
PIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDPH
ETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQCQ
PLHNEL*
f) hIDSsp-SGSH aminoacid sequence (* = stop)
(SEQ ID No. 22)
MPPPRTGRGLLWLGLVLSSVCVALGRPRNALLLLADDGGFESGAYNNSAI
ATPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDV
HHFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSV
LQVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCE
KFGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGR
MDQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLL
VSSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTG
RSLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMP
FPIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDP
HETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQC
QPLHNEL*
g) hAATsp-SGSH-ApoB aminoacid sequence (* = stop)
(SEQ ID No. 24)
MPSSVSWGILLLAGLCCLVPVSLARPRNALLLLADDGGFESGAYNNSAIA
TPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDVH
HFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSVL
QVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCEK
FGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGRM
DQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLLV
SSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTGR
SLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMPF
PIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDPH
ETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQCQ
PLHNELSSRSVIDALQYKLEGTTRLTRKRGLKLATALSLSNKFVEGSRS*
*
h) hIDSsp-SGSH-ApoB aminoacid sequence (* = stop)
(SEQ ID No. 26)
MPPPRTGRGLLWLGLVLSSVCVALGRPRNALLLLADDGGFESGAYNNSAI
ATPHLDALARRSLLFRNAFTSVSSCSPSRASLLTGLPQHQNGMYGLHQDV
HHFNSFDKVRSLPLLLSQAGVRTGIIGKKHVGPETVYPFDFAYTEENGSV
LQVGRNITRIKLLVRKFLQTQDDRPFFLYVAFHDPHRCGHSQPQYGTFCE
KFGNGESGMGRIPDWTPQAYDPLDVLVPYFVPNTPAARADLAAQYTTVGR
MDQGVGLVLQELRDAGVLNDTLVIFTSDNGIPFPSGRTNLYWPGTAEPLL
VSSPEHPKRWGQVSEAYVSLLDLTPTILDWFSIPYPSYAIFGSKTIHLTG
RSLLPALEAEPLWATVFGSQSHHEVTMSYPMRSVQHRHFRLVHNLNFKMP
FPIDQDFYVSPTFQDLLNRTTAGQPTGWYKDLRHYYYRARWELYDRSRDP
HETQNLATDPRFAQLLEMLRDQLAKWQWETHDPWVCAPDGVLEEKLSPQC
QPLHNELSSRSVIDALQYKLEGTTRLTRKRGLKLATALSLSNKFVEGSRS
**
It is another object of the invention the chimeric sulfatase as above disclosed for medical use, preferably for the treatment of MPS, more preferably MPS type IIIA.
It is another object of the invention a pharmaceutical composition comprising the chimeric sulfatase as above disclosed and suitable diluents and/or eccipients and/or carriers.
It is another object of the invention a method for treatment of a MPS pathology comprising the step of administering to a subject a suitable amount of the pharmaceutical composition comprising the viral vector for gene therapy as above disclosed. Preferably the MPS pathology is MPS type IIIA.
It is another object of the invention a method for treatment of a MPS pathology comprising the step of administering to a subject a suitable amount of the pharmaceutical composition comprising the chimeric sulfatase as above disclosed. Preferably the MPS pathology is MPS type IIIA.
Major advantage of the invention is that the chimeric molecule of the invention as produced and secreted by the liver is able to cross the BBB and thus potentially target to all brain districts.
Regarding the gene therapy approach, with respect to prior art Fraldi et al. HMG 2007 that describes AAV2/5 mediated gene therapy for MPS-IIIIA, the instant invention is less invasive because AAV8 vectors are administered systemically and not directly into the brain.
As to the enzyme replacement therapy approach with respect to the prior art Hemsley, K. M. and J. J. Hopwood, Behav Brain Res, 2005; Savas, P. S et al., Mol Genet Metab, 2004 and Hemsley, K. M., et al., Mol Genet Metab, 2007, the instant invention overcomes the necessity to repeat the injection of the enzyme and it is designed to cross the BBB. It is worth to point out that for ERT approaches the BBB and the high cost of the enzyme production are very important limitations.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 . Non-modified SGSH: Preliminary in vivo study 1 (newborn treatment). Analysis of GFP signal in liver of newborn MPSIIA mice injected with AAV2/8-TBG-GFP. Newborn MPSIIIA were injected with AAV2/8-TBG-SGSH vectors (expressing a not-modified sulfamidase). As control, newborn MPSIIIA and Heterozygous (phenotypically normal) mice were injected with AAV2/8-TBG-GFP vectors. Liver sections from MPS-IIIA injected mice were analyzed for GFP staining at different time after injection (1,2,3,5 and 10 weeks after injection). The GFP signal was very strong at early time points. However, a significant decrease of GFP signal was observed at later time point after injection
FIG. 2 . Non-modified SGSH: Preliminary in vivo study 1 (newborn treatment). SGSH activity in the liver and serum of newborn injected mice. The sulfamidase activity was measured in the serum (A) and liver (B) of MPSIIIA mice injected with AAV2/8-TBG-SGSH and control mice (MPS-IIIA and heterozygous mice injected with AAV2/8-TBG-GFP). (A) The SGSH activity in plasma of AAV2/8-TBG-SGSH-treated MPS-IIIA mice increased during the first two weeks period after neonatal treatment, and then decreased through the time to reach the levels measured in control GFP-injected MPS-IIIA mice. (B) The analysis of liver SGSH activity showed a trend similar to that observed in the plasma with higher levels of activity detected within the first week after injection.
FIG. 3 . Non-modified SGSH: Preliminary in vivo study 2 (adult treatment). Analysis of GFP signal in liver of adult MPSIIA mice injected with AAV2/8-TBG-GFP. 1.5 months old MPSIIIA were injected with AAV2/8-TBG-SGSH vectors (expressing a not-modified sulfamidase). As control, 1.5 months old MPSIIIA and Heterozygous (phenotypically normal) mice were injected with AAV2/8-TBG-GFP vectors. Liver sections from MPS-IIIA injected mice were analyzed for GFP staining at 1 and 5 weeks after injection. A high and stable expression of the GFP was observed.
FIG. 4 . Non-modified SGSH: Preliminary in vivo study 2 (adult treatment). SGSH activity in the serum and liver of adult injected mice. The sulfamidase activity was measured in the serum (A) and liver (B) of MPSIIIA mice injected with AAV2/8-TBG-SGSH and control mice (MPS-IIIA and heterozygous mice injected with AAV2/8-TBG-GFP). (A) In the liver of MPSIIIA mice injected with AAV2/8-TBG-SGSH a strong increase in the SGSH activity was observed compared to the low enzyme activity detected in the animals injected with GFP vector. In addition, this activity remained stable for 5 weeks after injection (the last time point analyzed). (B)
Consistently, the analysis of SGSH activity in the serum of MPS-IIIA mice treated with AAV2/8-TBG-SGSH was very high and stable during throughout the analyzed post-injection time.
FIG. 5 . Chimeric sulfamidase constructs. The signal peptide (SP) of sulfamidase was replaced with that of either human a-antitrypsin (hAAT) or Iduronate-2-sulfatase (IDS). The constructs were designed as “partially engineered sulfamidase proteins” (IDSsp-SGSHflag and hAATsp-SGSHflag). To build the final chimeric sulfamidase proteins, the ApoB LDLR-binding domain (ApoB-BD) was fused at the C-terminus of the Flag tag to obtain the resulting “finally engineered constructs” (IDSsp-SGSHflag-ApoB and hAATsp-SGSHflag-ApoB). The ApoB sequence (114 bp) was amplified by PCR from the human blood cDNA using forward and reverse oligonucleotides with 5′ BglII sites. The backbone plasmid containing the SP-SGSH sequence was prepared inserting by mutagenesis the BglII site before the stop codon of Flag tag. All the resulting chimeric sulfamidase sequences (IDSsp-SGSHflag, hAATsp-SGSHflag, IDSsp-SGSHflag-ApoB and hAATsp-SGSHflag-ApoB) were inserted in mammalian expression plasmids under a CMV promoter.
FIG. 6 . Receptor-mediated transport. Crossing the BBB via receptor-mediated transcytosis. The Low Density Lipoprotein receptor (LDLR)-binding domain of the Apolipoprotein B (ApoB LDLR-BD) confers to the sulfamidase the capability to reach the brain cells by binding LDL receptors, which are abundant on the endothelial cells of BBB. This mechanism may substitute the mannose-6-phosphate receptor (M6PR)-mediated transport of the sulfamidase throughout the BBB, which is inefficient.
FIG. 7 . In vitro study. SGSH activity in the pellet and in the medium of transfected MPS-IIIA MEF cells. MEF cells derived from MPS-IIIA mice were transfected with either partially or finally engineered constructs. (A) The activity of sulfamidase was measured in the medium (light grey) and in the pellet (dark grey) of transfected cells. (B) The corresponding efficiency of secretion (activity in medium/total activity) was also evaluated.
FIG. 8 . In vitro study. Western blot analysis of all engineered sulfamidase proteins. MEF cells derived from MPS-IIIA mice were transfected with either partial or final engineered constructs or with control SGSH not modified construct. (A) blot analysis with anti-flag antibodies showing the correct expression of all the chimeric proteins. As a control of transfection efficiency the cells were co-transfected with the same concentration of a plasmid containing flag-tagged Syntaxin7, an unrelated protein. (B) Pulse and chase experiments were performed in the transfected cells to evaluate the turnover rate of the chimeric proteins (C) Cos-7 cells were transfected with either partially or finally engineered constructs or with control SGSH non modified construct. Lysosomal localization were observed in all transfected cells by immunostaining with anti-SGSH antibodies.
FIG. 9 . In vivo study. Preliminary in vivo results in MPS IIIA mice injected with finally engineered sulfamidase. Authors obtained preliminary but extremely encouraging results in MPS-IIIA mice injected with one of the final sulfamidase constructs: hAATsp-SGSHflag-ApoB. Adult MPS-IIIA mice were systemically injected with AAV2/8-TBG- hAATsp-SGSHflag-ApoB. A group of MPS-IIIA were also injected with AAV2/8-TBG-SGSH (containing the non-modified sulfamidase) as control. The mice were sacrificed one month after injection. In the mice injected with the chimeric sulfamidase we observed higher liver sulfamidase activity and a very strong increase in the sulfamidase secretion with respect to control mice. Moreover, we detected a significant increase in SGSH activity into the brain of mice injected with the chimeric sulfamidase compared to SGSH activity measures in the brain of mice injected with not-modified sulfamidase.
FIG. 10 . Map of AAV2.1 plasmid. Map of pAAV2.1 plasmid used for AAV2.8 viral vectors production. The plasmid contains the GFP gene under the control of the liver specific promoter TBG. The GFP sequence was replaced with the cDNAs coding the chimeric sulfamidase cassettes by using NotI and HindIII restriction sites. The resulting plasmid was transfected along with pAd helper, pAAV rep-cap plasmid in 293 cells to produce AAV2.8 viral vectors (see Methods).
DETAILED DESCRIPTION OF THE INVENTION
Methods
Construction of Chimeric SGSH Cassettes, Recombinant Nucleic Acid Vectors and Viral Vectors
The alternative signal peptides were produced by ligation of two fragments: a sequence from human SGSH cDNA (fragment I) and the signal peptide sequence (fragment II). Fragment I was amplified from a hSGSH expressing plasmid and started at the 3′ terminus of hSGSH signal peptide sequence (corresponding to the nucleotide in position 61 on the SGSH sequence) and extended to a unique XbaI site and contained the entire SGSH cDNA (oligos used: SGSHFOR 5′-CGT CCC CGG AAC GCA CTG CTG CTC CT-3′ (SEQ ID No. 28) and SGSHREV 5′-GCG GCC TCT AGA TGA CAG CTC ATT GTG GAG GGG CTG-3′ (SEQ ID No. 29)). Fragment II was unique for each expression cassette. For hAATsp-SGSH-cFlag, fragment II was synthesized by annealing two specific oligonucleotide sequences (hAATspFOR 5′-GGC CGC ATG CCG TCT TCT GTC TCG TGG GGC ATC CTC CTG CTG GCA GGC CTG TGC TGC CTG GTC CCT GTC TCC CTG GCT 3′ (SEQ ID No. 30) and hAATspREV 5′-AGC CAG GGA GAC AGG GAC CAG GCA GCA CAG GCC TGC CAG CAG GAG GAT GCC CCACGA GAC AGA AGA CGG CAT GC-3′ (SEQ ID No. 31)) containing the human α1-antitrypsin signal peptide sequence [human a1-antitrypsin cDNA: 72 bp].
The fragment encoding for such signal peptide was:
(SEQ ID No. 1)
5′-ATGCCGTCTTCTGTCTCGTGGGGCATCCTCCTGCTGGCAGGCCTGTG
CTGCCTGGTCCCTGTCTCCCTGGCT-3′.
For IDSsp-SGSH-cFlag expression cassette, fragment II was synthesized by annealing two specific oligonucleotide sequences (IDSspFOR 5′-GGC CGC ATG CCC CCG CCC CGC ACC GGC CGC GGC CTG CTG TGG CTG GGC CTG GTG CTG AGC AGC GTG TGC GTG GCC CTG GGC-3′ (SEQ ID No. 32) and IDSspREV 5′-GCC CAG GGC CAC GCA CAC GCT GCT CAG CAC CAG GCC CAG CCA CAG CAG GCC GCG GCC GGT GCG GGG CGG GGG CAT GC-3′ (SEQ ID No. 33) containing the human Iduronate sulfatase signal peptide sequence [Homo sapiens iduronate 2-sulfatase (IDS) cDNA: 75 bp]. The fragment encoding for such signal peptide was: 5′-ATGCCGCCACCCCGGACCGGCCGAGGCCTTCTCTGGCTGGGTCTGGTTCT GAGCTCCGTCTGCGTCGCCCTCGGA-3′ (SEQ ID No. 3) or an optimized sequenze 5′-ATGCCCCCGCCCCGCACCGGCCGCGGCCTGCTGTGGCTGGGCCTGGTG CTGAGCAGCGTGTGCGTGGCCCTGGGC-3′ (SEQ ID No. 5). The two above sequences differ only for the codon usage and encode for the same signal peptide aa. sequence (SEQ ID No. 4 or 6). The oligonucleotide sequences of fragment II have 5′ NotI site and 3′ blunt end site. The forward and reverse oligonucleotide sequences were incubated for three minutes at 100° C. After chilling at RT we added the PNK to oligos for 30 minutes at 37° C. The fragment I (5′NotI-3′blunt) and fragment II (5′blunt-3′Xba) were ligated with p3×Flag-CMV14 vector plasmid (5′Not-3′Xba). DH5α competent cells was transformed with the resulting ligation mix.
To obtain the complete SGSH chimeric constructs, the amino acid sequence 3371-3409 of human ApoB (114 bp: 5′TCTGTCATTGATGCACTGCAGTACAAATTAGAGGG CACCACAAGATTGACAAGAAAAAGGGGATTGAAGTTAGCCACAGCTCTGTC TCTGAGCAACAAATTTGTGGAGGGTAGT-3′ (SEQ ID No. 9) was amplified by a human cDNA library (oligos: ApoBDFOR 5′-AGA TCT CTG TCA TTG ATG CAC TGC AGT-3′ (SEQ ID No. 34) and ApoBDREV 5′-AGA TCT ACT ACC CTC CAC AAA TTT GTT GC-3′(SEQ ID No. 35)) and cloned into the BglII sites at 5′ terminus of 3×Flag tag of either hAATsp-SGSH-cFlag or IDSsp-SGSH-cFlag.
The different expression cassettes containing either the partial chimeric constructs (hAATsp-SGSH-cFlag and hIDSsp-SGSH-cFlag) or the complete chimeric constructs (hAATsp-SGSH-cFlag-ApoB and hIDSsp-SGSH-cFlag-ApoB) were subcloned in the pAAV2.1-TBG-GFP between NotI (5′) and HindIII (3′) (the GFP sequence was replaced with the expression cassettes). The resulting plasmids ( FIG. 10 ) were used to produce recombinant AAV serotype 8 (AAV2/8) (19). The AAV vectors were produced using a transient transfection of three plasmids in 293 cells: pAd helper, pAAV rep-cap (packaging plasmid containing the AAV2 rep gene fused with cap genes of AAV serotype 8), pAAV Cis (this plasmid is pAAV2.1-TGB vector expressing the chimeric sulfamidase proteins). The recombinant AAV2/8 viral vectors were purified by two rounds of CsCl, as described previously (19). Vector titers, expressed as genome copies (GC/ml), were assessed by real-time PCR (GeneAmp 7000 Applied Biosystem). The AAV vectors were produced by the TIGEM AAV Vector Core Facility (http://www.tigem.it/core-facilities/adeno-associated-virus-aav-vector-core).
Trasfections and Secretions in Cells.
Hela and MPSIIIA MEF Cells were maintained in DMEM supplemented with 10% FBS and penicillin/streptomycin (normal culture medium). Sub-confluent cells were transfected using Lipofectamine™ 2000 (Invitrogen) according to manufacturer's protocols. One day after transfection the medium was replaced with DMEM 0.5% FBS. Two days after transfection we collected the conditioned medium and the pellet for the enzyme assays and western blot analysis.
WB Analysis
3×flag Lysis buffer 1× (50 mM Tris-HCl pH8, 200 mM NaCl, 1% Triton X100, 1 mM EDTA, 50 mM HEPES) was added to the cell pellets. The lysates were obtained by incubating the cell pellets with lysis buffer for 1 hour in ice. Protein concentration was determined using the Bio-Rad (Bio-Rad, Hercules, Calif., USA) colorimetric assay. The conditioned medium was concentrated in the vivaspin 500 (Sartorius) by centrifugation of the medium at 13.000 rpm for 7 min. Flagged sulfamidase proteins were revealed by Western Blot analysis using a anti-FLAG M2 monoclonal peroxidase-conjugate antibodies (A8592 Sigma-Aldrich) diluted 1:1000 in 5% milk.
Immunofluorescence
Cells were washed three times in cold PBS and then fixed in 4% paraformaldehyde (PFA) for 15 min. Fixed cells were washed four times in cold PBS, permeabilized with blocking solution (0.1% Saponin and 10% FBS in PBS) for 30 min and immunolabelled with appropriate primary antibody: Rabbit anti h-sulfamidase (1:300, Sigma). After four washes in PBS we incubated the cells with secondary antibody Anti-Rabbit Alexa fluor-488 conjugated (1:1000). Cells were then washed four times in cold PBS and mounted in Vectashield mounting medium.
Pulse and Chase
To determine degradation rates of sulfamidase enzyme, MPSIIIA MEFs transfected with different chimeric constructs were radiolabeled with 30 μCi/10 6 cells [35S]methionine:cysteine mixture (EasyTag™ EXPRE35S35S Protein Labeling Mix, [3S]; PerkinElmer) for 30 minutes in methionine:cysteine-free medium (Sigma) supplemented with 1% fetal calf serum. After extensive washing, cells were maintained in the presence of 5% fetal calf serum and supplemented with methionine and cysteine. Cells were recovered at different time points and lysed using 3×flag Lysis buffer. Lysates were cleared by centrifugation and supernatants were immunoprecipitated by using agarose-conjugated antibody against flag (anti-flag M2 affinity Gel, A2220Sigma-Aldrich). After extensive washing with lysis buffer, the immunoprecipitate was subjected to SDS-PAGE. Dried gels were exposed to a PhosphorImager screen and quantified with a PhosphorImager system.
Animals
Homozygous mutant (MPS-IIIA, −/−) and heterozygous (phenotypically normal +/−) C57BL/6 mice were utilized. Consequently, the term ‘normal mice’ is used to refer to the mouse phenotype. Experiments were conducted in accordance with the guidelines of the Animal Care and Use Committee of Cardarelli Hospital in Naples and authorized by the Italian Ministry of Health.
Systemic Injection and Tissues Collection
Newborn MPS-IIIA and normal mice at postnatal day 0-1 were cryo-anesthetized. The vectors were delivered in the systemic route via temporal vein (2×10 11 particles in 100 μl). The adult MPSIIIA mice (1 month) were injected via caudal vein (2×10 11 particles in 100 μl). The serum of animals were collected at at different time points after injection for the enzyme assays. To evaluate liver and brain transduction the animals were sacrificed at different time points. Some of them were perfused/fixed with 4% (w/v) paraformaldehyde in PBS, the liver was then removed for GFP staining. The remaining mice were sacrificed and liver and brain removed to measure SGSH activity.
SGSH Activity Assay
SGSH activity was measured following protocols described in Fraldi et al., Hum Mol Gen 2007).
GFP Analysis
Liver tissues were subjected to a saccharose gradient (from 10 to 30%) and incubated O/N in 30% saccharose at 4° C. Finally, tissues were embedded in OCT embedding matrix (Kaltek) and snap-frozen in a bath of dry ice and ethanol. Tissue cryosections were cut at 10 μm of thickness, washed with PBS for 10 min, mounted in Vectashield mounting medium and processed for GFP analysis.
Results
The aim of the project was to develop a low-invasive systemic gene therapy strategy based on the intravenous injection of AAV serotype 8. This serotype displays high tropism to the liver (18-20) and can be used to delivery of an engineered gene encoding a chimeric modified sulfamidase optimized (i) to be highly secreted from the liver thus reaching high levels of circulating enzyme in the blood stream. Sulfamidase is poor secreted respect to other sulfatase enzymes such as the iduronate-2-sulfatase (IDS). Sulfamidase signal peptide was replaced with that of either IDS or human α-antitrypsin (AAT), a highly secreted enzyme; (ii) to efficiently cross the BBB. The chimeric sulfamidase was further engineered with a specific brain-targeting protein domain, the (LDLR)-binding domain of the apolipoprotein B (ApoB LDLR-BD).
In Vivo Results in MPS IHA Mice
The efficacy of the new treatment is strictly dependent on the ability of the liver to be highly transduced by the transgene in order to efficiently secrete in the blood stream the sulfamidase that will then cross the BBB and transduce the brain by means of its brain-target sequence. Therefore, the serum levels of the therapeutic enzyme may represent critical factor in determining the efficacy of the therapy. No previous studies have been done to analyze liver transduction and the systemic levels of SGSH upon systemic gene delivery of exogenous SGSH in MPS-IIIA mice. Thus, we decided to investigate this issue in order to produce useful preliminary data for designing an effective therapeutic strategy.
The delivery of therapeutic enzyme to neonatal mice is a useful tool to prevent pathology in MPS-IIIA mice. We then decided to test whether the AAV2/8-mediated systemic injection in newborn MPSIIIA could be a feasible approach to develop our new therapeutic strategy. To this aim we injected MPS-IIIA newborn mice with AAV2/8 containing the sulfamidase coding sequence under the control of a liver specific promoter (Thyroid hormone-globulin, TBG) in order to specifically target the liver and make it like a factory organ of the therapeutic enzyme. Mice were injected via temporal vein with 1×10 11 particles of virus. Three experimental groups of mice were established: control mice (heterozygous mice; these mice display a normal phenotype) treated with AAV2/8-TBG-GFP, MPS-IIIA mice treated with AAV2/8-TBG-GFP and MPS-IIIA mice treated with AAV2/8-TBG-SGSH.
To test the efficiency of injection we analyzed the GFP fluorescence in the liver of GFP-injected mice (normal and MPS-IIIA mice). The GFP signal was present at either early or late time point after injection; however, a significant decrease of GFP signal was observed in the liver of mice analyzed at later time point after injection ( FIG. 1 ). The MPS-IIIA mice injected with AAV2/8-TBG-SGSH were checked for SGSH activity in plasma and in the liver at different time points after injection (5, 8, 10, 14 days and at 3, 4, 5, and 10 weeks). The SGSH activity in plasma of AAV2/8-TBG-SGSH-treated MPS-IIIA mice increased during the first two weeks period after neonatal treatment, and then decreased through the time to reach the levels measured in control GFP-injected MPS-IIIA mice ( FIG. 2A ). The analysis of liver SGSH activity showed a trend similar to that observed in the plasma with higher levels of activity detected within the first week after injection ( FIG. 2B ).
This preliminary study in newborn mice demonstrated that although the liver is efficiently transduced by AAV2/8-mediated neonatal delivery of sulfamidase, the enzyme is present at low levels (comparable to control GFP-injected MPS-IIIA mice) into both the liver and serum after 1 week post-injection making this approach unfeasible to treat the brain.
To evaluate whether the proliferation of hepatocytes during the period after the treatment is responsible for the liver dilution of vector after neonatal injection we performed a new study based on the systemic (caudal vein injection) AAV2/8-mediated delivery of SGSH in adult mice (1.5 month of age), in which the liver has completed its growth.
Also in this study we established three experimental groups of mice: normal mice treated with AAV2/8-TBG-GFP, MPS-IIIA mice treated with AAV2/8-TBG-GFP and MPS-IIIA mice treated with AAV2/8-TBG-SGSH. The analysis of GFP expression, at different time points after treatment (1 week and 5 weeks after injection) underlined a high and stable expression of the transgene in the liver of adult treated mice ( FIG. 3 ). MPSIIIA treated mice were also checked for the SGSH activity in the liver and in the serum at different time points (1 week, 2-,3-,4-, 5-weeks) after the treatment. In the liver of MPSIIIA mice injected with AAV2/8-TBG-SGSH we observed a strong increase of SGSH activity compared with low enzyme activity in the animals injected with GFP vector, and this activity remained stable until 5 weeks after injection (the later time point analyzed) ( FIG. 4A ). Also the analysis of SGSH activity in the serum of treated mice was very high and stable until during the entire post-injection period analyzed ( FIG. 4B ). Importantly, this treatment did not result in any detectable sulfamidase activity into the brain of AAV2/8-injected MPS-IIIA mice (not shown).
In conclusion these preliminary studies show that: (i) liver is highly transduced by AAV2/8-mediated systemic injection (ii) the decrease of SGSH activity in the newborn treated mice was due to the dilution of vector in the liver and allow us to consider the adult mice a good model to test the systemic treatment with AAV2/8 containing the chimeric sulfamidase (iii) the secreted (non modified) sulfamidase did not result in a detectable enzymatic activity into the brain. The latter is an expected result and further justifies the rationale behind the aim of our project.
Construction and Validation of the Chimeric Sulfamidase Proteins
In order to increase sulfamidase secretion from the liver and thus the amount of the enzyme in the blood stream available to specifically target the brain, we engineered the sulfamidase by replacing its own signal peptide (SP) with an alternative one. Two signal peptides have been tested, the Iduronate-2-sulfatase (IDS) signal peptide and the human a-antitrypsin (AAT) signal peptide ( FIG. 5 ). The rationale behind the use of these two signal peptides is that IDS is a lysosomal enzyme that was demonstrated to be secreted at high levels from the liver [21] while the AAT is a highly secreted enzyme. The final goal of our project is to produce a modified sulfamidase capable to cross the BBB and target the CNS via receptor-mediated transcytosis ( FIG. 6 ). For this reason before starting the experiments aimed at evaluating the therapeutic efficacy of the substituting
SP signal in SGSH, we further engineered the modified SGSH with a specific brain-targeting protein domain, the Low Density Lipoprotein receptor (LDLR)-binding domain of the Apolipoprotein B (ApoB LDLR-BD). The Binding Domain of ApoB will allow the sulfamidase to reach the brain cells by binding LDL receptors, which are abundant on the endothelial cells of BBB ( FIG. 6 ). The two finally engineered sulfamidase constructs contain at C-terminal the ApoB LDLR-BD and at N-terminal either an IDS or an hAAT signal peptide (IDSsp-SGSHflag-ApoB and hAATsp-SGSHflag-ApoB) ( FIG. 5 ).
To evaluate the functionality of chimeric sulfamidase proteins we transfected MPSIIIA MEF cells with either partial or final engineered sulfamidase proteins and compared the outcomes with those resulting from the transfections with not-engineered sulfamidase. Surprisingly, we observed that SGSH activity in the pellet and in the conditioned medium was higher in the cells transfected with the final chimeric constructs compared with the activity measured in the cells transfected with the other constructs, indicating that finally engineered sulfamidase were efficiently secreted ( FIG. 7A ). Indeed, these results were associated with a higher secretion efficiency of the finally engineered sulfamidase enzymes with respect to non-engineered sulfamidase ( FIG. 7B ). However, this secretion efficiency was similar to that measured after transfection of partially chimeric sulfamidase (containing only the alternative signal peptide) ( FIG. 7B ). Remarkably, we observed that the modifications of the sulfamidase, in particular those present in the finally engineered sulfamidase, confer to the chimeric proteins a higher stability compared to the non-engineered sulfamidase ( FIGS. 8A and B). Thus, we concluded that the increase in the sulfamidase protein levels in the medium of cells transfected with engineered sulfamidase proteins was due to both increased efficiency in secretion and increased stability of engineered sulfamidase.
Moreover, immunostaining with anti-SGSH antibodies showed a lysosomal-like localization for both partial and final engineered constructs ( FIG. 8C ).
In conclusion these results demonstrate that: (i) the chimeric sulfamidase enzymes containing the alternative signal peptide are functional and active; (ii) they are more stable with respect to non-modified sulfamidase; (iii) they are secreted with increased efficiency compared to non-engineered sulfamidase enzyme; (iv) the introduction of the ApoB LDLR-BD to produce the finally engineered sulfamidase did not affect either the functionality or the increased secretion efficiency observed in the cells transfected with the partially engineered sulfamidase. In addition, the finally engineered constructs appear to be more stable compared to partially engineered constructs.
In Vivo Results in MPS IIIA Mice Injected with Finally Engineered Sulfamidase
We produced AAV2/8 vectors containing one of the finally engineered sulfamidase (hAATsp-SGSHflag-ApoB) under the liver specific promoter TBG. We obtained very preliminary but extremely encouraging results in MPS-IIIA injected with this viral vector. Adult MPS-IIIA mice were systemically injected with AAV2/8-TBG- hAATsp-SGSHflag-ApoB. A group of MPS-IIIA were also injected with AAV2/8-TBG-SGSH (containing the not modified sulfamidase) as control. The mice were sacrificed one month after injection. In the mice injected with the chimeric sulfamidase we observed higher liver sulfamidase activity and a very strong increase in the sulfamidase secretion respect to control mice ( FIG. 9 ). Moreover, we detected a significant increase in SGSH activity into the brain of mice injected with the chimeric sulfamidase ( FIG. 9 ).
Use of Other Vectors
We completed the production of the AAV2/8 vectors containing all the engineered sulfamidase proteins (partial and final). Specifically, besides the AAV2/8-TBG-hAATsp-SGSHflag-ApoB, we now produced AAV2/8-TBG-hlDSsp-SGSHflag-ApoB; AAV2/8-TBG- hAATsp-SGSHflag and AAV2/8-TBG-hlDSsp-SGSHflag.
These vectors may be used to perform a large in vivo study by the following procedure: MPS-IIIA mice (1 month of age) are injected (by a caudal vein route of administration) with AAV2/8 vectors containing the engineered constructs in order to test the clinical efficacy of the chimeric sulfamidase enzymes. Results are useful to evaluate (i) the efficiency of CNS transduction and (ii) the rescue of CNS pathology in the treated mice.
BIBLIOGRAPHY
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12. Urayama, A., Grubb, J. H., Sly, W. S. and Banks, W. A. (2008) Mannose 6-phosphate receptor-mediated transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther, 16, 1261-6.
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The invention provides for nucleotide sequences encoding for a chimeric sulfatase, viral vectors expressing such sequences for gene therapy and pharmaceutical uses of the chimeric expressed protein. The invention is particularly applied in the therapy of mucopolysaccharidosis, preferably type IIIA.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of Japanese Patent Application No. JP2003-18935, filed in Japan on Jan. 28, 2003, the entire contents of which are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a system and method for deposition of a magnetic multilayer film, a method of evaluation of film deposition, and a method of control of film deposition. One aspect of the invention relates to management of the surface characteristics of a film during the process of deposition of a multilayer film for depositing a metal oxide film while evaluating the surface state or for successively stacking films or oxide films of the same continuously in an environment shielded from the atmosphere during the production of a semiconductor device and electronic component.
[0004] 2. Description of the Related Art
[0005] In recent years, various techniques have been developed in magnetic recording media and magnetic heads for stabilizing and improving the magnetic recording density of HDDs. In particular, in recent years, tunnel magnetoresistance thin film (TMR) heads have been employed as devices with large MR ratios. Further, magnetic random access memories (MRAMs) having a TMR structure have been gathering attention as the next generation of semiconductor devices. The film depositing a TMR device is comprised of at least one magnetic layer above and below sandwiching an insulating film. Each of the magnetic films is individually deposited utilizing sputtering, while the insulating film is deposited by oxidation of a metal film. To produce a plurality of magnetic films continuously, it is necessary to continuously stack them on a substrate. The assignee of the present invention has proposed one such method of continuous stacking (Japanese Patent Publication (A) No. 2002-167661).
[0006] According to the method disclosed in Japanese Patent Publication (A) No. 2002-167661, magnetic films or nonmagnetic films are continuously deposited in a stacked state in for example three different film deposition chambers. Further, an Al film is deposited by an Al target arranged in for example one film deposition chamber, then that Al film is oxidized in an oxidation treatment chamber of a separately provided similar vacuum environment.
[0007] Note that as related art of the present invention, there is the method of rotating a member having a spheroid shape while depositing a film of a suitable thickness on its surface by sputtering by the method of monitoring the spectral characteristics of the film while by an optical system in real time while depositing the film (Japanese Patent Publication (A) No. 2002-30435). Further, a high sensitivity reflection infrared spectrum measurement method for quantitatively analyzing the state of orientation of molecules of the measured object at an interface between a substrate and measured object has been proposed (Japanese Patent Publication (A) No. 9-264848).
[0008] In the above TMR device, due to the need for reducing the contact resistance, the thickness of the insulating layer is made an extremely thin one of 1 nm. Smoothness and sufficient oxidation are required. The electrical characteristics of a TMR device are heavily influenced by the state of oxidation. With sufficient oxidation, a high MR ratio is obtained.
[0009] However, in a general conventional system, to determine whether an Al film has been completely oxidized or not, the only approach was to take a monitoring use substrate out from the film deposition system and measure its electrical and magnetic characteristics after processing the device in an atmospheric environment. Therefore, even if a problem arose in the middle of the series of processes for making a device such as a TMR device, there was no means for judging this until the final product stage and therefore massive product loss occurred before eliminating the problem.
OBJECTS AND SUMMARY
[0010] An object of the present invention is to solve the above problem and provide a system for deposition of a magnetic multilayer film and method for deposition of a magnetic multilayer film which constantly manage the state of oxidation of a film and thereby oxidize the film precisely during the process of oxidation of film in a series of steps of production of a device using a metal oxide etc. as an insulating film. Another object of the present invention is to provide a method of evaluation of film deposition when oxidizing a metal film and a method of control of deposition of a metal oxide film.
[0011] The system and method of deposition of a magnetic multilayer film, method of evaluation of film deposition, and method of control of film deposition according to the present invention are configured as follows to achieve the above objects.
[0012] According to a first aspect of the present invention, there is provided a magnetic multilayer film deposition system having a plurality of treatment chambers for depositing a multilayer film including a plurality of magnetic films on a substrate, a conveyance mechanism for conveying the substrate on which a film is deposited in a state shielded from the atmosphere, and a metal film treatment chamber, provided with a treatment apparatus for treating the metal film included in the multilayer film in the metal film treatment chamber, an optical measurement device for optically evaluating the surface state etc. of the metal film, and a controller for controlling the operation of the treatment devices based on a measurement signal output from the optical measurement device. Due to this, when depositing a multilayer film on a substrate in the film deposition system, it is possible to manage the surface state etc. of the metal film during the treatment of the metal film or after treatment without exposing the substrate to the atmosphere and possible to suitably manage the metal film. Further, it is possible to continuously treat the thus deposited metal film without exposure to the atmosphere and deposit other necessary films on the same.
[0013] Preferably, the optical measurement device is a reflection type infrared spectrophotometer. This optical measurement device is comprised of a light source for generating infrared light provided at the outside of the metal film treatment chamber, an incident window for guiding the infrared light to the surface of the metal film of the substrate arranged in the treatment chamber, a reflected light window for taking out measurement light passing the surface of the metal film to the outside of the treatment chamber, a detector for detecting the measurement light, and a processor for determining the surface state of the film from a detected signal. Due to the above configuration, it is possible to detect a part of a sample where the surface state etc. of an extremely thin film is not destroyed and is arranged in a vacuum from the atmospheric side, optimally controlling the treatment by feeding back the detected information to the system performing the treatment, and thereby manage the treatment process.
[0014] More preferably, the measurement light is light arising at the interface between a treated part and nontreated part of the metal film. It is possible to obtain measurement light based on the state of treatment of the metal film.
[0015] Alternatively, the measurement light is infrared light reflected by the relationship with another film positioned at the back surface of the metal film. Since this is a system for depositing a multilayer film on a substrate, it is possible to obtain measurement light without providing a special reflector at the back surface of the metal film to be treated.
[0016] Preferably, the plurality of treatment chambers and the metal film treatment chamber are arranged around the conveyance chamber provided with the conveyor, the substrate is moved in a state shielded from the atmosphere, and the evaluation process of the metal film in the metal film treatment chamber is performed in a vacuum. Due to this configuration, it is possible to perform the evaluation according to the state of treatment of the metal film without exposure to the atmosphere and possible to treat a predetermined metal film precisely while evaluating the surface state of the substrate while maintaining the film depositing process.
[0017] Preferably, the treatment performed in the metal film treatment chamber is an oxidation treatment. Due to this configuration, it is possible to manage a suitable state of oxidation of an extremely thin Al oxide film at a device such as a TMR device. Further, it is possible to detect the state of oxidation while oxidizing the film and then end the oxidation step.
[0018] According to a second aspect of the present invention, there is provided a method of deposition of a magnetic multilayer film for depositing a multilayer film including a plurality of magnetic films on a substrate, wherein metal film included in the multilayer film is optimally treated while optically measuring and evaluating the surface state etc. of the metal film at a stage in the middle of film deposition and in a state shielded from the atmosphere.
[0019] Preferably, the surface state etc. of the metal film is measured and evaluated based on detection of the state of oxidation of the metal film.
[0020] According to a third aspect of the present invention, there is provided a method of evaluating a deposition of a metal film on a substrate, the method comprising treating the metal film in a state shielded from the atmosphere and evaluating the state of progress of treatment at the metal film while optically measuring the relationship between a treated part and nontreated part of the metal film.
[0021] Preferably, the treatment state of the metal film is evaluated based on detection of the state of oxidation of the metal film.
[0022] Preferably, the metal film is made of Al and the increase in the oxidized part is evaluated from the difference in absorption strength of a peak position (Al—O) of an oxidized part expressed by oxidation based on the Al before oxidation for light of a predetermined frequency.
[0023] According to a fourth aspect of the present invention, there is provided a method of control of deposition of a metal film on a substrate comprising oxidizing the metal film in a state shielded from the atmosphere, optically measuring the relationship between an oxidized part and nonoxidized part of the metal film, and evaluating the state of progress of oxidation at the metal film.
[0024] As clear from the above explanation, it is possible to provide a system for deposition of a multilayer film including a magnetic film of a magnetic head comprised of a TMR device, MRAM, etc. which can perform oxidation treatment while managing the state of oxidation of the Al film deposited by a film deposition chamber as an insulating film of the TMR device and which can form good quality devices with a good yield while maintaining the vacuum environment without exposing substrates to the atmosphere.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] These and other objects and features of the present invention will become clearer from the following description of the preferred embodiments given with reference to the attached drawings, wherein:
[0026] [0026]FIG. 1 is a plan view schematically showing the overall configuration of a typical embodiment of a multilayer film deposition system according to the present invention;
[0027] [0027]FIG. 2 is a vertical sectional view of the schematic configuration of an embodiment of an oxidation treatment system included in the multilayer film deposition system according to the present invention (oxidation treatment chamber);
[0028] [0028]FIGS. 3A to 3 B are views of examples of the structure of a magnetic multilayer film;
[0029] [0029]FIG. 4 is a view of the relationship between the absorption strength of a band near 970 cm −1 (Al—O stretching vibration) and Al film oxidation time; and
[0030] [0030]FIG. 5 is a view of the relationship between a peak position of an Al—O stretching vibration absorption band and Al film oxidation time.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] Below, preferred embodiments of the present invention will be explained with reference to the attached drawings.
[0032] First, the configuration of the system according to an embodiment of the present invention will be explained with reference to FIG. 1 and FIG. 2. The system shown in FIG. 1 is a system for deposition of a multilayer film including a plurality of magnetic films. The system shown in FIG. 2 is a metal film treatment system performing oxidation treatment and corresponds to the oxidation treatment chamber included in a multilayer film deposition system.
[0033] The magnetic multilayer film deposition system 10 shown in FIG. 1 is a cluster type system provided with a plurality of film deposition chambers. In this system, a conveyance chamber 12 provided with a robot conveyor 11 is positioned at the center. The robot conveyor 11 is provided with an arm 13 able to extend and contract in the radial direction and a hand 14 for carrying the substrate. The base end of the arm 13 is rotatably attached to a center 12 a of the conveyance chamber 12 . The conveyance chamber 12 of the magnetic multilayer film deposition system 10 is provided with two load/unload chambers 15 and 16 which load/unload substrates 43 . These load/unload chambers 15 and 16 are alternately used to enable deposition of a multilayer film with good productivity.
[0034] In the above magnetic multilayer film deposition system 10 , the conveyance chamber 12 is provided around it with for example three film deposition chambers 17 A, 17 B, and 17 C, one oxidation treatment chamber 18 , and one cleaning chamber 19 . In the oxidation treatment chamber 18 , for example Al film (in general a metal film) is oxidized to deposit an oxide film on its surface. Between each two chambers is provided a gate valve 20 separating the two chambers and able to open and close in accordance with need. Note that each chamber is provided with a not shown vacuum evacuation mechanism, gas introduction mechanism, and power feed mechanism.
[0035] At each of the film deposition chambers 17 A, 17 B, and 17 C of the magnetic multilayer film deposition system 10 , magnetic film is deposited on the substrate by sputtering. For example, the ceilings of the film deposition chambers 17 A, 17 B, and 17 C are provided with four targets ( 23 , 24 , 25 , and 26 ; 29 , 30 , 31 , and 32 ; and 35 , 36 , 37 , and 38 ) arranged on suitable circles. Substrates 22 , 28 , and 34 are arranged on substrate holders 21 , 27 , and 33 positioned below them coaxially with the same circles.
[0036] The plurality of targets are provided at inclines so as to suitably face the substrates in order to efficiently deposit magnetic films of suitable compositions, but it is also possible to provide them in states parallel to the substrate surfaces. Further, the plurality of targets and substrates are arranged so as to be able relatively rotate. As such a configuration, for example, it is possible to use one based on the rotating cathode mechanism disclosed in Japanese Patent Publication (A) No. 2002-088471 according to a patent application filed previously by the assignee. For example, the film deposition chamber 17 B is provided with an Al target and other magnetic film targets based on the above arrangement. As a result, a multilayer film having a multilayer film structure explained later is deposited on the substrate.
[0037] In the film deposition chambers 17 A, 17 B, and 17 C, metal films are successively deposited in accordance with need, then the substrates 22 , 28 , and 34 are conveyed to the oxidation treatment chamber 18 provided with the oxidation mechanism where the metal films are oxidized. In the example shown in FIG. 1, a substrate 40 is carried on a substrate holder 39 in the oxidation treatment chamber 18 .
[0038] In the cleaning chamber 19 as well, a substrate 42 is carried on the substrate holder 41 .
[0039] [0039]FIGS. 3A to 3 B show examples of magnetic multilayer film structures. FIG. 3A shows an example of the multilayer structure of an eight-layer MRAM, FIG. 3B shows an example of the multilayer structure of a 10-layer TMR head/MRAM, and FIG. 3C shows an example of the multilayer structure of a 13-layer advanced GMR head. For example, after deposition of the Al film in the example of FIG. 3B and after deposition of the CoFe film of the B configuration in the example of FIG. 3C, the robot controller 11 introduces the substrate into the oxidation treatment chamber 18 where it is oxidized. As a result, a Al—O film is formed in the example of FIG. 3B and a nano oxide layer (NOL) is made by oxidizing the CoFe film in the example of FIG. 3C.
[0040] First, a mechanism for management of the state of oxidation of an Al film will be explained.
[0041] In the oxidation treatment chamber 18 , a surface chemical reaction is performed for oxidizing the Al film. This surface chemical reaction is for example plasma oxidation, ozone oxidation, ultraviolet ray ozone oxidation, radical oxidation, etc. Among these, the example of plasma oxidation will be explained.
[0042] The oxidation treatment chamber 18 shown in FIG. 2 is provided with a mechanism for plasma oxidation. This oxidation treatment chamber 18 is formed as a vacuum chamber 51 overall. Inside this vacuum chamber 51 are provided a top electrode 52 and a bottom electrode 53 . The top electrode 52 is fixed to the ceiling of the vacuum chamber 51 via an insulator (not shown), while the bottom electrode 53 is fixed to the bottom of the vacuum chamber 51 via an insulator (not shown). The bottom electrode 53 corresponds to the substrate holder 39 shown in FIG. 1.
[0043] As the electrical connections, the top electrode 52 is connected to the ground, while the bottom electrode 53 is connected to an RF power source (high frequency power source) 55 through a matching box 54 . The bottom electrode 53 carries the substrate 40 . When the plasma conditions stand, plasma 56 is produced in the space between the top electrode 52 and the bottom electrode 53 . Further, an infrared light incident window 57 and a reflection light window 58 are provided in the wall of the vacuum chamber 51 . Further, the ceiling of the vacuum chamber 51 is provided with a gas inlet 59 for introducing feedstock gas for producing the plasma.
[0044] At the outside of the oxidation treatment chamber 18 is provided an optical measurement device. This optical measurement device preferably is a Fourier transform infrared (FTIR) spectrophotometer using the high sensitivity reflection method utilizing infrared light. Outside of the infrared light incident window 57 is provided a light source 60 for outputting infrared light. The infrared light L 1 output from the light source 60 passes through the incident window 57 and passes through the Al oxide film on the substrate 40 arranged in the oxidation treatment chamber 18 to reach the Al film or underlying CoFe film. The infrared light L 1 incident at the multilayer film deposited on the substrate 40 is at first reflected at the Al film, thereafter at the interface of the Al oxide film (Al—O) and Al film along with the progress of oxidation of the Al film, and finally at the surface of the CoFe film.
[0045] The infrared light L 2 reflected in the above way is taken from the reflection light window 58 to the outside of the oxidation treatment chamber 18 as measurement light and detected by a detector 61 . The signal concerning the reflected light L 2 based on the infrared light L 1 , which is detected by the detector 61 , is further analyzed by a control analysis system 62 . This control analysis system 62 calculates an absorption strength, an absorption band position, and other data concerning the reflected light L 2 of the infrared light L 1 due to the state of the Al oxide (Al—O) film. The data is sent to an oxidation control system 63 . The oxidation control system 63 optimally controls the output of the RF power source 55 for optimal oxidation by the oxidation treatment of the Al film of the multilayer film on the substrate 40 .
[0046] In the above, when evaluating the state of oxidation of the Al film on the substrate 40 by the FTIR technique in order to control the oxidation at the Al film, the following steps are performed. When oxidation of the Al film progresses and the Al oxidation film (Al—O film) is gradually formed, a peak value of the absorption strength about the Al oxide (Al—O) film is calculated from the difference between the absorption strength value concerning the Al—O part and the standard absorption strength value concerning the Al film part near about 970 cm −1 , and further the state of oxidation at the Al film is controlled by evaluating the increase state in the above peak value. In this way, when oxidation progresses at the Al film, in order to evaluate the state of the oxidation, the peak value of the absorption strength at the Al—O part, which is being oxidized, is used in comparison with the absorption strength value at the Al film part as a standard value before performing the oxidation.
[0047] By controlling the oxidation of the Al film, evaluation is possible even without taking the film out into the atmosphere. Therefore, it is possible to deposit an optimal oxide film. This is preferable when depositing a single layer of oxide film on a substrate or when depositing an oxide film included in a multilayer film. In particular, when depositing the multilayer film on the substrate, since it is not necessary to take the substrate out into the atmosphere, there is the advantage that it is possible to continuously deposit other necessary films on top to form the final film structure.
[0048] In the above control of oxidation of Al film, where to stop the oxidation treatment is a problem. In general, it is stopped by the following method.
[0049] Step 1: Before performing the oxidation, the absorption strength of the Al film at a place which the peak of absorption strength of the Al—O film will be appeared is detected. This detected absorption strength value is used as a standard value.
[0050] Step 2: The peak value of the absorption strength of the Al—O film during the oxidation treatment is detected. At this time, the absorption strength at a specific wave number due to oxidation of the metal is detected.
[0051] Step 3: The difference value between the standard value of the Al film and the peak value of the Al—O film is obtained by calculating the difference between the both values. This is based on the fact that the same material indicates absorption strength proportional to the existing amount thereof. (Lambert-Beer law). However, since the peak position as to the Al—O film shifts to the side of a lower wave number with the advance of the oxidation, it is necessary to detect a light level for the absorption of the peak in a certain range of the absorption wave number region in the vicinity of a specific wave number due to the metal oxidation. The differences in strength of the some peaks of the Al—O film are compared and managed as numerical values. Further, the peak value may be successively plotted along with the elapse of time to draw a curve of change for management from the viewpoint of the inclination of the curve of change.
[0052] Step 4: The above step 1 and step 2 are repeated successively to compare the previous detected amount and new detected amount. When the amount of increase falls below a certain value, the state of oxidation is evaluated as optimal and the oxidation treatment is stopped. As one example, the system is set to stop the oxidation treatment when 100% or 95% of the Al film has been oxidized. Such a value depends on the later annealing or other processes. Therefore, whether to completely oxidize the film or stop just before complete oxidation is dependent on a design condition.
[0053] The above method of control of oxidation of an Al film etc. is effective for calculation of the state of oxidation in advance and is effective in a production line performing oxidation by these set conditions.
[0054] In the above configuration of an oxidation treatment chamber 18 , for example, the material of the infrared light incident window 57 and the reflection light window 58 is for example Ge (germanium) having a transmission region in accordance with the detection light. The light source 60 is a silicon carbide sintered body and He—Ne laser for the correction of the wavelength of the light source light. The detector 61 is an MCT (Hg—Cd—Te) detector.
[0055] Further, the high sensitivity reflection infrared spectrum measurement method, as disclosed for example in Japanese Patent Publication (A) No. 6-241992 or Japanese Patent Publication (A) No. 9-264848, is used in numerous fields as a method for analysis which arranges a metal reflector at the back surface of a measured object to reflect the incident infrared light and thereby obtain information such as the thickness of the measured object, the type of chemical bond, the functional groups, etc.
[0056] In the above high sensitivity reflection infrared spectrum measurement method, as explained above, a metal reflector by which infrared light irradiated to the surface of the substrate is reflected at the back surface of the measured object, for example, one reflecting infrared light by a reflectance of at least 20% in the above known publications, is preferable. Gold, silver, copper, aluminum, etc. is necessary.
[0057] For this, in the configuration of the present embodiment of the present invention, a metal multilayer film having a CoFe film as its topmost layer is deposited at the bottom of the film desired to be oxidized as shown in FIG. 3. Further, since the multilayer film structure is deposited by continuous stacking in a state with a good uniformity of thickness, the characterizing feature of the embodiment of the multilayer film deposition system according to the present invention, the multilayer film surfaces formed (interfaces) are extremely smooth. Therefore, in the present embodiment, in order to measure the reflection infrared spectrum, there is no need to arrange a smooth metal film at the back surface of the measured object required. It is possible to make measurements in the state of the substrate with the multilayer film deposited as it is.
[0058] Next, the configuration of a multilayer film including magnetic film will be explained with reference to FIG. 3. In the present embodiment, the sample part measured based on the infrared light reflection action is the Al oxide film (Al 2 O 3 film) or CoFe oxide film in the middle of deposition of the multilayer film including a plurality of magnetic films deposited on the substrate. An example of an Al film will be explained. As shown in FIGS. 3A and 3B, an MRAM or TMR head is comprised of a multilayer film including a plurality of magnetic films. “A” indicates an antiferromagnetic layer, “B” a multilayer magnetic layer (pin layer), “Al—O” an Al oxide film, “C” a multilayer magnetic layer (free layer), and “Ta” a protective film. Each layer is comprised of an extremely thin film of several nm. “Ox” shows oxidation treatment. As shown in FIG. 3, the structure B and structure C are isolated from each other by an insulating layer comprised of an Al oxide film of about 1 nm.
[0059] W. Zhu et al. ( Appl. Phys. Lett. 78, 3103 (2001)) publishes the results of evaluation of the oxidation of an Al film on Co required for high MR ratio magnetic tunneling junctions (MTJ) by Fourier transform infrared (FTIR) spectroscopy. The inventors experimented with similar evaluation in the middle of depositing the multilayer film structure in a vacuum system and obtained good results. The method used is shown below:
[0060] Oxidation treatment method: Oxygen plasma oxidation Conditions: RF 20W, Ar 20 sccm, O 2 2 sccm
[0061] Oxidation time: 20 sec, 60 sec, 80 sec, 180 sec
[0062] Sample
Sample Al oxidation time Sample 1 0 sec Sample 2 20 sec Sample 3 60 sec Sample 4 80 sec Sample 5 180 sec
[0063] Sample (structure): Si substrate/CoFe (2 nm)/Al (1.2 nm)
[0064] Measurement method: Fourier transform type infrared spectroscopy
[0065] Measurement technique: High sensitivity reflection
[0066] Resolution: 8 cm −1
[0067] Cumulative number: 256
[0068] Measurement range: 4000 to 700 cm −1
[0069] Detector: MCT detector
[0070] [0070]FIG. 4 is a graph of the relationship between the absorption intensity near 970 cm −1 considered to be absorption by Al 2 O 3 (Al—O stretching vibration) and Al film oxidation time. In FIG. 4, the abscissa indicates the oxidation time (sec), while the ordinate indicates the absorption strength (Arb. Unit: any unit). Further, FIG. 5 is a graph of the relationship between the peak position of the absorption band and the Al film oxidation time. In FIG. 5, the abscissa indicates the oxidation time (sec), while the ordinate indicates the wave number (cm −1 ).
[0071] In FIG. 4, it is learned that the longer the oxidation time, the stronger the Al—O stretching vibration strength and the closer to a constant value. Further, in FIG. 5, it is learned that the longer the oxidation time, the closer to the low wave number side the peak position is shifted to. According to the above W. Zhu et al., it is reported that as the oxidation time becomes longer, the thickness of the oxide layer becomes greater and the Al—O stretching vibration peak position shifts more to the low wave number direction. The current experiment exhibited a similar trend. The above results evaluated the state of oxidation of the Al oxide film in the oxidation treatment chamber 18 after the end of plasma oxidation, but similar evaluation is possible even during the oxidation treatment.
[0072] With oxygen plasma, light of about 0.8 μm (777 nm) comprised mainly of oxygen atom radicals is produced, but infrared light used for measurement is generally 2.5 to 25 (m and is not interfered with. Further, in the FTIR method based on viewing the difference between the Al reflected light of the infrared light passing through and/or reflected at the plasma and the reflected light after absorption by Al—O, the relative difference between the two can be sufficiently obtained.
[0073] To form an actual device, to fix the magnetic layer (pin layer) of the structure B in FIG. 3B, annealing is necessary after depositing the multilayer film. For example, annealing is performed at 260° C. for about 5 hours. To obtain a good device through this process, in the case of a 1.2 nm Al film, if performing oxidation so that the strength of the Al—O stretching vibration at FIG. 4 becomes somewhat before saturation (60 to 80 sec), it is learned that a device having good magnetic properties is obtained. Note that this suitable state of oxidation differs according to the conditions during the process, so depends on the degree of oxidation or its production process.
[0074] Based on the above, according to the system or method according to the present embodiment, it is possible to detect the state of oxidation of Al film after oxidation or during oxidation by for example oxygen plasma etc. and possible to obtain an optimal Al oxide film by detecting the absorption position of Al—O or the absorption band of an oxidized compound by an underlying film of CoFe—O etc.
[0075] Note that the present invention is not limited to the above embodiments and enables management of not only the state of oxidation of an Al film, but also the state of oxidation of another metal. Further, the invention is not limited to a multilayer film and may also be applied to oxidation of a single layer of metal film. Further, it is not limited to oxidation and may also be applied for evaluation of a metal film treated by nitrification etc.
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A magnetic multilayer film deposition system having a plurality of treatment chambers for depositing a multilayer film including a plurality of magnetic films on a substrate, a conveyance system for conveying the substrate in a state shielded from the atmosphere, a metal film treatment chamber, a treatment system having treating metal film included in the multilayer film in the treatment chamber, an optical measurement system for optically evaluating the surface state of the metal film, and a control system for controlling the operation of the treatment system based on a measurement signal output from this optical measurement system, wherein when depositing a multilayer film on a substrate in the film deposition system, it is possible to manage the surface state of the metal film during the treatment process of the metal film and possible to treat the metal film precisely.
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This a Continuation-In-Part of application U.S. Ser. No. 09/165,409 filed Oct. 2, 1998, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to office furniture. More particularly, the invention concerns an improved, multifunction office furniture system having a novel interlocking connecting mechanism which permits the easy assembly of a variety of different structural components in a variety of different configurations to form highly efficient work areas.
2. Discussion of the Prior Art
Office furniture systems that exhibit superior structural characteristics and which exhibit flexibility and interchangeability among the parts to create multipurpose and multi-function work stations are in wide demand for many institutional applications. Entities having great need for such office systems include schools, hotels, business offices, and various governmental entities. Particularly in demand are flexible office systems that are easily altered to fit the work environment and meet the work requirements.
While many types of office systems have been suggested in the past, a typical drawback of such office systems is lack of flexibility to fit the space allowed for the work environment requiring the work environment to fit the office system. As a general rule, when the prior art furniture designers have attempted to overcome this limitation in prior art designs, such designs lack the structural strength and flexibilty to meet the work requirements.
The prior art systems typically use a variety of different arrangements to interconnect together desk tops, cabinets, files and other structural components to form variously configured work stations. Exemplary of a typical prior art adjustable desk system is that described in U.S. Pat. No 5,544,593 issued Canfield et. al. The Canfield patent discloses a basic superstructure that permits various cantilever supports to be connected thereto for supporting desk tops, pedestals and the like so that the various components can be adjusted relative to one another. The basic Canfield superstructure also permits back to back mounting of cabinets, desk tops and like components to provide separated work spaces.
Another prior art desk system is disclosed in U.S. Pat. No. 5,038,539 issued to Kelly et. al. This later patent describes a work space management system for dividing an open work space into separate, discrete work areas. The Kelly et al system includes a wall system having a framework formed of rigid rectangular frames joined together at their edges to form the defined work areas. The Kelly et al patent also discloses various wire management components which are secured to the frames for routing communication and power wiring.
A drawback of many of the prior art adjustable desk systems resides in the fact that the systems are generally quite complex, are often ergonomically unsound and, while often providing for adjustability of some components, fail to provide the overall convenience and flexibility required by modem computer intensive offices. In this connection, the constantly changing technology and the rapid emergence of computer networking systems have created an ever increasing demand for easily adaptable office furniture. Additionally, because of increases in repetitive stress injuries, there is a great demand for systems of the aforementioned character which offer ergonomic features that effectively guard against stress injury.
As will be discussed in detail in the paragraphs which follow, the desk system of the present invention overcomes many of the drawbacks of prior art systems by providing a system which is of a simple, ergonomically sound design and yet has great versatility. The system of the present invention is not only practical in use but provides an extremely attractive, structurally sound, freestanding work-area defining unit which is ideally suited for modem office complexes. The system is easy to assemble and disassemble by relatively unskilled workers and is uniquely designed to provide a safe and productive work environment.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel office system construction that is ideally suited for use in schools, hotels, business offices, and governmental offices, and similar commercial establishments.
Another object of the present invention is to provide a flexible construction for an office system that will permit the user to fit the office system to the work environment rather than fitting the work environment to the office system.
Another object of the invention is to provide a highly versatile work station system which is very attractive, is easy to assemble, disassemble and adjust, and yet, is structurally sound and durable in use.
Another object of the invention is to provide a system of the character described which is capable of readily accommodating changing work conditions in the users facilities.
Another object of the invention is to provide a fully adjustable, highly versatile work station system which includes a number of ergonomic features which provide a safe and productive work environment.
Another object of the invention is to provide a desk system which includes uniquely configured, vertical support columns to which a number of different types of structural components can be quickly and easily connected.
Another object of the invention is to provide a system of the character described in the preceding paragraph which is specially designed to eliminate under work surface obstacles.
Another object of the invention is to provide an adjustable desk system that includes a novel cable management systems which enables effective cable management within the structural components of the apparatus so that the cables are well protected from damage and yet are easily accessible so as to provide a wide range of electrical and communication capabilities.
Another object of the invention is to provide a desk system of the class described that is designed for ease and speed of installation and is readily adjustable into various configurations using a number of different types of readily interchangeable components.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a generally perspective view of one form of the desk system of the present invention.
FIG. 2 is a generally perspective, exploded view illustrating the manner by which certain of the components, such as the divider panels of the system, are releasably interconnected with one of the novel vertical support columns of the apparatus.
FIG. 3 is a generally perspective, exploded view similar to FIG. 2 illustrating the manner by which the outwardly extending side members of the leg assembly of the desk system are releasably interconnected with one of the novel vertical support columns of the apparatus.
FIG. 4 is a generally perspective, exploded view similar to FIGS. 2 and 3 illustrating the manner of interconnection of the structural panels of the system with one of the novel vertical support columns of the apparatus.
FIG. 5 is a cross-sectional view of one of the novel vertical support columns of the apparatus and a portion of one of the angularly extending attachment brackets that can be engaged into incremental notches formed in the corners of the support columns.
FIG. 6 is a generally perspective view of a closure shroud element which is receivable within radially outwardly extending grooves formed in each of the vertical support columns.
FIG. 7 is a cross-sectional view of a stiffener element of the character used to interconnect together two or more lengths of the support columns of the invention.
FIG. 8 is a generally perspective, exploded view illustrating the manner of interconnection of several of the different component parts of the desk system with longitudinally spaced apart vertical support columns of the character shown in FIGS. 2 through 5.
FIG. 9 is a generally perspective, exploded view illustrating the manner of interconnection of the wing-like side members of the leg assemblies and the floor engaging, stabilizing members of the leg assembly with an elongated connector element that permits interconnection of the leg assemblies with a selected one of the vertical support columns of the invention.
FIG. 10 is a generally perspective, exploded view of one form of the structural panel of the desk system.
FIG. 11 is a generally perspective, exploded view of one form of the connector means of the invention which is used to interconnect first and second lengths or segments of the vertical support columns.
FIG. 12 is an enlarged, cross-sectional view showing the wing-like sides of the leg assembly interconnected with one of the vertical support columns and also illustrating the column segment connector means of the invention including the stiffener element shown in FIG. 7 which is disposed internally of the vertical support column
DESCRIPTION OF THE INVENTION
Referring to the drawings and particularly to FIGS. 1 through 8, one form of the desk system of the present invention is there illustrated. As best seen in FIG. 1, one embodiment of the desk system comprises four identical, individual work stations 12 which are interconnected in a back-to-back relationship to provide a free standing array. Each of the four work stations 12 includes a generally horizontally extending first work surface 14 and a second elevated work surface 16 . The back edges 14 a and 14 b and 16 a and 16 b of each of the work surfaces 14 and 16 extend at right angles to one another and the front edges of each of the work surfaces are curved in the manner shown in FIG. 1 to permit ergonomically desirable access to the work surfaces by one or two persons using the work station.
One end of work surface 14 is supported by a storage unit 18 which includes a plurality of slidably mounted, stacked drawers 20 . The other, or right edge of work surface 14 as viewed in FIG. 1 is supported by one of the novel leg assembly of the invention generally designated in FIG. 1 the numeral 22 . This novel leg support assembly 22 includes a pair of outwardly extending, floor engaging stabilizer members 24 and a pair of wing-like side members 30 which are connected to central support 27 in a manner presently to be discussed.
A key aspect of the desk system of the present invention is the previously mentioned support member or column 27 which has the unique cross-sectional configuration shown in FIGS. 2 through 5 of the drawings. This novel support is used in several key locations in the system configuration shown in FIG. 1 . For example, the central support column is used in the previously identified leg assembly 22 , in a somewhat similar leg assembly 22 a disposed at the left end of the work station as viewed in FIG. 1, and in an intermediate location where the leg assembly is designated as 22 b . This highly novel support column not only functions to support the work surfaces of the system, but also functions to support plurality of laterally extending and longitudinally extending structural panels 32 which are disposed below the work surface 14 . Additionally, the novel support columns support a plurality of longitudinally and laterally extending divider panels 34 which are disposed above the work surface. Divider panels 34 function to separate the four back-to-back work stations in the manner illustrated in FIG. 1 .
The lower structural panels 32 , which are of a unique construction presently to be described, provide structural integrity to the array and extend generally perpendicularly outwardly from the walls of support columns 27 in the manner illustrated in FIGS. 1 and 6. For example, several lateral structural panels extend from column 27 of leg assembly 22 , while several longitudinal structural panels extend from column 27 of leg assembly 22 a (FIG. 1 ). Similarly, a lateral divider panel extends from an upper column segment 27 a of leg assembly 22 while a longitudinal divider panel extends from an upper column segment 27 a of leg assembly 22 a . At least one of the longitudinally extending structural support panels, (designated in FIG. 8 by the numeral 33 ), comprises a wire management control panel. This novel wire support panel 33 includes a tray-like member 33 a which functions to support and separate electrical cables and the like which can be connected to conventional floor outlet 35 and then introduced into the interior of a selected one or more of the support columns 27 and the structural panels 32 a . The cables can also be connected to a ceiling outlet and run downwardly through stacked column segments.
Another novel feature of the desk system of the present invention comprises the column segment connector means which functions to connect together first and second lengths or segments of support columns 27 . For example, as shown in FIG. 6, the previously identified lower support columns 27 can be interconnected with upper support columns designated in FIG. 6 as 27 a to conveniently extend the overall height of the support column. For example, the novel segment connector means, the details of which will presently be described, can be used to securely interconnect lower segments 27 with upper segments 27 a so that the upper segments 27 a can rigidly support the longitudinally extending divider panels 34 in the manner indicated in FIGS. 1 and 8.
As also indicated in FIG. 8, certain of the wing-like, side members 30 can be provided with vertically spaced-apart slots 39 which are adapted to receive outwardly extending cantilever type support members 40 which can, where desired, function to support outward extending, auxiliary work surfaces such as the work surface identified in FIG. 8 by the numeral 42 .
Turning next to FIGS. 2 through 5, the details of construction of the important central support members or columns 27 and 27 a of the invention are there illustrated. As best seen in FIG. 5, each of the support members 27 has a central axis 46 , first and second opposing side walls 48 and 50 respectively. Front and back walls 52 and 54 are integrally formed with or otherwise connected to side walls 48 and 50 in the manner best seen in FIG. 3 . Each of the front, back and side walls includes a central portion 56 and first and second spaced-apart marginal portions 58 . Disposed between the central portions and the marginal portions of each of the walls are first and second generally coplanar grooves generally designated in the drawings by the numeral 60 . Each of the marginal portions 58 of each of the side walls 48 and 50 includes a first edge 62 . Similarly, each of the marginal portions 58 of each of the front and back walls 54 and 56 includes a second edge 64 (FIG. 3 ). Disposed between each of the edges 62 and 64 is a corner groove 67 which extends generally radially outwardly from central axis 46 of the support column. These radially outwardly extending grooves 67 are closed by back walls which are provided with spaced-apart slots 67 a (FIG. 2 ). Slots 67 a are adapted to receive engagement fingers 150 a of cantilevered supports 150 which are of the same general character as those shown in FIG. 8 and can be used to support auxiliary work surfaces such as shelves.
A unique feature of the desk system of the present invention resides in the fact that each of the components which is interconnected with the columns 27 includes a specially configured connector strip which is provided with a pair of spaced-apart tongues that are slidably receivable within grooves 60 provided in each of the support column segments 27 and 27 a . This novel feature permits the various components of the desk system to be quickly and easily interconnected with and removed from the various spaced-apart support columns 27 which provide vertical support to the components of the assembled array. More particularly, as can best be seen by referring to FIG. 2, each of the divider panels 34 includes a uniquely configured connector member 70 which is provided with spaced-apart tongues 70 a . As indicated in FIG. 2, tongues 70 a are slidably receivable within selected grooves 60 provided in the support column 27 a . As indicated in FIG. 2, connector member 70 is, in turn, adapted to be interconnected along its length with a selected divider panel 34 by any suitable means such as threaded connector or the like. It is apparent that with this construction, selected panels 34 can be quickly and easily removably interconnected with any one of the support columns 27 a to construct the arrays shown in FIGS. 1 and 8.
Referring particularly to FIGS. 3 and 12, it is to be noted that each of the wing-like side members 30 which form the previously identified leg assemblies 22 , 22 a and 22 b include a specially configured connector member 74 which includes spaced-apart substantially coplanar tongues 74 a and 74 b which are slidably receivable within substantially coplanar grooves 60 provided in the support column 27 shown in FIG. 3 . In this latter case, connector member 74 is also provided with a pair of grooves 74 b which slidably accept spaced-apart tongues 76 formed proximate the in-board ends of wing-like members 30 . Connector member 74 further includes a pair of substantially coplanar grooves 74 c which are disposed proximate tongues 74 a and 74 b and are constructed and arranged to receive marginal portions 58 of the side walls (FIG. 12 ).
Turning to FIGS. 4 and 10, it can be seen that, in similar fashion, each of the structural panels 32 and 33 of the invention include novel end plates 80 , each of which is provided with a pair of spaced-apart tongues 80 a which are slidably receivable within grooves 60 formed in the side walls 48 and 50 of the various spaced-apart support columns which are spanned by the structural support panels 32 in the manner shown in FIG. 8 . Once again, it is apparent that with the novel construction of the structural panels as is shown in FIGS. 4, 6 , and 10 , the panels can be readily interconnected with spaced-apart support columns 27 in the manner shown in FIG. 8 to provide a high degree of structural integrity to the desk system arrays shown in FIGS. 1 and 8. It is also to be understood that the wire management panels such as panel 33 also includes connector members 80 provided at each end thereof which connector members are also slidably receivable within grooves 60 provided in the spaced-apart support columns which function to support the wire management panels.
Referring particularly to FIGS. 4 and 10, each of the structural panels 32 can be seen to comprise, in addition to end connector assemblies 80 , first and second uniquely configured structural beams 84 and 86 which are connected to and span spaced-apart end connectors 80 . Structural beams 84 and 86 are generally mushroom shaped in cross-section so as to resist bending forces exerted on the members and each includes laterally spaced-apart, tab-receiving openings 87 a and 87 b (FIG. 10 ). Openings 87 a and 87 b are adapted to closely telescopically receive tab-like protuberances 80 a and 80 b formed proximate the upper and lower ends of each connector member 80 .
Connected proximate to each end of beams 84 are 86 are connector blocks 88 , each of which has spaced-apart screw receiving openings 88 a which are sized to receive connector means shown here as a plurality of thread forming metal screws 89 (FIG. 10 ). Thread forming metal screws 89 extend through openings 91 formed in each of the end plates 80 and are theadably received within the screw receiving channels 88 a formed in connector blocks 88 . With the construction thus described, when tabs 80 a and 80 b of end connectors 80 are inserted into openings 87 a , and 87 b , provided in each of the structural beams 84 , the assemblage thus formed can be securely drawn together and locked in position relative to the end plates by threading the thread forming screws 89 into the screw receiving channels 88 a provided in each of the connector blocks 88 . It is to be understood that rivets can also be used as connectors to connect blocks 88 to end plates 80 . After the end connectors 80 have been securely interconnected with the structural beams and the connector blocks, the assemblage thus formed is covered by first and second side closure panels 96 and 98 so as to enclose therebetween the spanner members and the connector blocks.
Also forming a part of each of the structural panels 32 are locking means for locking the end connectors 80 in a fixed position relative to the structural supports 27 from which they extend in the manner shown in FIG. 8 . These locking means are here provided in the form of a spring loaded locking mechanism 100 which comprises a supporting bracket 102 which is connected to connectors 80 , and a spring biased locking finger 104 which is carried by a bracket. Locking finger 104 is continuously biased outwardly through a slot 105 formed in the connector body by biasing means, shown here as coil spring 106 (see also FIG. 4 ). With this construction, when the end plates 80 are assembled with a selected support column 27 , locking finger will snap into engagement with one of a plurality of slit like openings 109 formed in all four walls of the vertical support column segments 27 and 27 a (FIGS. 2 and 8 ).
It is to be understood that the locking means of the invention can also be disposed internally of leg assembly side members 30 and can function to position the side members relative to the support columns 27 with which they are associated (see for example FIG. 9 ).
Turning to FIG. 9, it can be seen that side members 30 are interconnected with the previously identified elongated connector member 74 with the locking means of the invention, or mechanisms 100 being interconnected to the interface of connector 74 . Receivable within the lower open end of side member 30 is a connector block 112 which enables interconnection of the stabilizer members 24 with side members 30 by means of threaded connectors 114 which are threadably received within block 112 . More particularly, connector block 112 is telescopically received within the lower open end of the side members 30 and is held in position by fasteners 112 a which extend through connector member 74 and function to connect connector block 112 with connector member 74 and member 30 . The assemblage thus formed is then connected with the stabilizer member 24 in the manner previously described. Cavity 116 includes a bottom wall which receives threaded connectors 114 so that when the connectors are threadably interconnected with connector block 112 , the assemblage made up of side member 30 and connector 74 will be securely locked in position relative to stabilizer member 24 to form a stable, securely interconnected subassembly. In the leg assemblage illustrated in FIG. 9, the side member 30 is provided with a cable receiving opening 117 which permits convenient cable routing into the wire management structural panels. Openings 117 can be closed by removable closure panels 117 a . Similarly, the outboard ends of members 30 and 30 a can be closed by elongated closure strips 119 .
In the desk system construction illustrated in FIG. 1, upper side members 30 a are connected to lower side members 30 in the manner there shown and function to provide structural stability to the upper portions of the array. Providing further structural stability are the divider panels 34 which are disposed proximate the right and left ends of the array as viewed in FIG. 1 . As shown in FIG. 9, side members 30 a are interconnected with vertical support column 27 a by means of an elongated connector member 74 a which is of a construction similar to that of connector 74 . The upper open end of side members 34 a are preferably closed by a plastic closure cap 120 of the general configuration shown in FIG. 9 .
When desired, floor engaging castors 122 can be connected to stabilizer 24 in the manner indicated in FIG. 9 (see also FIG. 1 ). When desired, similar castors 122 can be connected directly to side members 30 in the manner shown in FIG. 1 . In this latter instance, a connector bracket 125 , to which the castor is threadably connected is connected to side members 30 .
Turning next to FIGS. 11 and 12, the details of the construction of the previously identified segment connector means of the invention can there be seen. In the present form of the invention, the segment connector means comprise a plurality of spaced-apart connector assemblies 126 . Each of the side connector assemblies comprise a bearing plate 128 having corner portions which are cammingly received within internal grooves 131 formed in supports 27 (FIG. 2 ). Each assembly also includes a washer 130 , a self-clinching nut 132 , and a plate lock 134 . A first connector assemblage 126 a is secured internally of support columns 27 proximate the lower extremities thereof. And a second threaded connector element assembly 126 b is disposed within support columns 27 proximate their upper extremities (FIG. 11 ). The assemblies are held securely in position within the support columns by the bearing plates 128 which, when rotated within columns 27 will cam into grooves 131 . The resiliently deformable, outwardly extending wing-like tabs 134 a formed on the plate locks 134 bite into the interior walls of the support columns 27 and prevent the bearing plates 128 from counter-rotating out of grooves 131 once the connector assembly is in position. In similar fashion, a connector assembly 126 c is disposed within the upper portion of the column segment 27 a . Connector assembly 126 c is similar in construction to assemblies 126 a and 126 b . However, the self-clinching nut 132 has been replaced with an internally threaded coupling nut 132 a which allows for further extension of the support columns as may be necessary.
Also forming a part of the connector means of the invention is a uniquely configured stiffener member 138 which is telescopically received within the upper portion of support column 27 and within the lower portion of support column 27 a . The configuration of this stiffener member, which is of the character shown in FIG. 7, provides a substantial reinforcement against and tendency column segment 27 a may have to bend relative to column segment 27 . As best seen in right-hand portion of FIG. 11, connector assemblies 126 b and 126 c are interconnected by an elongated, externally threaded tie rod 140 which extends interiorly of stiffener member 138 . Where desired, a castor 144 can be connected to connector assembly 126 a in the manner shown in the lower right-hand portion of FIG. 11 . If desired, a tie rod 140 can be used to interconnect connector assemblies 126 a and 126 b (see FIG. 12 ). To close the open upper ends of support columns, plastic closure caps 142 such as are shown in FIGS. 1 and 9 are used.
Turning once again to FIG. 7, it is to be noted radially outwardly extending grooves 67 formed in each of the vertical support columns 27 and 27 a is closed by a closure shroud 144 which is of the unique configuration shown in FIG. 6 . Each of the shrouds 144 is provided with a longitudinally extending, generally arrow-shaped protuberance 144 a which is receivable within a similarly shaped cavity 146 formed at each corner of the support columns 27 and 27 a (FIG. 5 ). Each shroud 144 also has a yieldably deformable curved wall portion 144 b which functions to close each of the radially extending grooves 67 in the manner best seen in FIG. 5 . With this novel construction, cantilever supports, such as supports 150 (FIGS. 7 and 8 ), can be inserted into a selected radially extending groove 67 by deforming the shroud member 144 in the manner shown in the lower right-hand portion of FIG. 7 .
Having now described the invention in detail in accordance with the requirements of the patent statutes, those skilled in this art will have no difficulty in making changes and modifications in the individual parts of their relative assembly in order to meet specific requirements or conditions. Such changes and modifications may be made without departing from the scope and spirit of the invention, as set forth in the following claims.
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An improved, multifunction office furniture system having a novel interlocking connecting mechanism which permits the easy assembly of a variety of different structural components in a variety of different configurations to form highly efficient work areas. The system includes uniquely configured, vertical support columns to which a number of different types of structural components can be quickly and easily connected and provides a highly versatile work station system which is very attractive, is easy to assembly, disassemble and adjust, and yet, is structurally sound and durable in use. Because of its novel construction, the system is capable of readily accommodating changing work conditions in the users' facilities.
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TECHNICAL FIELD
The present invention relates generally to a method and apparatus for treating an ocular disorder, and more particularly, to treating eyelid margin disease.
BACKGROUND
Ocular disorders such as those relating to eyelid margin disease are particularly common pathological conditions of the ocular adenexa. By way of example, these disorders include blepharitis, meibomitis, and dry eye syndrome. Despite advances in ophthamology and medical treatments in general, the recommended treatments for these exemplary common ocular disorders has remained essentially unchanged for decades.
Historically, treatment of eyelid margin disease begins and ends with the patient. The patient first begins to notice symptoms including eyelid redness, flaking of skin on the eyelids, crusting and/or cysts at the eyelid margins, and a gritty sensation of the eye culminating in irritation, burning, and reduced vision. Should these symptoms remain unchanged or worsen, the patient routinely seeks the advice of an eye specialist, such as an ophthalmologist. After carefully considering the patients' medical history and investigating various possible causes, the specialist may prescribe a hygienic home treatment procedure for the patient to perform regularly in conjunction with antibiotics and/or topical steroids until the disease subsides.
The goal of the hygienic home treatment procedure is to remove debris, oil, and scurf that have collected along the eyelid margin during progression of the disorder. Removal of this debris is critical to both healing the eye and preventing a resurgence of the disorder. Without proper, regular removal of accumulated debris, such ocular disorders regularly worsen despite periodic treatments.
Hygienic home treatment of such ocular disorders is generally a two-step process. First, the patient softens the debris and scurf by applying a warm compress, diluted baby shampoo, or a specialized liquid solution to the eyelid margin. This first step is intended to prepare the debris for removal while preventing further irritation to the eye. Second, the patient attempts to remove the debris by physically scrubbing the eyelid margin, the base of the eyelashes, and the pores of the meibomian glands. This scrubbing is routinely attempted with either a generic cotton swab, a fingertip, or a scrub pad placed over the fingertip and applied against the eye. By cleaning debris and scurf free from the base of the eyelashes and unclogging the pores of the meibomian glands, the patient may improve the overall health of the eyelid margin; thereby reducing irritation, burning, and other symptoms related to the disorder.
Unfortunately for many patients, such hygienic home treatment is met with limited success due to the practical difficulties of cleaning one's own eye with an imprecise instrument such as a fingertip or cotton swab. For instance, many patients do not have the necessary dexterity to manipulate their fingertip or a cotton swab along the eyelid margin. Moreover, a shake, tremor, or poor near vision further complicate such self-treatment. Even for those capable of incorporating hygienic home treatment into their daily routine, many, if not most people, are wary of placing objects near their eyes to actively scrub along the eyelid margin. Given this anxiety, discomfort, and the inability to specifically target debris deposits, patients routinely fail to totally cleanse the margin of the eyelid, the base of the eyelashes, and the meibomian glands. While the attempted treatment may temporarily abate the patient's symptoms, subtle continuation of the disease often persists; thus permitting a low-grade inflammation to develop and, ultimately lead to chronic dry eye syndrome. Further, this treatment is typically required to be performed for the rest of the patient's life; thereby, creating a substantial hurdle to regular and effective compliance during hygienic home treatment.
Evidence suggests that medical costs associated with dry eye syndrome, often induced by ocular diseases such as blepharitis, are currently over 68 billion dollars each year. Many of these expenses are needlessly incurred due to the patients' failure to perform regular and effective treatments resulting in increased doctor visits, medications, and artificial tears. These expenses create a significant financial burden for insurance carriers, especially Medicare, which provides primary medical coverage for many individuals particularly prone to dry eye disease, such as the elderly.
There is a need for a method and apparatus for use in treating ocular disorders, such eyelid margin diseases, that addresses present challenges and characteristics such as those discussed above.
SUMMARY
One exemplary embodiment of the method according to this invention comprises using a swab operably connected to an electromechanical device to treat an ocular disorder. The disorders to be treated via this method result in a build-up of a removable debris on the eye. The swab, which moves relative to the electromechanical device, contacts the portion of the eye that includes the removable debris. Thereby, the swab impacts the debris to remove the debris from the eye. Removing the debris further includes at least one of breaking the debris free of the eyelid margin, scrubbing the eyelid margin, exfoliating the eyelid margin, buffing the eyelid margin, or un-roofing the meibomian gland.
In one aspect, the swab is positioned near the eyeball along the eyelid margin to target the debris with the swab. The eyelid margin is accessed with the swab without the aid of a magnification device and without lifting the eyelid margin.
In another aspect, effecting movement of the swab relative to the electromechanical device includes at least one of rotating, vibrating, or reciprocating the swab. Furthermore, the movement of the swab may be set to a desirable speed.
Treating the eye for the ocular disorder may include repeating the effecting movement, the contacting the portion of the eye, and impacting the debris with the swab to remove the debris after periodic intervals until the ocular disorder is sufficiently remedied.
In another exemplary embodiment, a device for the removal of debris from the eye during the treatment of the ocular disorder comprises a swab having a tip portion and a base portion. The tip portion is of a sufficient size to access debris on the eye. The device also includes a rigid member and a mechanical drive unit. As such, the rigid member and the swab extend from an instrument. The rigid member has a distal end portion and a proximal end portion such that the distal end portion is affixed to the base portion of the swab and the proximal end portion is secured to the mechanical drive unit, which also includes a body. The mechanical drive unit operably moves the swab relative to the body facilitating removal of the debris from on the eye.
In one aspect, the swab is a generally egg-shaped sponge having an approximate length of two millimeters and a width of one millimeter. Affixed to the sponge, the rigid member is a plastic material that is formed onto the distal end portion of the rigid member.
In yet another aspect, the mechanical drive unit includes an electric motor, a chuck, and a control switch. The chuck projects from the body of the mechanical drive unit and is operably connected to the electric motor. Also, the control switch is operably coupled to the electric motor. With respect to the rigid member, the proximal end portion of the rigid member is removably secured to the chuck. In addition, the device is handheld and includes an electric power source operably coupled to the mechanical drive unit, the electric power source being a battery.
Various additional objectives, advantages, and features of the invention will be appreciated from a review of the following detailed description of the illustrative embodiments taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with a general description of the invention given above, and the detailed description given below serve to explain the invention.
FIG. 1 is a perspective drawing of one embodiment of the device.
FIG. 2A is a drawing of the device of FIG. 1 treating a lower eyelid margin of an eye.
FIG. 2B is a drawing of the device of FIG. 1 treating a upper eyelid margin of an eye.
DETAILED DESCRIPTION
With reference to FIG. 1 , an embodiment of the device 10 for treating an ocular disorder, particularly with respect to eyelid margin diseases, includes a mechanical drive unit 12 which operably moves a swab 14 to facilitate removal of debris from an eye 15 (see FIGS. 2A-2B ). The swab 14 is connected to a rigid member 16 having both a distal end portion 18 and a proximal end portion 20 . The swab 14 is affixed to the distal end portion 18 of the rigid member 16 to create an instrument 22 , which may be secured to the mechanical drive unit 12 . As shown in FIG. 1 , the proximal end portion 20 is removably secured to the mechanical drive unit 12 in order to transmit motion from the mechanical drive unit 12 , through the rigid member 16 , and to the swab 14 . It will be appreciated that any known method may be used to removably secure the instrument 22 to the mechanical drive unit 12 . Moreover, it will also be appreciated that device 10 is not intended to be limited to the instrument 22 being removably secured to the mechanical drive unit 12 . For instance, in another embodiment, the rigid member 16 may be either permanently secured or removably secured to either one of the swab 14 and/or the mechanical drive unit 12 .
In one aspect of the instrument 22 , the swab 14 includes a tip portion 24 and a base portion 26 . While the swab 14 may be of a size sufficient to access debris on the eye 15 as shown in FIGS. 1-2B , at least the tip portion 24 is of a size sufficient to access debris on the eye 15 . For instance, the swab 14 has an approximate length between 1.0-3.0 millimeters and an approximate width of between 0.5-1.5 millimeters. More particularly, the swab 14 has an approximate length of 2 millimeters and an approximate width of 1 millimeter. It will be appreciated that the swab 14 may be manufactured of any material suitable for contacting the eye 15 without harming the eye 15 . However, as shown in the embodiment of FIG. 1 , the swab 14 is a sponge. As described herein, “sponge” broadly refers to any material that is soft, porous, and resilient. Particularly, the swab 14 is a medical grade sponge or a surgical grade sponge capable of removing debris from on the eye 15 without harming the eye 15 . As shown in the exemplary embodiment of FIGS. 1-2B , the swab 14 is a methyl cellulose sponge. It will be appreciated; however, that similar materials capable of removing debris from on the eye 15 without harming the eye 15 are readily apparent and may also be used.
In another aspect of the instrument 22 , the rigid member 16 is a plastic, cylindrical shaft including a central axis 27 . The shaft extends along the central axis 27 between the mechanical drive unit 12 and the swab 14 . The rigid member 16 is sufficiently rigid to effectively transmit motion from the mechanical drive unit 12 to the swab 14 . As shown in FIG. 1 , the swab 14 is permanently affixed to the distal end portion 18 by forming the base portion 26 to the rigid member 16 during manufacturing. However, it will be appreciated that any known method of affixing the swab 14 to the rigid member 16 may be used. In an exemplary embodiment, any material or shaft shape may be used so long as the rigid member 16 is rigid enough to transmit sufficient motion from the mechanical drive unit 12 to the swab 14 in order to remove debris from on the eye 15 .
Furthermore, the mechanical drive unit 12 includes a body 28 , an electric motor 30 , a chuck 32 , and a control switch 34 . As such, the device 10 is electromechanical in nature. In an exemplary embodiment, the electric motor 30 , the chuck 32 , and the control switch 34 are integrated into the body 28 so that the electromechanical device 10 is configured to be handheld as shown in FIG. 1 . However, the electromechanical device 10 is not intended to be limited to a handheld configuration, and it will be appreciated that other configurations of the device 10 are readily apparent.
According to the present embodiment, the electric motor 30 is positioned within the body 28 . The chuck 32 is operably connected to the electric motor 30 at a forward end portion 36 of the body 28 . The proximal end portion 20 of the rigid member 16 is removably secured to the chuck 32 . As described herein, the chuck 32 is generally any element capable of removably securing the rigid member 16 to the mechanical drive unit 12 . As such, the chuck 32 may be tightened or loosened to respectively secure or remove the instrument 22 to the chuck 32 . Thereby, the operable connection of the electric motor 30 transmits a movement 38 through the chuck 32 to the instrument 22 . The movement 38 is any motion relative to the mechanical drive unit 12 or, more particularly, to the body 28 , that creates relative motion to the debris on the eye 15 such that upon contacting the debris with the swab 14 , the debris is removed. As shown, the movement 38 may include, but is not limited to, a reciprocating movement 38 a , a rotating movement 38 b , or a vibrating movement 38 c . The reciprocating movement 38 a may be either along the central axis 27 of the rigid member 16 or orthogonal to the central axis 27 of the rigid member 16 . In addition, the speed of the movement 28 of the swab 14 is any speed sufficient to remove debris from on the eye 15 . It will be appreciated that the speed discussed herein collectively refers to both relative speed of the swab 14 and the frequency of the movement 38 of the swab 14 . For instance, the frequency may range from sonic frequencies to ultrasonic frequencies. Furthermore, the speed of the swab 14 may be variable or otherwise selectable such that an operator of the device 10 may select a desirable speed or a forward or reverse direction via the control switch 34 .
Moreover, the control switch 34 is operably connected to the electric motor 30 and an electric power source 42 to power the device 10 on and off. In an exemplary embodiment, the electric power source 42 is a battery power source 42 contained within the body 28 . The battery power source 42 may be either disposable or rechargeable. The electric power source 42 operably provides electrical power to the electric motor 30 , which the operator controls via the control switch 34 . It will be appreciated that any known control switch 34 or plurality of control switches 34 may be configured to power the device 10 on and off.
Furthermore, it will be appreciated that the device 10 may be manufactured from various materials suited to specific environments of use. For instance, operators within the professional clinic setting may desire a durable, reusable mechanical drive unit 12 and single-use instruments 22 . Some examples of such a professional mechanical drive unit 12 is an Algerbrush I, an Algerbrush II, or similar medical device. However, operators within the home treatment setting may desire the device 10 to be generally disposable and single-use.
With respect to FIGS. 2A and 2B , the device 10 is used in a method for treating ocular disorders of the eye 15 . For purposes of describing the environment in which this method occurs, FIGS. 2A and 2B generally show a portion of a face 50 having a nose 52 , an eyebrow 54 , and the eye 15 . The eye 15 described herein generally includes, but is not limited to, an eyeball 56 including a cornea 58 , an upper eyelid margin 60 , a lower eyelid margin 62 , and a plurality of eyelashes 64 . In the exemplary embodiment, the device 10 is the swab 14 operably connected to the mechanical drive unit 12 thereby creating the electromechanical device 10 for use in removing debris deposited on at least one of either the upper eyelid margin 60 or the lower eyelid margin 62 .
As shown in FIG. 1 , the electromechanical device 10 is powered on and may be set to a desirable speed by the operator; thereby, the operator effects movement of the swab 14 relative to the electromechanical device 10 . Such movement may include, but is not limited to, reciprocating the swab 14 as shown by arrows 38 a , rotating the swab 14 as shown by arrow 38 b , and/or vibrating the swab 14 as shown by lines 38 c . The swab 14 is positioned near the eyeball 56 and along either one of the upper or lower eyelid margins 60 , 62 for treatment. In the exemplary embodiment as shown in FIGS. 2A and 2B , the swab 14 moves with constant movement relative to the electromechanical device 10 while near the eyeball 56 . Alternatively, it may be desirable to vary the movement of the swab 14 relative to the electromechanical device 10 such that the operator has greater control of treating the ocular disorder.
In an exemplary embodiment, the operator preferably targets the debris present on the eye 15 with the swab 14 of the electromechanical device 10 . The debris may be targeted by visually inspecting the eye 15 with or without the aid of a magnification device. Once the debris is targeted, the swab 14 contacts the portion of the eye 15 that includes the debris. For purposes of treating the ocular disorder, the debris may be removably attached on either the upper and lower eyelid margins 60 , 62 the plurality of eyelashes 64 , or between the eyelashes 64 and the inner edge of the eyelid margins, 60 , 62 . Thereby, upon contacting the portion of the eye 15 with the debris, the swab 14 impacts the debris to remove the debris from the eye 15 . Furthermore, a liquid solution configured to loosen the debris may be absorbed within the swab 14 to further aid in removing the debris from the eye 15 and/or minimizing irritation to the eye 15 . It will be appreciated that any liquid solution sufficiently capable of loosening the debris to further aid in removing the debris may be so used.
The electromechanical device 10 operably drives the swab 14 to break the debris free from either of the upper or lower eyelid margins 60 , 62 . Further treatment may be performed to enhance the effects of the debris removal by helping to improve healing and reducing further infection of the eye 15 . Such treatment may include scrubbing, exfoliating, or buffing the eyelid margin or un-roofing a meibomian gland 66 with the swab 14 .
In another aspect, the cornea 58 of the eye 15 is directed away from the position of the swab 14 to minimize contacting the swab 14 to the cornea 58 during treatment. As shown in FIG. 2A , while treating the lower eyelid margin 62 , the eyeball 56 directs the cornea 58 upward, thereby bringing the cornea 58 closer to the upper eyelid margin 60 than the lower eyelid margin 62 . However, as shown in FIG. 2B , while treating the upper eyelid margin 60 , the eyeball 56 directs the cornea 58 downward, thereby being closer to the lower eyelid margin 62 than the upper eyelid margin 60 .
As shown in FIG. 2A , accessing the portion of the eye 15 with the debris, such as the upper or lower eyelid margins 60 , 62 , may be accomplished without further moving or lifting other portions of the eye 15 . However, as shown in FIG. 2B , if accessing the portion of the eye 15 with the debris is difficult, the operator may use a hand 68 , or similar gripping device, to move or lift a portion of the eye 15 , such as lifting the upper or lower eyelid margin 60 , 62 from against the eyeball 56 , to improve access to the debris. Such lifting may be particularly beneficial for improving access to the meibomian gland 66 . It will be appreciated that, in order to improve access to the debris, any portion of the eye 15 may be moved or lifted regardless of which eyelid margins 60 , 62 are being treated. FIGS. 2A and 2B are merely exemplary embodiments showing both non-assisted access and assisted access of the swab 14 to the eye 15 respectively.
Furthermore, the method of treating the ocular disorder may be repeated as directed by a physician or patient in order to sufficiently remedy the disorder. For instance, in the case of physician directed treatment, the physician may direct the patient to visit the physician in periodic intervals for treating the ocular disorder with the electromechanical device 10 . More specifically, the physician directs the patient to visit the physician in periodic monthly or weekly intervals so that the physician may treat the patient. In the exemplary embodiment, periodic intervals are treatments with the electromechanical device 10 once every month. It will be appreciated that any periodic interval of repeating the method of treating the ocular disorder with the electromechanical device 10 may be so used.
Alternatively, in the case of home treatment by the patient, the patient may treat his or her own ocular disorder with the electromechanical device 10 in periodic intervals. However, according to the exemplary embodiment, the physician repeats the method of treating the ocular disorder in periodic intervals with the electromechanical device 10 and the patient also treats the ocular disorder in between physician treatments using traditional treatments. This method of treating the ocular disorder with the electromechanical device 10 in treatments occurring in periodic intervals achieves superior removal of the debris compared to traditional treatments, because the periodic intervals act as reminders to the patient. Thus, the patient is less likely to forget to treat the ocular disorders once symptoms begin to subside, which may result in a resurgence of the disorder. However, the traditional treatments, despite being less effective, may be performed regularly by the patient to further treat the ocular disorder in conjunction with physician treatments with the electromechanical device 10 .
In any case, the physician or patient treats the ocular disorder until the ocular disorder is sufficiently healed and thereafter to prevent a recurrence of the disorder. It will be appreciated that sufficiently healed refers to the dissipation of inflammation and/or discomfort related to the debris within the eye 15 at which time the treatments by the physician may decrease in frequency, but may continue in periodic intervals during home treatment by the patient. In the event that the inflammation, discomfort, or debris worsens, the method of treating the ocular disorder may resume as the physician or patient desires. However, the treatment may be required in periodic intervals throughout the remainder of the patient's life.
While the present invention has been illustrated by the description of one or more embodiments thereof, and while the embodiments have been described in considerable detail, they are not intended to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. The invention in its broader aspects is therefore not limited to the specific details, representative apparatus and method and illustrative examples shown and described. Accordingly, departures may be from such details without departing from the scope or spirit of the general inventive concept.
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A method and apparatus for treating ocular disorders such as blepharitis, meibomitis, and dry eye syndrome. The method includes using an electromechanical device to move a swab relative to the eye to create cyclical movement that impacts debris present at the eyelid margin and effectively removes the debris from the eye to encourage healing and prevent further digression of the health of the eye. The apparatus is an electromechanical device that includes a mechanical drive unit operatively connected to a swab to create a precise relative movement of the swab to the eye to remove debris present therein.
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BACKGROUND OF THE INVENTION
[0001] The operation of cleaning of dust, loose dirt, etc. in dimly lit or confined areas is often difficult to perform using a vacuum cleaner with conventional attachments. Various vacuum cleaner hose attachments with illumination means have been proposed to improve the function of the operation of cleaning in the areas described. Although effective in illuminating the surface area intended to be cleaned, existing devices exhibit obstructed operator lines of sight that impact the effectiveness of the operator to clean the illuminated surface.
[0002] Therefore, it is desirable to have an illumination accessory for a vacuum cleaner hose that can illuminate the surface to be cleaned that exhibits a clear operator line of sight around and through the attachment device. It is also desirable to have this device illuminate the interior of the initial vacuum cavity of the attachment to provide the operator an illuminated line of sight of the contents being vacuumed.
BRIEF SUMMARY OF THE INVENTION
[0003] It is the object of the present invention to provide an initial vacuum intake accessory for a vacuum cleaner hose that utilizes a transparent extension that is a vacuum passage device that is also a lighting device for illuminating a surface to be cleaned, whereby an operator can find dust and loose dirt in a dimly lit or confined location with a clear line of sight around and through the transparent extension of the area to be cleaned. It is also the object of this present invention to provide illumination of the initial vacuum cavity inside the transparent attachment, whereby an operator has an illuminated clear line of sight of the contents being vacuumed.
[0004] In order to obtain the aforementioned objective, it is also the object of the present invention that the light means, such as a Light Emitting Diode (LED), be positioned in line with the transparent extension medium wherein the transparent extension medium is the path for the light means illumination to transverse to the distal end and out the distal end to provide utility lighting.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 depicts the overall arrangement of an example vacuum cleaner with an example embodiment of the present invention illumination accessory attached;
[0006] FIG. 2 is an enlarged perspective of the present invention example illumination accessory attached to an example vacuum cleaner nozzle;
[0007] FIG. 3 depicts the overall arrangement of an example vacuum cleaner with an example embodiment of the present invention illumination accessory assembly attached;
[0008] FIG. 4 is an enlarged perspective of the example embodiment of the present invention illumination accessory assembly with transparent extension and with body cover detached from the example vacuum cleaner nozzle;
[0009] FIG. 5 is an exploded enlarged perspective of the example embodiment of the present invention illumination accessory assembly depicted removed from the example vacuum cleaner nozzle and with body cover removed to depict the body, light means, alternative power means, and alternative switch means;
[0010] FIG. 6 is a plan view of the example embodiment of the present invention illumination accessory assembly with body cover in place;
[0011] FIG. 7 is a plan view of the example embodiment of the present invention illumination accessory assembly with the body cover removed;
[0012] FIG. 8 is a section view of the example embodiment of the present invention illumination accessory assembly with the body cover removed;
[0013] FIG. 9 is a section view of the example embodiment of the present invention illumination accessory assembly with the body cover in place and the assembly installed on the end of the example vacuum cleaner nozzle;
[0014] FIG. 10 is a section view of the example embodiment of the present invention illumination accessory assembly with the transparent extension removed and the body assembly with cover removed from the example vacuum cleaner nozzle;
[0015] FIG. 11 depicts the overall arrangement of an example vacuum cleaner with an example embodiment of the present invention illumination accessory as a permanent nozzle attached to the example vacuum cleaner hose; and
[0016] FIG. 12 is an enlarged perspective of the present invention example illumination accessory as a permanent nozzle attached to an example vacuum cleaner hose.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention will be described as a vacuum cleaner accessory. It is understood that the present invention is not limited in use by the term vacuum cleaner and can be used on other vacuum utility devices such as a shop vac or canister vacuum. It is also understood that the present invention is not limited in use by the term accessory and can be a permanent component of a vacuum cleaner.
[0018] FIG. 1 and FIG. 2 depict an example embodiment of an illumination accessory for a vacuum cleaner according to the present invention. As illustrated in FIG. 1 the example vacuum cleaner 10 with connected example vacuum cleaner hose 12 and connected example vacuum cleaner nozzle 14 are depicted with the disclosed illumination accessory 17 attached to example vacuum cleaner nozzle 14 .
[0019] FIG. 2 depicts the illumination accessory 17 as comprised of the transparent extension 20 with first end 36 and light means 21 embedded between the outer wall 27 and inner wall 28 of transparent extension 20 . Depicted is light means power source wiring 23 that connects light means 21 to the power source means not depicted in example vacuum cleaner 10 in FIG. 1 . The light means power source wiring 23 is depicted attached to example vacuum cleaner hose 12 and example vacuum cleaner nozzle 14 .
[0020] The utility light features of the present invention illumination accessory 17 results from the light means illumination 25 entry into attachment extension 20 . The light means illumination 25 transverses through the attachment extension 20 medium 13 and emanates through distal end 35 of attachment extension 20 as directional illumination 22 . The light means illumination 25 transverses through the attachment extension 20 medium 13 and emanates through the outer wall 27 of attachment extension 20 as peripheral illumination 24 . The light means illumination 25 transverses through attachment extension 20 medium 13 and emanates through the inner wall 28 of attachment extension 20 as internal vacuum cavity illumination 26 .
[0021] FIG. 2 depicts the illumination accessory 17 attached to example vacuum cleaner nozzle 14 wherein the example vacuum nozzle 14 vacuum cavity 18 is extended by illumination accessory 17 as vacuum cavity 15 .
[0022] FIG. 3 through FIG. 10 depict an example embodiment of an illumination accessory assembly 30 for a vacuum cleaner according to the present invention.
[0023] As illustrated in FIG. 3 the example vacuum cleaner 10 with connected example vacuum cleaner hose 12 and connected example vacuum cleaner nozzle 14 are depicted with the disclosed illumination accessory assembly 30 attached to example vacuum cleaner nozzle 14 .
[0024] FIG. 4 and FIG. 5 depict the illumination accessory assembly 30 as comprised of the body assembly 32 , the transparent extension 34 , and the body cover 90 . The body assembly 32 is comprised of the body 40 , the light means 41 , power source means 45 , and the switch means 46 .
[0025] Body 40 has a first end 50 that is to be connected to an example vacuum cleaner nozzle 14 . Body 40 is configured so the distal end 48 is to be connected to the transparent extension 34 . Body 40 is also comprised of body vacuum cavity 54 and body outer surface 52 as depicted in FIG. 8 through FIG. 10 .
[0026] FIG. 5 depicts top cover 91 as a housing comprised of power source access opening 94 , switch means access opening 96 , reflective means 81 , and top cover end wall 89 . Panel 98 is depicted as a removable component of the top cover 91 that connects to the power source access opening 94 , with the purpose of providing access to the power source means 45 . Top cover 91 connects to body 40 along connection line 93 . Panel 98 connects to power source access opening 94 along connection line 97 .
[0027] FIG. 5 depicts the bottom cover 92 as a housing comprised of reflective means 81 , and bottom cover end wall 87 . Bottom cover 92 connects to body 40 along connection line 95 .
[0028] FIG. 5 depicts the light means 41 example as a LED 29 that is comprised of the LED illumination emitter 42 , the LED wiring 43 , and the LED circuit panel 44 .
[0029] FIG. 5 depicts transparent extension 34 as tubular housing 60 with medium 59 which is thick enough at the first end 70 to receive the light source means illumination 80 from the LED illumination emitter 42 . Tubular housing 60 is depicted with light means notch 62 . Light means notch 62 is sized larger than the LED illumination emitter 42 and is intended for the reception of LED illumination emitter 42 . Light means notch 62 surface 63 is a polished surface to receive light means illumination 80 entry into transparent tube 60 medium 59 .
[0030] FIG. 8 through FIG. 10 depict alignment notch 61 in tubular housing 60 for the reception of alignment stud 56 which is attached to body 40 . Alignment stud 56 guides the proper installation of tubular housing 60 to protect LED illumination emitter 42 . FIG. 10 depicts reflective means 83 on first end 70 .
[0031] The utility light features of the present invention illumination accessory assembly 30 that result from the light means illumination 80 entry into tubular housing 60 medium 59 . The light means illumination 80 transverses through the tubular housing 60 medium 59 and emanates through distal end 64 as directional illumination 82 . The light means illumination 80 transverses through the tubular housing 60 medium 59 and travels through the outer wall 66 of tubular housing 60 as peripheral illumination 84 . The light means illumination 80 transverses through the tubular housing 60 medium 59 and travels through the inner wall 68 of tubular housing 60 as internal vacuum cavity illumination 86 .
[0032] FIG. 4 depicts the illumination accessory assembly 30 detached from example vacuum cleaner nozzle 14 . Depicted also is the vacuum cavity 18 of example vacuum cleaner nozzle 14 . It is through the connection of illumination accessory assembly 30 to example vacuum nozzle 14 that vacuum cavity 18 is extended by the illumination accessory assembly 30 as vacuum cavity 54 and vacuum cavity 72 .
[0033] FIG. 11 and FIG. 12 depict an example embodiment of an illumination accessory for a vacuum cleaner as a permanent component of a vacuum cleaner according to the present invention. As illustrated in FIG. 11 the example vacuum cleaner 10 with connected example vacuum cleaner hose 12 are depicted with the disclosed illumination accessory 117 connected to example vacuum cleaner hose 12 .
[0034] FIG. 12 depicts the illumination accessory 117 as comprised of the transparent extension 120 with first end 136 and light means 121 embedded between the outer wall 127 and inner wall 128 of transparent extension 120 . Depicted is light means power source wiring 123 that connects light means 121 to the power source means not depicted in example vacuum cleaner 10 in FIG. 11 . Wiring 123 is depicted attached to example vacuum cleaner hose 12 .
[0035] The utility light features of the present invention illumination accessory 117 results from the light means illumination 125 entry into attachment extension 120 . The light means illumination 125 transverses through the attachment extension 120 medium 113 and emanates through distal end 135 of attachment extension 120 as directional illumination 122 . The light means illumination 125 transverses through the attachment extension 120 medium 113 and emanates through the outer wall 127 of attachment extension 120 as peripheral illumination 124 . The light means illumination 125 transverses through attachment extension 120 medium 113 and emanates through the inner wall 128 of attachment extension 120 as internal vacuum cavity illumination 126 .
[0036] FIG. 12 depicts the illumination accessory 117 attached to example vacuum cleaner hose 12 wherein the example vacuum hose 12 vacuum cavity 11 is extended by illumination accessory 117 as vacuum cavity 115 .
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An illumination accessory assembly for vacuum cleaner includes a transparent extension having a first end capable of releasable connection to a vacuum cleaner hose and having a distal vacuum cavity intake end. A LED is positioned so the LED illumination transverses the transparent extension medium and exits the distal end and walls of the transparent extension. The invention provides the operator an illuminated clear line of sight around and through the transparent extension of the area to be cleaned and illuminates the contents in the initial vacuum cavity of the transparent extension for improved operator cleaning efficiency.
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This is a division of application Ser. No. 324,445, filed Jan. 17,1973, now U.S. Pat. No. 3,827,682.
BACKGROUND OF THE INVENTION
Conventional practice for weldment of plates of steel, other metal, plastic or other similar material for the purpose of forming sections to the required sizes, generally dictates the use of a trunnion, assisted by a crane, to rotate the section for the purpose of completing the weldment of the seams on the back sides of the plates which constitute the plate section. As an example steel will be used as the material to be welded in describing the depicted embodiment.
Rotation of the plates in this manner is cumbersome and time-consuming while requiring the costly use of crane service and manpower. A prime disadvantage is that of having prohibitive downtime of the automated welding equipment on stand-by time awaiting the plate section to be rotated thereby creating production delays. It would be extremely advantageous in the art to provide a device which eliminates the initial cost of overhead crane runways and cranes and which can be located anywhere in a welding fabrication line without extensive material and installation costs. It could be extremely advantageous to be able to weld plates and accessories in the form of sections of virtually any size within a designed framework with an effective increase in the volume of production.
SUMMARY OF THE INVENTION
With the above background in mind, it is among the primary objectives of the present invention to provide an apparatus and method for weldment of plates which meets the above suggested criteria and eliminates overhead crane runways and cranes and minimizes material and installation costs.
The present method and means improves the technique of the handling of steel plates which constitute a predetermined section of a ship, waterworks, bridge structure, building, or similar structures on a turnover frame which is capable of receiving the plates on a flat or curved horizontal position for weldment into a predetermined section. The system contemplates lifting of frame and steel section after weldment is complete, in a vertical direction by hydraulic lifts or other similar means for rotation purposes. The rotation is accomplished through an arc of 180° with the section of plates being held to the frame by holding devices on the frame. This action permits and facilitates the weldment of seams on the opposite side of the section of plates. Thereafter, the frame and section of plates can be returned by rotation to the original horizontal position for removal of the section of plates from the apparatus to a roller assembly line for additional work.
More specifically, the procedural method commences with the arrangement of various steel plates which constitute a predetermined section on a conveyor assembly where the seams are aligned and tack welded together. With the completion of the tack welding, the steel section is moved along the conveyor assembly by rollers onto the rotation frame of the apparatus.
The steel section is then positioned and aligned and properly secured by holding devices to the rotation frame for the purpose of complete weldment of all seams on the exposed face of the steel section. The welding gantry, with automated welding equipment, moves into position and completes the weldment of the seams. Upon completion of the weldment of the seams, the frame and section is lifted vertically by a lifting mechanism to provide the necessary clearance for rotation of the frame and section. A drive gear assembly which rotates the frame is engaged and the frame and section are rotated through an arc of 180° and then are lowered to the original position on the roller table assembly of the apparatus. Holding devices which secure the plate section to the rotation frame are released and the rotation frame is lifted to a predetermined height to provide clearance for the welding gantry to move into position and complete the weldment of seams on the newly exposed face of the steel section. With the weldment of seams completed, the rotation frame is lowered and the holding devices are again activated to secure the steel section to the frame. Frame and steel section are then lifted vertically and rotated through an arc of 180° and thereafter are returned to the original position. The holding devices are released and the steel section is moved from the rotation frame to the connecting roller conveyor assembly line for additional work.
In general, the apparatus needed to carry out the above described method for rotating steel plate sections composed of various plates welded together for the purpose of providing a more efficient method to increase productivity includes the following interconnected elements. A rotating frame is connected to a lift system for lifting the frame in a vertical direction to provide for the necessary clearance for rotation of the frame. Means are provided to secure the steel section to the frame by holding devices. Means are also provided for utilizing a drive assembly to rotate the frame in an arc 180° and, furthermore, means are provided to control the braking of the frame during rotation.
The present apparatus is designed to minimize the steps required in the method for the fabrication of steel sections comprised of various plates which require the weldment of the seams, channels, beams or other metallic objects on both faces of the section as compared to conventional methods.
In conclusion, an apparatus and method are provided for facilitating the weldment of adjoining plates to form a plate section. The apparatus includes a supporting frame to hold the plates and means on the supporting frame to secure the plates thereto during weldment operations. Shifting means are provided to shift the frame holding the plates between an operative and an inoperative position. Finally, rotation means are provided to rotate the frame and plates between a first welding position and a second welding position when the frame is in the operative position to thereby facilitate access to the plates for substantially complete welding operations.
The general method steps include placing the plates on a supporting frame structure in an inoperative position and securing the plates on the supporting frame structure. Thereafter, the plates are partially welded together and the frame is then shifted to an operative position where the frame is rotated to a second welding position. Thereafter, the welding of the plates is completed and the frame is shifted to the inoperative position from which the plates are removed from the frame.
With the above discussed objectives, among others, in mind, reference is had to the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a block diagram of an in-line weldment production conveyor line with the apparatus of the invention located therein;
FIG. 2 is a top plan view of the apparatus of the invention;
FIG. 3 is a sectional elevation view thereof taken along the plane of line 3--3 of FIG. 2;
FIG. 4 is a sectional end view thereof taken along the plane of line 4--4 of FIG. 2 with arrows showing the direction of rotation of the frame portion thereof;
FIG. 5 is an enlarged fragmentary top plan view of the rotating mechanism portion of the apparatus of the invention; and
FIG. 6 is a sectional view thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As an operative example of the apparatus and method of the present invention, the depicted embodiment is shown in operation for welding plates such as steel plates together in shipbuilding operations. For instance, FIG. 1 shows an environmental view of apparatus 20 installed in a conveyor line 21 of that type. In operation, the plates would come from a blast cabinet 22 into a spray booth 23 and then into a oven 24.
Upon exit from the oven, the plates are placed in the welding line on the portion of the conveyor 25 where the plates are aligned and tack welded. The plates then progress to weldment apparatus 20 where the welding of both sides of the plates is accomplished. The plates are then removed from apparatus 20 onto a continuation portion 26 of the conveyor system where reeve preparation is accomplished along with weld inspection. Thereafter the welded section is conveyed to the reeving portion 27 of the conveyor and on down the line in a conventional fashion to a second directional welding portion 28. From then on, the welded section can be handled in any conventional manner (not shown).
Apparatus 20 is shown in detail in FIGS. 2 and 3 of the drawings. A frame 29 is provided with a built-in central girder 30 which is designed to incorporate a steel shaft 31 at both ends of the girder. Shaft 31 is installed into a pillar box housing 32 located on platform 33. Hydraulic arm 34 located within a hydraulic lifting device 35 supports platform 33.
The force utilized for rotation of frame 29 is obtained from electric motor 36 coupled to a small gear box 37. Coupled to gear box 37 is a larger gear box assembly 38 which drives pinion gear 39 thereby delivering the necessary torque to gear 40. Shaft 31 has gear 40 mounted thereon so that rotation of gear 40 rotates shaft 31 and, consequently, interconnected frame 29. Brake 41 provides for control of the rotation of the frame to its interconnection with motor 36. A plurality of electric magnets 42 are affixed to the cross members 43 of frame 29 in any desired arrangement and are exposed to the upper surface of the frame for engagement with plates to be welded. A separate control panel 44 interconnected with the frame assembly provides means for operating the electric magnets 42 and for rotating the frame. Additionally, controls for the hydraulic lift mechanism can also be incorporated in the central control panel 44 and connected in a conventional fashion to the hydraulic system 35 including the arm 34. It can be noted from the drawings that a separate drive assembly 45 for rotational purposes can be located on each side of frame 29 with identical elements in each assembly. Similarly, a separate hydraulic lift assembly 35 can be located on each side of frame 29 to support and lift the frame and drive assembly in the same manner as the hydraulic assembly 35 on the opposite side of the frame.
To facilitate placement and removal of the cumbersome, heavy steel panels with respect to frame 29, a plurality of rollers 46 are mounted on the bed 47 for the frame and extend upwardly therefrom so that when the frame is in the lower position, rollers 46 will extend upward through the openings between the cross bars of the frame. In this manner, rollers 46 form a bearing surface for sliding the plates on and off the frame 29 from an adjacent conveyor system. It should be kept in mind that the frame 29 is a grid-like structure with the cross members 43 having the electric magnets 42 mounted at certain of the formed interstices. In general, frame 29 is open at the top and the bottom with the exception of the cross members 43 and electric magnets 42.
FIG. 3 shows apparatus 20 in the raised position with the steel plates 48 mounted thereon. In actual operation, as shown in general in FIG. 1, the steel plates are passed through the conveyor system 21 until they engage with rollers 46 and are positioned on frame 29. Control panel 44 is then activated to operate the electric magnets 42 in a conventional manner and secure the steel plates under the force of magnetism to frame 29. The control panel then is activated to conventionally cause hydraulic assembly 35 to lift frame 29 along with the secure plates to the uppermost position as shown in FIG. 3. The force is applied on both sides of the frame through hydraulic arms 34 in engagement with platforms 33.
It should be kept in mind that while the frame is in the lower position and has the plates secured to the surface thereof, welding of the seams of one side of the plates 48 is accomplished. The object is to complete welding of the opposite side of the plates. Therefore, when apparatus 20 has frame 29 with the partially welded plates 48 thereon in the upper position, control panel 44 is activated to operate motor 36. The shaft of motor 36 is connected to gear boxes 37 and 38 and to pinion gear 39 so that pinion gear 39 is rotated as the motor shaft is rotated. Pinion gear 39 is engaged with rotational gear 40 on shaft 31 so that as pinion gear 39 is rotated gear 40, shaft 31 and the interconnected frame assembly 29 with the plates secured thereon by magnetism are also rotated. As shown in FIG. 4, the rotation is accomplished through 180° so that the undersurface of the partially welded plates 48 are then exposed for welding. Welding can take place at that time to complete the weldment of plates 48 into a plate section. Thereafter, control panel 44 can be operated to lower the hydraulic apparatus 35 and bring the frame downward to base 47. The electric magnets 42 are released and welded plates 48 are then removed from frame 29 with the assistance of rollers 46 for any desired purpose such as further treatment as shown in FIG. 1. Details of the rotational drive assembly 45 are shown in FIGS. 5 and 6.
An alternative operational method for the welding procedure which can be used similarly with the apparatus described in detail above includes bringing the plates to be welded on conveyor system 21 to station 25 where the seams are aligned and tack welded together. Upon completion of the tack welding, the plates are moved along the conveyor assembly with the assistance of rollers 46 onto frame 29.
The plates are then positioned and aligned and properly secured by means of magnets 42 to frame 29 for the purpose of complete weldment of all seams on the exposed face of the plates. A welding gantry (not shown), with automated welding equipment, moves into position and completes the weldment of the seams on one face of the plates. Thereupon, the frame and partially welded plates are lifted vertically by hydraulic lift assembly 35 to provide the necessary clearance to rotate the frame and plates.
Drive gear assembly 45 which rotates the frame 29 is engaged and frame 29 and partially welded plates 48 are rotated through an arc of 180° and then are lowered to the original position on roller table or base 47 of apparatus 20. The holding devices or magnets 42 which secure the plates 48 to frame 29 are released and frame 29 is lifted to a predetermined height to provide clearance for the welding gantry to move into position and complete the weldment of the seams on the newly exposed face of the plates. With the weldment of seams completed, the rotation frame 29 is lowered and magnets 42 are activated which secure the welded plate section 46 to the frame 29. Frame and welded section 48 are then lifted vertically and rotated through an arc of 180° and returned to the initial position. The frame is then once again lowered by hydraulic means 35 and magnets 42 are released so that the welded section 48 can be moved from the rotation frame with the assistance of rollers 47 to the next receiving station 26 of conveyor system 21 for additional work.
It is contemplated that the present apparatus can incorporate other types of holding devices in place of magnets 42 such as clamps. Similarly, other conventional lifting means can be utilized in place of the hydraulic lifting device depicted and described above. It is also contemplated although not shown that both rotational apparatus 45 can be located on one side of frame 29 rather than on opposite sides of the frame and also a single rotational assembly 45 has been found to operate satisfactorily. Finally, motor 36 may either be an electric motor or a hydraulic motor to supply the power for rotation of frame 29. The present apparatus and method have been found effective for handling extremely large sized steel utilized in shipbuilding. For example, plates having dimensions of 38 by 55 feet and weighing approximately 80 tons can be effectively welded.
Thus, the above discussed objectives of the present invention, among others, are effectively attained.
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A method for facilitating the weldment of plates and stiffners which form a section of predetermined size with the least amount of handling. The method utilizes a fixture including a frame suitable to support the plates, holding devices to secure the plates to the frame, lifting mechanisms to lift the frame and plates for rotational purposes and a drive assembly to rotate the frame in an arc of 180° to facilitate the weldment of the plates together to form a plate section. The fixture is designed for use as part of an in-line conveyor system.
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BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates in general to the handling of large hay bales and more specifically to an improved device that is used to unroll bales on the ground.
The recent trend among farmers and ranchers toward the use of large cylindrical hay bales has been accompanied by attendant difficulties in handling of the hay. In particular, unrolling of the cylindrical bales on the ground in order to feed animals cannot practically be accomplished manually or with conventional hay handling equipment due to the large size and heavy weight of the bales. Specialized equipment has been developed to handle the large bales; however, such equipment has not been altogether satisfactory for use in bale unrolling. This type of equipment is constructed primarily to transport large bales, and it is therefore complex, expensive, difficult and time consuming to operate, and generally unsuited to unroll bales.
For the most part, existing implements that are adapted to unroll large bales are heavy units which are powered by hydraulic cylinders or other power elements. Because of their large size and weight, implements of this type can be moved only by tractors and other heavy duty towing vehicles. Such devices are thus not readily portable, and the extent to which they can be used is restricted accordingly. In addition, the large size of the implements presently available leads to problems as to adequate storage when not in use.
In view of these difficulties associated with existing hay handling devices, it is the primary object of the present invention to provide an improved device which is specifically constructed to unroll large cylindrical hay bales on the ground.
Another important object of the invention is to provide a hay handling device which is light in weight and readily foldable to a small size so as to be easily carried and to occupy little space when stored. Since the device of the present invention is portable for ease of carrying either manually or in a small truck or the like, it is a considerable improvement over existing units which are not portable and thus relatively combersome to move about.
An additional object of the invention is to provide a hay handling device of the character described which operates without the need for a power source and which is readily adapted for hitching to towing vehicles of various types.
A further object of the invention is to provide a hay handling device of the character described which is simple and inexpensive to construct and operate, and which requires little maintenance.
Other and further objects of the invention, together with the features of novelty appurtenant thereto, will appear in the course of the following description.
DETAILED DESCRIPTION OF THE INVENTION
In the accompanying drawing which forms a part of the specification and is to be read in conjunction therewith and in which like reference numerals are used to indicate like parts in the various views:
FIG. 1 is a side elevational view illustrating a hay handling device constructed in accordance with the present invention applied to a large cylindrical hay bale in position to assist in unrolling same, the bale being shown in broken lines in a partially unrolled condition;
FIG. 2 is a top plan view of the device shown in FIG. 1, with the broken lines indicating movement of the arms to their folded positions; and
FIG. 3 is a sectional view on an enlarged scale taken generally along line 3--3 of FIG. 2 in the direction of the arrows.
Referring now to the drawings in greater detail, a hay unrolling device which is constructed according to the present invention is generally designated by reference numeral 10. As best illustrated in FIG. 2, the device includes a cross bar 11 and a pair of arms 12 which extend generally from the opposite ends of bar 11. Bar 11 and arms 12 are preferably tubular structural members. For the pivotal mounting of arms 12, a pair of rigid metal straps 13 are welded to each end of bar 11 to extend therefrom at a right angle. Straps 13 are thin plate like members which are each welded at one end to the top or bottom of bar 11, as best shown in FIG. 1. The straps 13 in each pair are vertically spaced from one another and are parallel to one another. The length of bar 11 is slightly greater than the length of a large cylindrical hay bale, and arms 12 are slightly longer than the maximum bale radius.
With continued reference to FIG. 1, the forward ends of arms 12 are inserted between the respective pairs of straps 13. A pivot coupling 15 in the form of a nut and bolt assembly pivotally pins each arm 12 between the corresponding pair of straps 13 at a location offset somewhat from the forward end of the arm. Couplings 15 are located at the rearward ends of straps 13 to prevent the straps from bending or spreading apart as could possibly occur if they were located elsewhere on the straps. In addition, since couplings 15 are offset considerably from the axis of cross bar 11, arms 12 are able to readily pivot about the couplings without engaging or otherwise being interfered with by cross bar 11.
Each arm 12 is bored near its forward end to receive a locking pin 16 which may also be inserted through aligned apertures that are formed through straps 13 at appropriate locations thereon. Pins 16 are retained on short chains 17 which are each secured at one end to cross bar 11. When arms 12 are oriented perpendicular to bar 11 and parallel to one another as shown in solid lines in FIG. 2, pins 16 may be inserted through the arms and straps 13 to lock the arms against pivotal movement about couplings 15. In this locked position, arms 12 extend rigidly from bar 11 in position to unroll the hay bale, as will be explained in more detail. Locking pins 16 are located more closely to bar 11 than pivot couplings 15 in order to facilitate pivoting of arms 12 without the arms engaging bar 11 at their pivoting ends, as might otherwise occur.
The rearward end of each arm 12 carries a spike 18. The spikes 18 are perpendicular to arms 12 and point directly toward one another when the arms are locked in the bale engaging position of FIG. 2. Each spike 18 has a pointed tip which is able to easily penetrate a hay bale and remain firmly imbedded therein. With particular reference now to FIG. 3, each spike 18 is mounted to rotate about its own axis. A cylindrical bushing 19 is welded to the end of each arm 12 at a right angle relative thereto. Spike 18 is reduced in diameter opposite its pointed end, and the reduced diameter portion of the spike is fit in bushing 19 for free rotation therein. A bearing cap 20 is secured to the end of spike 18 by a set screw 21. Caps 20 and the shoulders formed at the reduced diameter portions of spikes 18 cooperate to prevent the spikes from sliding axially in bushings 19. Each bushing 19 is provided with a grease fitting 19a.
A flexible chain is used to couple cross bar 11 with a towing vehicle (not shown) which assists in the unrolling of the bale. As best shown in FIG. 2, a pair of chain sections 22 of equal length are connected to eye bolts 23 which are secured to bar 11 at locations spaced equally from the center of the bar. Chains 22 converge in a V-shape and are connected at their forward ends at the apex of the V with a third chain 24 which carries a hook 25 at its forward end. Hook 25 may be hooked to a ball hitch 26 (FIG. 1) or to any other type of hitch which is carried on the draw bar 27 of a suitable towing vehicle such as a tractor or small truck (not shown). The chain arrangement provides a two point attachment with bar 11 and a single point attachment with the towing vehicle for added stability.
In use, the device 10 assists in unrolling large cylindrical hay bales such as that indicated by numeral 28 in FIG. 1. Locking pins 16 are removed so that arms 12 may be pivoted outwardly far enough for spikes 18 to clear the opposite ends of the bale. The arms are then pivoted inwardly to drive spikes 18 into the center of the bale on opposite ends thereof. Pins 16 are then inserted through arms 12 and straps 13 to rigidly lock the arms in place such that spikes 18 remain firmly engaged in the bale.
With the device thus locked in bale engaging position, the hook 25 is hitched to ball 26 or to another portion of the towing vehicle (not shown) which is then driven forwardly. This causes the outer layer 29 of the bale to unroll flatly on the ground, with spikes 18 being able to rotate as the unrolling of the bale takes place. The device 10 automatically lowers as the bale diameter decreases during unrolling, and bales of any diameter and at any stage of unrolling are thus readily accommodated.
When the bale 28 has been unrolled to the extent desired, pins 16 are removed to permit outward pivoting of arms 12 for the withdrawal of spikes 18 from the bale. After the spikes have been withdrawn so that the device is separated from the bale, arms 12 may be folded inwardly for easy carrying or storage. The arms are pivoted inwardly about couplings 15 at least to the broken line position shown in FIG. 2 and preferably beyond such position until the arms are generally parallel to bar 11. The pivot couplings 15 and straps 13 give arms 12 sufficient play to permit one spike 18 to clear the top of bar 11 and the other spike 18 to clear the bottom of the bar. When folded, arms 12 overlap one another slightly and spikes 18 overlap with cross bar 11 at least partially. The device is light enough to be easily carried manually in its folded condition and is small enough to occupy little room when stored or when carried in a truck bed or the like. The flexible chains 22 and 24 may be wrapped around the folded arms 12 to retain them in their folded positions when carried or stored.
From the foregoing, it will be seen that this invention is one well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure.
It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims.
Since many possible embodiments may be made of the invention without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawing is to be interpreted as illustrative and not in a limiting sense.
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A portable device which assists in the unrolling of large cylindrical hay bales on the ground. A pair of arms are pivoted between rigid straps which extend from the opposite ends of a cross bar. Rotatable spikes for penetrating opposite ends of the bale are mounted on the arms. Locking pins secure the arms in rigid perpendicular extension from the cross bar with the spikes embedded in the opposite ends of the bale. A flexible chain couples the cross bar with a towing vehicle which is driven forwardly to unroll the bale. The arms are foldable after removal of the locking pins to lie generally parallel to the cross bar for carrying and storage of the device.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present patent application claims the benefits of priority of commonly assigned Canadian Patent Application No. 2,631,252, entitled “WATER PLAY INSTALLATION” and filed at the Canadian Intellectual Property Office on May 13, 2008.
FIELD OF THE INVENTION
[0002] The present invention generally relates to participatory water play structures, systems, apparatuses and installations where participants can play and/or interact with water dispensing elements for recreational enjoyment.
BACKGROUND OF THE INVENTION
[0003] Over the past 15 years, cities, amusement parks, hotels, and other facilities catering to family recreation and leisure have been installing zero-depth aquatic or water play area installations. These installations are generally referred to as splash pads, spray parks, spray grounds and wet decks (hereinafter “water play area installation”). These play area installations are typically provided with water dispensing elements and structure such as, but not limited to, water canons, spray arches, ground sprays, and the like. U.S. Pat. Nos. 5,194,048; 5,405,294 and 5,662,525 disclose examples of prior art water play area installations.
[0004] Typically, in prior art water play area installations, the water dispensing elements are generally configured to be activated by participants using one or several user interfaces located in the designated play area as an independent device or integrated into one or several water dispensing elements. In certain of these installations, the user interfaces are in electric communication with a system controller which controls electrically or hydraulically activated solenoid valves connected to a water distribution manifold.
[0005] In use, participants touch, engage or act upon the user interface which sends signals to the system controller which, in response, opens and/or close the valves in accordance with one or more pre-programmed sequences in order to feed the activated water dispensing elements with water.
[0006] In conventional water play area installations, especially those comprising electronic systems, the system controller, the solenoid valves and the water distribution manifold are typically installed in a building, in an underground enclosure, or in an aboveground enclosure installed at a significant distance from the water play area. This configuration is understandable since it is generally most preferable to avoid contact between water and electric and electronic systems. However, in these conventional water play area installations, since the user interfaces are usually located on the water play area, electrical wiring must still be installed between the user interfaces and the system controller.
[0007] Accordingly, conventional water play area installations require the independent installation of the user interfaces, the system controller and the water distribution manifold. Moreover, they require space for the installation of these equipments, which is not always available, and they require the installation of electrical wiring from the system controller to the activation devices, and water piping from the manifold to water dispensing elements. Hence, despite ongoing development, there is still a need for a novel water play installation which mitigates the shortcomings of the prior art.
SUMMARY OF THE INVENTION
[0008] The aforesaid shortcomings are generally mitigated by providing a novel water play installation wherein the user interface, the system controller and the water distribution manifold are integrated into a command center generally located in close proximity and preferably underneath the water play area, thereby defining an elegant and compact structure.
[0009] More particularly, a water play installation in accordance with the present invention generally comprises a water play area provided with preferably several water dispensing elements. Though the water dispensing elements may vary in form, shape and configuration, each water dispensing element is adapted to dispense water. Examples of water dispensing elements are water canons, spray arches, ground sprays, water tunnels and water sprinklers. Understandably, the foregoing list is not exhaustive and other forms of water dispensing elements could be provided. The water dispensing elements are generally disposed on the play area such as to define an entertaining and ludic environment.
[0010] In accordance with the present invention, the water dispensing elements are all fluidly connected to a command center preferably located in close proximity of the periphery of the play area and most preferably located underneath the water play area in a central region thereof. The command center generally comprises an enclosure having a bottom wall, one or more side walls and a top cover which define an inner chamber into which are located an electronic system controller, one or more preferably electrically actuated solenoid valves and a water distribution manifold to which is connected a water supply line. Understandably, the water dispensing elements are connected to the water distribution manifold via the solenoid valves.
[0011] In accordance with the present invention, the command center further comprises a user interface connected to the system controller and used to activate the water dispensing elements via the system controller. Understandably, different types of user interface could be used; for example, motion detector, pressure sensor, tactile screen, etc.
[0012] According to another aspect of the present invention, the command center can contain an integrated drainage system to collect the water dispensed by the water dispensing elements. The enclosure is therefore preferably, though not necessarily, provided with draining pipes preferably connected to a water recovery system.
[0013] In use, participants would go on the water play area and would activate the water play installation by acting upon the user interface of the command center. In response, the user interface would send one or more signals to the system controller which would turn on or off the solenoid valves in order to supply water to the water dispensing elements in accordance with one or more predetermined programs stored in the system controller.
[0014] As the skilled addressee would readily understand, a sound system and/or a lighting system could also be connected to the system controller for providing sound and/or lighting effects for additional enjoyment.
[0015] The features of the present invention which are believed to be novel are set forth with particularity in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The above and other objects, features and advantages of the invention will become more readily apparent from the following description, reference being made to the accompanying drawings in which:
[0017] FIG. 1 is a perspective view of an exemplary embodiment of a water play installation in accordance with the present invention.
[0018] FIG. 2 is a perspective view of the command center of the water play installation of FIG. 1 .
[0019] FIG. 3 is a perspective view of the command center of the water play installation of FIG. 1 , with the cover installed.
[0020] FIG. 4 is a perspective view of another exemplary embodiment of a water play installation in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0021] A novel water play installation will be described hereinafter. Although the invention is described in terms of specific illustrative embodiments, it is to be understood that the embodiments described herein are by way of example only and that the scope of the invention is not intended to be limited thereby.
[0022] Referring first to FIG. 1 , a broad perspective view of an embodiment of the water play installation 10 of the present invention is shown. The water play installation 10 typically comprises a water play area 20 generally made from one or more slabs of concrete though other materials could be used.
[0023] Disposed on the water play area 20 are several water dispensing elements 30 . Though only five (elements 30 a, 30 b, 30 c, 30 d and 30 e ) such water dispensing elements 30 are shown in FIG. 1 , it is to be understood that this number is illustrative and that more or less water dispensing elements 30 could be provided. The number and disposition of the water dispensing elements 30 are generally chosen according to the available space and in order to define an entertaining and ludic environment. Typically, the water dispensing elements 30 are structures of various shapes and configurations which are all adapted to dispense water.
[0024] Non limitative examples of water dispensing elements 30 include water canons, water mist generators, ground sprays, water falls, etc. Understandably, water dispensing elements 30 could be more or less complex depending on the desired water effect. The present invention is not so limited.
[0025] Still referring to FIG. 1 , each water dispensing element 30 is fluidly connected to a command center 50 via water feed line 32 . As depicted in FIG. 1 , the command center 50 is preferably, but not exclusively, approximately located in a central region of the water play area 20 . The command center 50 is also preferably substantially located underneath the surface of the water play area 20 . Still, in certain embodiments as the one depicted in FIG. 4 , the command center could possibly be located outside the water play area though near its periphery. In those embodiments, the command center should be located within 10 meters of the periphery, preferably within 5 meters, and most preferably within 1 meter.
[0026] Referring now to FIGS. 2 and 3 , the command center 50 generally comprises an enclosure 52 having bottom wall 54 , side wall 56 and preferably removable cover 58 . The enclosure 52 defines an inner space into which is located a water distribution manifold 60 . The manifold 60 is fed with water through a water supply line 62 connected to a water source (not shown). The manifold 60 is further connected to the water feed lines 32 of the water dispensing elements 30 via preferably electrically actuated solenoid valves 64 . As best shown in FIG. 2 , each water feed line 32 preferably has its own valve 64 such that each water dispensing element 30 can independently be fed with water. The present invention is however not so limited. Indeed, a valve 64 could possibly feed more than one water feed lines 32 with the use of appropriate pipes and couplings.
[0027] In accordance with the preferred embodiment, the solenoid valves 64 are in electric communication with an electronic system controller 66 generally mounted near or on the enclosure of the water distribution manifold 60 as depicted in FIG. 2 . The system controller 66 is fed with electricity through an electric cable 63 generally extending along the water supply line 62 . The system controller 66 is in further electronic communication with a user interface 68 preferably, but not exclusively, mounted thereon. The user interface 68 , which can take various configuration (e.g. motion detection, pressure sensor, tactile screen, etc.), allows a participant to activate the water play installation 10 .
[0028] As depicted in FIGS. 2 and 3 , the user interface 68 is preferably integrated in the top of the command center 50 in a manner to make the user interface 68 accessible to participants. Still, the user interface 68 could be located substantially outside of the enclosure 52 . For instance, the user interface 68 could be mounted to a post or structure (not shown) extending outside the enclosure 52 via the opening 57 of the cover 58 . Understandably, the exact configuration of the user interface 68 can vary; the present invention is generally not limited to any particular configuration.
[0029] As a participant interacts with the user interface 68 , the interface 68 will send one or more electric signals to the system controller 66 . The system controller 66 will, in response and according to a predetermined program stored therein, turn on or off the solenoid valves 64 such that the water dispensing elements 30 are selectively provided with water.
[0030] The skilled addressee will understand that the system controller 66 can comprise several predetermined programs which can be run sequentially or randomly. In addition, depending on the user interface 68 and the system controller 66 , the system controller 66 could react differently to different stimuli provided to the user interface 68 . The present invention is not so limited.
[0031] As the skilled addressee will understand, the system controller 66 can be of various configurations. Typically, but not exclusively, the system controller 66 will comprise a processing unit such as a micro-controller in electronic communication with both the user interface 68 , for receiving input signals therefrom, and the solenoid valves 64 , for providing actuation signals thereto. The system controller 66 will also typically comprise data storage units such as electronic memory chips, in electronic communication with the processing unit, for storing one or more predetermined programs of activation of the water dispensing elements 30 . The system controller 66 could also be provided with input/output ports such as USB or RS232 ports and/or with a wireless transceiver, any of which would be in electronic communication with the processing unit. Such ports and/or transceiver would allow the upload and download of data (e.g. new water dispensing programs, maintenance data, system update, etc.) to and from the system controller 66 . The present invention is however not so limited.
[0032] As water is dispensed by the water dispensing elements, water accumulates at the surface of the water play area 20 . In order to prevent dangerous accumulation of water, a drainage system (e.g. drainage holes 59 ) is preferably integrated in the top cover 58 of the enclosure 52 .
[0033] As best depicted in FIG. 2 , the side wall or walls 56 of the enclosure 52 are also provided with one or more drain pipes 70 . Hence, as water accumulates inside the enclosure 52 , the water flows down the drain pipes to a sewage water collecting pipe or, preferably, to a water treatment system where the water can be treated and preferably recycled back through the installation 10 .
[0034] Understandably, since the user interface 68 , the system controller 66 , the water distribution manifold 60 and the solenoid valves 64 will be exposed to water during normal use of the installation 10 , it is most preferred that these components be made with water and corrosion-resistant materials (e.g. plastics, aluminium, stainless steel, etc.) and/or be made to be water proof with the use of sealed electrical connections and waterproof electrical enclosures (e.g. covered by elastomeric membranes, coated with sealant, etc.).
[0035] By being located close to the water play area 20 and preferably centrally located underneath the water play area 20 , the command center 50 can integrate several functions and requires less water pipes and electrical wiring. Also, the overall water play installation 10 has a smaller footprint. In addition, since most of the components (i.e. user interface 68 , the system controller 66 , the distribution manifold 60 and the valves 64 ) of the installation 10 are located in the command center 50 , maintenance of the installation 10 is simplified since most of the components are accessible through the removable cover 58 .
[0036] While illustrative and presently preferred embodiments of the invention have been described in detail hereinabove, it is to be understood that the inventive concepts may be otherwise variously embodied and employed and that the appended claims are intended to be construed to include such variations except insofar as limited by the prior art.
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A participatory water play installation comprises a water play area provided with several water dispensing elements which can be user-activated via a user interface connected to a command center. The command center is preferably located underneath the water play area and further comprises an electronic system controller, electrically actuated solenoid valves and a water distribution manifold. The command center is in fluid communication with the water dispensing elements whereby upon stimulation of the user interface, the command center initiates a predetermined sequence of water dispensing patterns from the activated water dispensing elements, resulting in recreational enjoyment of the participants.
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RELATED APPLICATIONS
This application is a continuation of application Ser. No. 11/973,747 filed Oct. 10, 2007 now U.S. Pat. No. 7,887,327, which application is a continuation in part of application Ser. No. 11/449,461, filed Jun. 8, 2006, now U.S. Pat. No. 7,261,927 and claims priority under 35 U.S.C. 120 therefrom, which application is a continuation of application Ser. No. 10/056,101, filed Jan. 24, 2002, now U.S. Pat. No. 7,059,856 and claims priority under 35 U.S.C. 120 therefrom, which application claims benefit under 35 U.S.C. 119 (e) of provisional application Ser. No. 60/316,832 filed Aug. 31, 2001 and provisional application Ser. No. 60/402,187 filed Aug. 10, 2002.
FIELD OF THE INVENTION
This invention relates generally to the construction of a dental or cranial prosthesis that is attached to an implant in the bone of a person's jaw or skull.
BACKGROUND OF THE INVENTION
Dental implants are a common treatment for the replacement of a missing tooth or missing teeth. An implant is placed into the bone in a person's jaw in a variety of fashions and using a variety of systems. The bone and the implant adhere together in a process known as osseointegration, thus enabling a person to have a new tooth or set of teeth held into position in the jaw utilizing screws to hold them down.
Many firms manufacture complete systems of dental implants and prosthetic components for subsequent attachment to the implant. In a typical construction, the implant has an axially threaded hole at its top, that is, the proximal end, near the gum surface. After the implant has integrated with the bone, the gum of the implant is opened to expose the tapped hole. Then a transmucosal abutment is attached to the tapped hole of the implant and extends to a level above the gum or substantially to the gum surface. The protruding free end of the abutment is constructed for attachment of a prosthesis. For preventing rotation of the prosthesis, the protruding end of the abutment requires a non-round shape and a hexagon protrusion has been widely used. A recessed hexagon is also popular with some systems. The abutment also includes a central threaded hole concentric with the threaded hole of the implant and extending inward toward the jaw bone.
A false tooth or frame is provided with a hole therethrough, known in the industry as a chimney, and a non-round recess in its base corresponds in shape to the protruding non-round cross section for the abutment. Thereby, the crown can be connected to the abutment and relative rotation between them is prevented so long as critical contours of the abutment and the recess in the crown are maintained.
To prevent the crown or bridge from lifting axially from the abutment, a final screw is passed into the chimney opening and engages the tapped hole in the implant by way of the abutment so as to hold the crown axially to the abutment and to the implant. Thus, the crown cannot rotate about the abutment or implant because it is mated with the special contours on the exposed end of the abutment. The abutment is similarly mated to the proximal or outer end of the implant. The crown cannot pull away from the abutment when the screw has been tightened into place.
Finally, the chimney above the screw is filled with a composite material that hardens and is shaped as part of the crown to look lie a natural tooth.
There are many variations in construction.
In an alternative method, the crown is attached directly to a non-round protrusion of the implant and is held directly to the implant by a gold screw without use of an intermediate abutment.
The implant is intended to be a permanent fixture in the jaw bone. The abutment and crown may be replaced if necessary due to damage or poor fit by gaining access to the screw head by way of the chimney, and backing off the screw so that the crown and abutment or crown to the implant can be separated from the implant. Thus repairs may be made of an abutment and crown with no or little inconvenience.
Therefore, the fit of an implant with the crown or frame must be perfect. If a prosthesis is placed into the mouth and does not seat correctly, the implant or abutment can be damaged. If an implant is damaged there are not many options for its repair. In cases where there have been a poor fit, the screws have broken inside the abutment requiring the replacement of the abutment. There have been cases where the screw broke inside the implant. The implants cannot be replaced without surgically removing them. Placing a new implant in the same spot is not an advised option.
Among related patents disclosing dental analogs include U.S. Pat. No. 6,142,782 of Lazarof, which shows a dental analog with annular wings. However, the annular wings do not hinder rotating and therefore misplacement of the analog within the replica cast stone. The annular wings of Lazarof do not intersect with the cast stone material enough to prevent rotation.
An alternative method for making dental prostheses that does not involve making an impression of the patient's mouth has been recently introduced. It is based on Solid Freeform Fabrication (SFF) which is an industrial prototyping technique whereby 3-D Computer Aided Design (CAD) files describing a part are used to guide the actual fabrication of a solid object by one of a variety of additive methods such as stereolithography, laminated object manufacturing, or fused deposition modelling. U.S. Pat. No. 6,978,188 of Christensen as well as his published patent application 2005/0133955 illustrate how CT scans or MRI scans can be substituted for CAD input to create the files necessary to drive a stereolithography system which can then be used to model human bone features. Medical Modeling LLC has used such a method in their AccuDental™ system to create dental prostheses. Prior to implantation of posts, a scan is made of a patient's jaw. This data is used to create files resulting in an accurate solid translucent resin model of a patient's jaw. Teeth and roots are rendered in a different hue to show clearly how the teeth are anchored in the jaw bone. A dental surgeon then indicates on the jaw model where analogs are to be placed in the model and at what angle they should be inserted. Holes are then drilled into the jaw model to accept the analogs. A surgical guide is thermally formed on top of the implant region of the model engaging the teeth or ridge surface with a close fit and transferring the analog positions accurately. Alternatively, computer generated surgical guides which fit onto a jaw model are used. Surgical guide sleeves at the appropriate angle are then bonded at the analog sites onto the surgical guide. The surgical guide is snapped off the teeth or ridge surface of the model and will be transferred to the patient's mouth and snapped onto the actual teeth or the ridge surface thereby providing accurate guides for drilling the holes for the actual implants while at a remote lab, the prosthesis is being fabricated using the analogs in the jaw model. Surgical guides fit not only on teeth, but can be used on totally edentulous jaws as well engaging soft tissue or bone surface as represented on the jaw model and on the actual patient jaw.
OBJECTS OF THE INVENTION
Accordingly, it is the object of the invention to provide a method for insuring the most accurate seating possible of a prosthesis to an abutment or implant in the jaw or skull of a patient.
SUMMARY OF THE INVENTION
The present invention comprises an implant analog that may include a standard abutment that can be mounted in the dental lab replica of the relevant section of a patient's mouth more securely than heretofore possible. Because of the inventive implant analog, dental labs can now create a crown that will attach more accurately to the implant in the patient's mouth. The analogs of the present invention are desirably longer than the analogs used heretofore and have a pin that projects from the base of the analog. Desirably, the inventive analogs have a side ridge. Moreover, the analog has substantially the same height and dimensions as a conventional implant and abutment. In a preferred embodiment, the analog of the present invention is formed from stainless steel.
A careful confidential experiment was conducted at New York University of School of Dental Medicine by Dr. C. Jager, Dr. G. R. Goldstein, Dr. E. Hittelman and the Applicant herein. The experiment was designed to compare the performance of a prior art analog of NOBEL BIOCARE®, as shown in FIG. 9 , to that of one embodiment of the present invention, as shown in FIG. 4 . A statistically significant improvement for the present invention was found in terms of framework fit. Also, resistance to applied torque was found to be significantly improved for the analog of this invention.
The experiment evaluated torque prostheses to laboratory dental implant analogs. The study evaluated the movement of the prior art analog of NOBEL BIOCARE®, as shown in FIG. 9 , and the embodiment shown in FIG. 4 of the present invention. Both were torqued to 20 Ncm in a reinforced type IV die stone. 80 analogs were divided into groups of 4 analogs, including three of the prior art analog shown in FIG. 9 with one of the present invention shown in FIG. 4 . These analogs were embedded in thirty equal blocks of Type IV plaster stone using a prefabricated four unit implant framework. Of the twenty analogs, ten were imbedded in the stone at a depth of four cm and ten were imbedded at a depth of six cm from the implant platform. These groups of ten were then divided into groups of five each, where five of the prior art analogs shown of the present invention in FIG. 9 were torqued to 20 Ncm in each group and five analogs shown in FIG. 4 were torqued to 20 Ncm. The initial framework was used to evaluate the fit of each analog therein. In the 4 mm depth group of the prior art shown in FIG. 9 , two of the five samples (40%) did not allow the framework to fit the analog. In the 6 mm depth of the prior art analogs shown in FIG. 9 , three of the five samples (60%) did not allow the framework to fit. However, all of the dental analogs shown in FIG. 4 of the present invention fit back to the cast.
As a result, the analogs of the present invention, as shown in FIG. 4 , were able to resist movement within a stone cast when torqued, unlike a significant portion of the prior art dental analogs shown in FIG. 9 .
Therefore, the dental analogs of the present invention have unexpected, beneficial results not achievable with the dental analogs of the prior art shown in FIG. 9 .
A method of preparing dental crowns efficiently and accurately, includes the steps of:
a. preparing an analog for a jaw implant supporting a dental crown mounting pin having at least one anti-rotation anchoring projection extending discretely and radially from said pin adjacent a bottom end thereof;
b. inserting bottom-end-down said prepared mounting pin into a dental crown casting mold;
c. securing said prepared mounting pin temporarily in place within said casting mold;
d. adding settable plaster or plastic molding material to said casting mold so as to embed said bottom end of said pin by surrounding said bottom end of said pin with said plaster or plastic molding material;
e. allowing said plastic molding material to set and harden with said prepared pin embedded within said molding material; and
f. utilizing said embedded mounting pin to make a dental crown.
Regarding the alternative method described in the previous section using a resin model of a patient's jaw, the analogs used must be resistant to pull-out and rotation as in the method using the stone plaster method. Whether the resin model is a product of stereolithography or otherwise fabricated, it is drilled to accept an analog post. The alternate embodiment of this invention describes analog posts with features for robustly grasping the side walls of these retaining holes in the resin model. Clearly, transverse or radially protruding features cannot be appended to the analog posts since these would not be compatible with insertion.
The first alternate embodiment uses a single axially attached rod or wing on the lower portion of the analog post. The post is then forced into a slightly undersized hole and resists both twisting and pull-out. A second embodiment using axial rod features uses two such rods on opposite sides of the analog post. A third such embodiment uses three such rods attached every 120 degrees around the bottom end of the post. Any number of such rods can be attached preferably in a symmetric array. The rods can also be enhanced in their gripping action by texturizing their outer surface; alternatively, axial grooves along their length at their outermost position can be added.
Another embodiment of analog post for hole engagement is made of a larger diameter with a tapered top; a regular array of longitudinal grooves or flutes on the outer side surface engage the hole sides. Yet another embodiment of analog post is one with a knurled outer surface and an annular groove near the bottom end. A final embodiment has male threads along the analog shank which permit screwing into the hole in the resin model much akin to the thread-forming action of a wood screw in a pilot hole in wood.
When using model based presurgical planning techniques, computer based stereolithography or non-computer methods are used to create an accurate jaw model of resin, plaster, or “stone” or other plastic material. Similarly, surgical guides which form fit onto the jaw model and onto the patient's jaw are also created. Once analogs are inserted into the jaw model, surgical guide sleeves are bonded to the surgical guide at the analog sites using cement or adhesive inside oversized holes in the surgical guide. These must be at the appropriate height, and the orientation must match that of the analogs in the jaw model. Another embodiment of this invention is a set of accessory parts and a method to insure that the alignment of the surgical guide sleeves bonded to the surgical guide will match that of the analog in registration.
After the analogs are inserted in the jaw model, at each analog site attachments to each analog are made which will orient the surgical guide sleeve rigidly and accurately to represent the orientation of the analog. After all the surgical guide sleeves are thereby attached to the analogs, the surgical guide with oversize holes at each analog site is lowered onto the jaw model and all surgical guide sleeves are bonded to the surgical guide while they are still attached to the analogs. After the cement or adhesive sets, screws are removed from each analog to free the surgical guide with all of the surgical guide sleeves accurately attached. The guide is then used inside the patient's mouth to drill accurate implant holes by using each of the surgical guide sleeves as drill guides.
The parts attached to each analog in the jaw model are a surgical guide sleeve supported by a form-fitting cylinder support mount, a tube adapter to adjust the height of the guide sleeve above the analog (if necessary), and a screw threaded through the three parts from the top to secure the assembly to the analog below.
Presurgical planning techniques using accurate whole skull models or models of skull portions other than jaws are also used for cranial and facial reconstruction. Attachments use surgical implants in bone. For example such an approach is used to repair missing bone in the cranium, ear prostheses, and nose prostheses. The procedure starts with an accurate model and a surgical guide with oversize holes in registration with the analogs inserted at sites determined by a surgeon on the skull model. Using the procedure and analog attachments as described above for dental implants, appropriately sized tube adapters, cylinder support mount, surgical guide sleeve and attachment screw are attached to each analog in the skull model. The surgical guide is then fitted carefully atop the protruding elements atop each analog, and the surgical guide sleeves are cemented or otherwise bonded within the oversize holes of the guide capturing the precise angle of the analog in the model. The analog screws are then removed releasing the surgical guide with guide sleeves attached for accurate drilling during the surgical procedure for insertion of the implants.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention can best be understood in connection with the accompanying drawings. It is noted that the invention is not limited to the precise embodiments shown in drawings, in which:
FIG. 1 is a view of a dental lab replica showing the position of an analog and an abutment;
FIG. 2 is a view of a lower jaw about to receive a prosthesis and having two implants;
FIG. 3 is a view of an embodiment of the present invention incorporating a conical abutment;
FIG. 3A is a partial view taken within the phantom circle of FIG. 3 , shown rotated ninety degrees for clarity;
FIG. 4 is a view of an embodiment of the present invention incorporating a standard abutment;
FIG. 5 is a view of an embodiment of the present invention corresponding to an implant with a hexagonal protrusion;
FIG. 6 is a view of an embodiment of the present invention corresponding to a large diameter implant with a hexagonal recess;
FIG. 7 is a side elevation view in partial cross section of an embodiment of the present invention corresponding to an implant with a hexagonal recess;
FIG. 7A is a top plan view thereof;
FIG. 8 shows a conventional impression coping with depth indications from 2-5 mm;
FIG. 9 shows a conventional prior art fixture replica, or analog, which is replaced by analog according to the present invention;
FIG. 10 shows the placement of a fixture replica, either a conventional or according to the present invention, in the lab replica that is to be secured to an abutment and a crown via a guide pin;
FIG. 11 shows the attachment of a fixture replica, either a conventional or according to the present invention, to an impression coping that is fixed in an impression of the relevant section of a patient's mouth prior to the casting of the lab replica;
FIG. 12 shows a dental impression tray modified to provide access to the impression coping that is secured to the implant in a patient's mouth by a guide pin;
FIG. 13 shows the excess material around the impression coping in a tray containing impression material, the impression coping being secured to the implant in the patient's mouth by a guide pin;
FIG. 14 shows a means of securing the impression coping to the tray containing the impression material with an acrylic resin;
FIG. 15 shows the impression containing the impression coping;
FIG. 16 is a top view of an engagement plate of this invention which is used to provide improved anchorage for a conventional analog;
FIG. 17 is an exploded side view of the engagement plate of FIG. 16 attached to a conventional analog;
FIG. 18 is a perspective view of an analog body with a transverse tube configured to screw into a variety of abutments;
FIG. 19 is a perspective view of an analog body with transverse wings;
FIG. 20 is a bottom view of an analog body with transverse wings;
FIG. 21 is a perspective view of an analog body with coplanar transverse tubes at right angles;
FIG. 22 is a perspective view of an analog body with non-coplanar oblique tubes;
FIG. 23 is a bottom view of an analog body with eight co-planar transverse tube segments;
FIG. 24 is a perspective view of an analog body with angled spikes;
FIG. 25 is a side elevation of an analog body with serrated side extensions;
FIG. 26 is a side elevation of an analog body with four serrated and perforated side extensions;
FIG. 27 is a perspective view of an analog body with looped side extensions;
FIG. 28 depicts a cross-sectional view of a protrusion in an analog having a substantially oval shape 2802 ;
FIG. 29 depicts a cross-sectional view of a protrusion in an analog having a substantially triangular shape;
FIG. 30 depicts a cross-sectional view of a protrusion in an analog having a substantially square shape;
FIG. 31 depicts a cross-sectional view of a protrusion in an analog having a substantially rectangular shape; and,
FIG. 32 depicts a cross-sectional view of a protrusion in an analog having a substantially hexagonal shape 3202 .
FIG. 33 is a (prior art) perspective view of a plastic resin jaw model and a surgical guide illustrating the relation between the two.
FIG. 34 is a (prior art) perspective view of a resin jaw model with analog posts installed.
FIG. 35 is a perspective view of an analog post of this invention with a single side rod or wing attached.
FIG. 36 is a perspective view of an analog post with two axial wings.
FIG. 37 is a top plan view of an analog post with three symmetrically attached side rods or wings.
FIG. 38 is a side elevation detail showing texturing on the side of a rod or wing.
FIG. 39 is a perspective detail of showing a longitudinal groove on the side of a rod.
FIG. 40 is a perspective view of a fluted analog post.
FIG. 41 is a perspective view of a knurled analog post with an annular groove adjacent the bottom end.
FIG. 42 is a side elevation of an analog post with male thread on its shank surface.
FIG. 43 is a perspective view of a cylinder sleeve support mount.
FIG. 44 is a side crossection of the mount of FIG. 43 .
FIG. 45 is a side crossection of the cylinder sleeve support mount inside a surgical guide sleeve to show the fit of the two parts.
FIG. 46 is a side elevation of a retaining shoulder screw.
FIG. 47 is a perspective view of a short tube adapter.
FIG. 48 is a perspective view of a medium height tube adapter.
FIG. 49 is a perspective view of a larger diameter and taller tube adapter.
FIG. 50 is a side exploded view of the five parts from top screw to bottom analog.
FIG. 51 is a side detail crossection of two assemblies attached to two analogs in a jaw model with a section of surgical guide in registration with the two analogs but spaced apart for clarity.
FIG. 52 is a perspective view of an accurate skull model showing analogs inserted for cranial repair, ear prosthesis, and nose prosthesis with accurate surgical guide for the cranial repair.
DETAILED DESCRIPTION OF THE INVENTION
Simplified, the construction of the prosthesis begins after the osseointegration of the implant with the dentist making an impression of the relevant section of the patient's mouth. When constructing the prosthesis, the dentist makes an impression including an impression coping. Desirably, the impression material employed is hard and elastic when set, such as the materials sold under the trade names IMPRAGUM, EXPRESS and PRESIDENT.
Once the impression material hardens, the tray containing the impression is sent to a dental lab where the prosthesis is made. The dental lab uses this impression to make a replica of the relevant section of the patient's mouth. Typically, the replica is made of gypsum to form plaster, and is made to reproduce the milieu into which the prosthesis is to fit, including, for example, any hexagonal protrusion or recession in the abutment the dentist is using. Alternately, the replica can also be made of plastic, such as resin.
For example, FIG. 1 shows a view of dental lab replica 130 with analog 120 and abutment 110 .
Moreover, FIG. 2 shows an actual patient lower jaw with two implants 220 , a three tooth prosthesis 210 and screws 230 to retain prosthesis 210 in implants 220 .
In making the impression, the impression coping is attached to the implant in the same way the final prosthesis will attach. The impression coping rests flush on top of the implant, or implant and abutment, with a guide screw passing through and into the implant. The impression coping remains in the impression in the same position that was in the mouth and the guide screw must be removed before the impression can be removed from the patient's mouth.
In making the dental lab jaw model, or replica, the analog is attached to the impression coping with a guide screw going through the impression coping and into the analog. All of the teeth in the relevant portion of the mouth are replicated in the model, which desirably is made of gypsum. The goal is to have the analog in the replica in the position that corresponds to the position of the implant in the patient's mouth, including the orientation of any protrusion or recess.
The present day tools offered by the implant manufacturers utilize brass or stainless steel analog.
The configuration of the prior art analogs replicates the internal thread dimension of the implant or abutment and copies the shape of the external or internal hexagon. However, the outside diameter of a prior art analog maintains a shape that is not consistent with the needs of the dentist or technician in constructing the prosthesis. Conventional analogs are too small and are removed from the gypsum model too easily. Moreover, the exterior surface of conventional analogs are too smooth which permits the analog, and thus the prosthesis, to rotate in the model during construction of the prosthesis. Such rotation moves the hexagonal position of the prosthesis into a position that does not match the corresponding position of the implant in the patient's mouth.
In contrast to the prior art conventional, easily rotatable and dislodgable dental analogs, the present invention is a new analog that will not allow any rotation in the gypsum model. In a preferred embodiment, as shown in FIGS. 3 and 3A , the analog 320 of the present invention is substantially longer and has a unique feature of a transverse pin 312 or other protruding geometric shaped member extending through hole 314 in its side.
FIG. 4 shows analog 420 with abutment 22 and hole 414 for insertion of a pin therein, similar to pin 312 of FIG. 3A .
As shown in FIGS. 5 , 6 , and 7 , these dental analogs 520 , 620 and 720 of the present invention are preferably ridged with annular recesses, these dental analogs 520 , 620 and 720 on their respective sides to gain better retention inside the gypsum model.
Analogs 420 , 520 , 620 and 720 have respective pins (not shown) similar to transverse pin 312 of analog 320 of FIG. 3A . These pins 312 are located at the base of the respective analogs 320 , 420 , 520 , 620 and 720 to lock the position. These transverse pins 312 prevent horizontal, vertical or cylindrical movement of the analogs 320 , 420 , 520 , 620 , and 720 within the model.
Conventional implants have a standardized system of heights, measurements and dimension for implants and abutments. The respective inventive analogs 320 , 420 , 520 , 620 , 720 of the present invention can have a shape which incorporates a conical abutment 322 ( FIGS. 3 and 3A ), a standard abutment 422 ( FIG. 4 ), a hexagonal protrusion 522 ( FIG. 5 ), a large hexagonal recess 622 ( FIG. 6 ) or a hexagonal recess 722 ( FIG. 7 ), as these terms are used in the dental industry. For example, FIGS. 28-32 depict cross-sectional views of protrusion embodiments having various shapes. Illustratively, FIGS. 28-32 are described with respect to protrusion 2012 however that description is not intended in any way to limit the scope of the invention. For example, it is appreciated that extensions 2051 may in various other embodiments have the shapes depicted in FIGS. 28-32 . FIG. 28 depicts a cross-sectional view of protrusion 2012 having a substantially oval shape 2802 . FIG. 29 depicts a cross-sectional view of protrusion 2012 having a substantially triangular shape 2902 . FIG. 30 depicts a cross-sectional view of protrusion 2012 having a substantially square shape 3002 . FIG. 31 depicts a cross-sectional view of protrusion 2012 having a substantially rectangular shape 3102 . FIG. 32 depicts a cross-sectional view of protrusion 2012 having a substantially hexagonal shape 3202 .
Analogs 520 , 620 and 720 also bear annular grooves 516 , 616 and 716 .
The analogs 320 , 420 , 520 , 620 and 720 of the present invention are machined to specified mechanical tolerances. In particular, the internal thread of the inventive analogs are closer to the threads of actual implants and abutment. This closer approximation to the actual implants insures that the guide screw goes into the implant the same number of turns the guide screw goes into the analog, and maintains the prosthesis in the same position relative to the patient's mouth as the prosthesis had with respect to the replica. The internal or external hexagon is also closer in dimensions to the actual implant. As a result, the prosthesis will fit on the analog and on the actual implant or abutment in the manner intended.
Another complication in the construction of dental analogs is that it is often necessary to construct a large frame using soldered connections. The present methods of soldering require a duplicate model of high heat tolerance gypsum investment be made with the present day analogs. The frame is soldered on that model. The success rate of these solder connections is far lower than expected in the industry. The present invention allows a more accurate solder connection. The present invention also holds better in the invested model and keeps the analogs from moving in the model.
Example
In the single tooth prosthetic work, the impression is taken from the fixture level. As shown in FIG. 8 , one type of conventional impression coping 800 has an internal hexagon at the base, which corresponds to the hexagon of the abutment. The coping has depth indications for assessment of proper abutment size, 2 mm, 3 mm, 4 mm, and 5 mm. The upper margin of the abutment-like part indicates 6 mm. The impression coping is typically made of titanium.
The impression coping is used together with a special guide pin (e.g., a DCA 098), 850 , for a single tooth (the guide pin used to secure the prosthesis to the implant typically has a different thread).
Typically, in the laboratory, any undercuts of the impression coping are blocked out before pouring the impression (including the depth indications). This blocking is especially important when the longest abutment is used. This precaution prevents fracturing the cast when separating the model and the impression coping.
During the Laboratory procedure, an analog, for example a conventional prior art analog 900 shown in FIG. 9 , or an analog of the present invention such as the analogs of FIGS. 3-7 , is used in the laboratory jaw model, or replica, to represent the implant in the working cast. This is illustrated in FIG. 10 where analog 1000 is set in the laboratory jaw model, or replica, 1010 , and the abutment 1020 and crown 1030 are secured to the jaw model by guide pin 1040 . The analog has the same top hexagon and internal thread as the implant. In contrast to the stainless steel analogs of the present invention, conventionally, analogs were typically made of nickel-plated brass.
FIG. 11 shows an impression 1100 containing an impression coping 800 being attached to an analog 1000 via guide pin 1040 . Once the analog 1000 is secured to the impression coping 800 by the guide pin 1040 , the impression 1100 is used to cast the laboratory jaw model, or replica, from stone, such as gypsum.
The impression 1100 containing the impression coping 800 can be prepared in any conventional manner. For example, as shown in FIG. 12 , one can make a hole 1200 in an acrylic-resin stock tray 1210 for access to the impression coping 800 which is secured to the implant by the guide screw.
FIG. 13 shows tray 1210 loaded with an impression material of choice 1300 in the mouth with impression coping 800 secured to implant 120 within the patient's jaw 1310 .
FIG. 13 also shows the removal of any excess material around impression coping 800 once impression material 1300 has set.
Impression coping 800 is then secured to tray 1210 with auto-polymerizing acrylic resin 1400 . The orientation of the hexagonal head of the implant 120 should be maintained when the impression 1100 is removed. Next, guide pin 850 is unscrewed and impression 1100 is carefully removed form the patient's mouth.
As noted before, FIGS. 3-7 show different embodiments of the dental analogs 320 , 420 , 520 , 620 and 720 of the present invention each using a transverse rod pin 312 or tube within hole 314 , 414 , 514 , 614 , or 714 , in the base section of each analog 320 , 420 , 520 , 620 , or 720 to enhance the anchoring of the analog in the plaster of the replica. Each of the different embodiments uses a different style of abutment 322 , 422 , 522 , 622 , or 722 to match that which the dentist had used in the patient's actual implant.
For example, FIG. 3 shows a conical abutment 322 for analog rod 320 and FIG. 4 shows a standard recessed abutment 422 for analog rod 420 . FIG. 5 shows an abutment 522 with a hexagonal protrusion for analog rod 520 , FIG. 6 shows a large diameter abutment 622 with a hexagonal recess, for analog rod 620 , and FIG. 7 shows an abutment 722 with a hexagonal recess for analog rod 720 .
FIG. 16 shows another embodiment of this invention in the form of a flat engagement plate 2000 which is used to provide enhanced anchoring of a standard prior art analog 900 (see FIG. 9 ) in the replica plaster.
As shown in FIG. 17 , the conventional analog 2003 is inserted through central hole 2001 and adhesively bonded 2004 at an oblique angle. Perforations 2002 enhance adhesion to immobilize plate 2000 in replica plaster. An optional hollow sleeve 2005 can be used to extend the vertical height of analog 2003 , to further promote its anchoring within the replica plaster.
It is further noted that optional removable hollow sleeve 2005 can also have any of the protrusions shown in the other drawing figures, such as protrusion rods 2012 of FIG. 18 or FIG. 21 , protrusion 2022 of FIG. 19 , protrusion wings 2030 of FIG. 23 , protrusion barbs 2032 , protrusion wings 2035 of FIG. 25 , protrusion wings 2040 of FIG. 26 or protruding loops 2051 of FIG. 27 .
FIG. 18 shows the concept for a series of additional embodiments of analogs of this invention which use a tubular body 2010 with external threads 2011 at the top end. These threads screw into mating female threads on a series of abutments 2013 (here illustrated as a conical abutment) which are supplied to match the style and size actually implanted in the patient's jaw.
Therefore, analogs of this general category of embodiments can be matched with a variety of abutments 322 , 422 , 522 , 622 , or 722 (as described in FIGS. 3-7 ). The analog 2010 with conical abutment 2013 of FIG. 18 , similar to analog 320 with a conical abutment 322 , uses a transverse tube or rod 2012 to aid in anchoring body 2010 in plaster. Slotted body 2020 as shown in FIG. 19 accepts two rectangular wings 2021 (as shown in bottom view of FIG. 20 ) with perforations 2022 as yet another embodiment to resist rotation within, and extraction from, the replica plaster.
The embodiment shown in FIG. 21 uses coplanar radial transverse tubes 2012 at right angles to each other to provide anchorage.
The embodiment shown in FIG. 22 uses two oblique tubes 2012 which penetrate body 2010 as anchorage.
The bottom view of the embodiment of FIG. 23 shows eight equally spaced tubular segments 2030 attached to body 2010 to provide anchorage in replica plaster.
FIG. 24 shows an embodiment of an analog using tubular body 2031 with upward angled spikes 2032 in two rows to provide anchorage.
The embodiment of FIG. 25 shows slotted body 2020 with a pair of serrated triangular wings 2035 to provide anchorage in the replica plaster.
FIG. 26 shows an embodiment of an analog with body 2039 with four slots accommodating four perforated and serrated triangular wings 2040 to rigidly anchor it to the plaster of a replica.
Furthermore, FIG. 27 shows an embodiment of an analog using tubular body 2050 with one or more outwardly extending looped extensions 2051 to promote anchorage.
FIG. 33 illustrates some features of the alternate method incorporating a resin jaw model to fabricate a prosthesis. Resin jaw model 4000 is translucent and shows teeth in a contrasting hue in the jaw. Marks 4001 placed by a dental surgeon indicate the location for the center of each analog hole to be drilled. Marks 4002 illustrate the proper angle for such analog retaining holes. Surgical guide 4010 is shown “popped-off” the teeth of jaw model 4000 over which it is formed by a thermal process. Surgical guide sleeves 4011 are shown attached at the proper angles to drill the implant post holes in the patient's jaw. Three analog posts 4020 are shown installed in jaw model 4000 in FIG. 34 .
The analog posts in FIGS. 35-42 all have features to resist pull-out and rotation when installed in holes of a resin jaw model. FIG. 35 shows analog post 4030 with one side rod or wing 4032 . FIG. 36 shows analog post 4035 with two wings 4032 attached to opposite sides of post shank 4031 . FIG. 37 shows a symmetric attachment of three side wings 4032 from a top view. In all cases, these analog posts are forced inside a hole slightly smaller than would normally accommodate an analog shank with its side wings. The wings will embed into the sides of the retaining holes. FIG. 38 shows texturing 4046 as applied to outer edge of side wing 4032 to aid in retention. FIG. 39 shows groove 4051 along the length of side wing 4032 which can be used for the same purpose alternatively.
In lieu of side wings or attached rods, FIG. 40 shows fluted analog post 4055 with longitudinal grooves 4057 and a tapered top end 4056 which would be below the top surface of the retaining hole. FIG. 41 illustrates yet another embodiment of analog post 4060 which is knurled 4061 along its entire outer shank. An annular groove 4062 also enhances pull-out resistance. The analog post 4065 of FIG. 42 is screwed into an analog hole via tapered bottom 4066 and thread-forming male threads 4067 along its shank.
FIGS. 43-51 illustrate a presurgical method for aligning surgical guide sleeves in a surgical guide so they can be bonded in the proper orientation for use in a patient's mouth to accurately drill holes for accepting implant posts. Three parts are used for this. FIG. 43 shows a cylinder sleeve support mount 4080 with center hole 4083 , shank 4082 and flange 4081 . FIG. 44 shows the key dimensions of the various parts while FIG. 45 shows the fit of support mount 4080 within surgical guide sleeve 4011 . The O.D. of flange 4081 (DD) matches the O.D. of guide sleeve 4011 . Shank 4082 of diameter D fits in a close clearance fit inside guide sleeve 4011 which is slightly longer (LL) than height dimension L. This is to insure rigid locking by shoulder screw 4090 of FIG. 46 which has a head 4091 also of dimension DD; threads 4093 engage the central threaded hole of an analog. Note that shoulder 4092 diameter d 1 is slightly smaller (close clearance fit) than hole of diameter d in support mount 4080 . FIGS. 47-49 illustrate three different heights h 1 , h 2 , and h 3 of tube adapters 4100 , 4110 , and 4120 respectively which match the outside diameter (O.D.) of an analog. Analog 4120 would be used with a larger diameter analog. Many such adapters would be made available to adjust the height of the surgical guide sleeve above the top of an analog as required. FIG. 50 shows an exploded view of the assembly of the five parts. Although analog 4065 of the screw-in variety is shown, any analog would usable with this method. Referring to FIG. 51 , side crossection detail 4150 of the jaw model shows two analogs, one 4065 screw type and one knurled type 4060 , rigidly installed. The method requires that the progression of parts as shown in FIG. 50 is assembled and accurately and rigidly held in place by tightening screw 4090 in each analog beneath. Note that analog 4065 has short tube adapter 4100 atop while analog 4060 uses a taller 4110 adapter. In FIG. 51 , the flange portion of each cylinder sleeve support mount 4080 is visible atop the tube adapter while surgical sleeve guide 4011 is captured and guided between the head 4091 of screw 4090 and flange 4081 of mounts 4080 . Note also that analogs 4065 and 4060 are tilted away from each other (not aligned) as required by the desired positioning in the jaw model. A section of surgical guide 4160 is shown above jaw model 4150 with oversize holes 4161 in registration with analogs 4065 and 4060 . After the surgical guide 4160 is carefully aligned with jaw model 4150 , surgical sleeve guides 4011 will be within holes 4161 where they will be bonded to surgical guide 4160 . After the adhesive or cement cures, screws 4090 will be removed thereby releasing surgical guide 4160 from jaw model 4150 with surgical sleeve guides accurately attached. Analogs 4065 and 4060 will then be used by the dental lab for fabrication of appropriate prostheses. When the prostheses are made (or before), surgical guide 4160 is returned to the dental surgeon. It is used to accurately drill implant post holes in the patient's jaw using the surgical sleeve guides as drill guides to replicate the orientation of the analogs in the jaw model for a close fit of the prostheses.
FIG. 52 shows a skull model 4200 which is typically created using stereolithography. Analog group 4215 (8 analogs) placed around cranial injury area 4210 will be used to plan the surgery. Also shown are a group of five analogs 4240 which will be used to attach an ear prosthesis, and a pair of analogs 4260 for a nose prosthesis. All three sites will also require accurate surgical guides for these procedures. One of these, 4220 for the cranial repair, is shown in the figure. Note the oversize holes 4215 in registration with the array of analogs 4215 . Two exemplary surgical guide sleeves 4227 are shown indicating that a total of 8 such sleeves will have to be accurately bonded inside holes 4225 . To facilitate this step, the parts shown in FIG. 50 , namely tube adapter 4100 , support mount 4080 , surgical guide sleeve 4011 ( 4227 in FIG. 52 ), and screw 4090 , are assembled in the order shown atop each analog 4215 . Then surgical guide 4220 is placed accurately over the repair area 4210 with guide sleeves 4227 inside holes 4225 . Sleeves 4227 are then bonded to guide 4220 . All screws 4090 are then removed thereby releasing surgical guide 4220 with accurately bonded guide sleeves 4227 ; the guide sleeves will be used for drilling holes for the actual implants in the surgical procedure. Surgical guides for the ear and nose prostheses (not shown) would be similarly prepared.
In the foregoing description, certain terms and visual depictions are used to illustrate the preferred embodiment. However, no unnecessary limitations are to be construed by the terms used or illustrations depicted, beyond what is shown in the prior art, since the terms and illustrations are exemplary only, and are not meant to limit the scope of the present invention.
It is further known that other modifications may be made to the present invention without departing from the scope of the invention, as noted in the appended Claims.
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Pre-surgical planning for cranial and facial reconstruction includes preparing a computer generated jaw or skull model for determining a locational position for a dental implant, a surgical bone implant to repair missing bone in the cranium, install ear prostheses, and/or install nose prostheses. The computer generated jaw or skull model is made from medical imagery and computer aided design. A surgical guide is prepared with oversize holes in registration with analogs for the dental or surgical bone implants to be inserted in the jaw or cranial skull model. The surgical guide is fitted atop each analog, and bonded to the jaw or skull model at a predetermined angle of the analog in the jaw or skull. The surgical guide is removed and attached to the jaw or skull of a patient for accurate drilling for insertion of the implants into the jaw or skull of the patient.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a vibrating plate according to the preamble of patent claim 1 .
[0003] 2. Description of the Related Art
[0004] Vibrating plates for soil compaction are known, and are made up in principle of a lower mass having a soil contact plate and an upper mass that is coupled to the lower mass by springs so as to be capable of motion, and that has a drive (e.g. an internal combustion engine or electric motor). The drive drives a vibration exciter device that appertains to the lower mass and that charges the soil contact plate.
[0005] The vibration exciter device introduces a directed vibration into the soil contact plate. The vibrating soil contact plate acts on the soil in order to compact it. In addition, the resultant overall force produced by the vibration exciter device can achieve propulsion in the longitudinal direction, as well as a steering of the vibrating plate. Because the principle of this design has long been known, more detailed description is not necessary here.
[0006] As a vibration exciter device, what is known as a one-shaft exciter, or plate compactor, is known, in which the drive rotationally drives an imbalance shaft that bears an imbalance mass. During its rotation, the imbalance shaft lifts the soil contact plate upward and forward in order to achieve forward motion. Subsequently, the soil contact plate is pressed downward by the action of the imbalance shaft, and strikes the soil that is to be compacted.
[0007] In larger vibrating plates, the vibration exciter device has two or three imbalance shafts that are coupled to one another mechanically, or with a positive fit, and that are situated parallel to one another. In a two-shaft exciter, such as that known for example from EP 0 358 744 A1, two imbalance shafts, each bearing an imbalance mass, are positively coupled to one another and are situated so as to be capable of rotation in opposite directions. The phase position of the imbalance
[0000] shafts relative to one another, it is possible to modify the direction of a resultant force vector, causing a change in the propulsion behavior. In particular, in this way it is possible to achieve forward and backward travel of the vibrating plate.
[0008] In a further development, the imbalance mass on one of the imbalance shafts is divided into two or more partial imbalance masses that can be adjusted relative to one another. If the partial imbalance masses on the imbalance shaft are adjusted asymmetrically to one another, a yaw moment can be produced around the vertical axis of the vibration exciter device, permitting steering of the vibrating plate. In the case of a symmetrical adjustment, in particular if, as in EP 0 358 744 A1, partial imbalance masses are fixedly attached to the relevant imbalance shaft and other partial imbalance masses are capable of being moved relative thereto, the resultant imbalance action can be adjusted, enabling setting of the resultant imbalance forces.
[0009] Standardly, in known vibration exciter devices the imbalance shafts are situated parallel to one another. In modern vibrating plates, it is therefore possible to achieve forward and backward travel, as well as to cause the vibrating plate to rotate in place or to travel on a curve. However, for some applications the user will desire a lateral movement of the vibrating plate, in order for example to enable travel behind lateral projections. When compacting soil on laterally inclined surfaces, the vibrating plate often drifts obliquely downward, so that the operator must orient the vibration plate obliquely in order to compensate this. However, in this case the soil at the upper and lower edge is compacted only by a corner of the soil contact plate, resulting in unsatisfactory compaction.
[0010] In these cases of application, it would be helpful for the vibrating plate to be capable of executing a lateral movement. However, in order to achieve such a lateral movement, the vibration exciter device would have to achieve a corresponding force action in the lateral direction.
[0011] From GB 1 166 025 A, another vibrating plate is known in which a vibration exciter device has four imbalance masses that are each capable of being driven rotationally about an axis of rotation.
[0012] From DE 100 53 446 A1, a vibrating plate is known that has an upper mass and a lower mass comprising a soil contact plate. The soil contact plate is charged by a vibration exciter device having two vibration exciters. Each of the vibration exciters is made up of two shafts, situated parallel to one another, that are positively coupled to one another and that rotate in opposite directions, each bearing an imbalance mass, and being situated so that their phase positions relative to one another can be adjusted. In contrast, the phase position of shafts of different vibration exciters is not adjustable.
OBJECT OF THE INVENTION
[0013] The underlying object of the present invention is to indicate a vibrating plate that is capable of movement with three degrees of freedom, i.e. in the longitudinal direction (main direction of travel), in the lateral direction, and rotationally about the vertical axis, with, simultaneously, a minimum number of imbalance shafts.
[0014] According to the present invention, this object is achieved by a vibrating plate according to patent claim 1 . Advantageous further developments of the present invention are indicated in the dependent patent claims.
[0015] A vibrating plate according to the present invention has an upper mass, usually including a drive, a lower mass that is elastically coupled to the upper mass and that has at least one soil contact plate, and a vibration exciter device that charges the soil contact plate. The vibration exciter device has at least four imbalance masses that can each be rotationally driven about an axis of rotation, the axes of rotation of at least two of the imbalance masses standing at angles to the axes of rotation of the other imbalance masses.
[0016] The imbalance masses are each standardly borne by a respective imbalance shaft, so that the axis of rotation of an imbalance mass is also simultaneously the axis of rotation of the imbalance shaft that bears it. A situation of the axes of rotation “at an angle” is to be understood as a situation that is not parallel or coaxial. Whereas up to now the axes of rotation of the imbalance masses have standardly been situated parallel to one another, according to the present invention a situation at an angle of at least two of the imbalance masses is now proposed. The situation at an angle of the axes of rotation on the soil contact plate has the result that the imbalance masses not only produce force actions in the longitudinal direction (main direction of travel of the vibrating plate), but also produce force components in the lateral direction. Given a suitable controlling of the rotation of the imbalance masses, it is therefore possible to produce a lateral movement of the vibrating plate. In addition, it continues to be possible also to produce a yaw moment about the vertical axis of the vibrating plate in order to steer the vibrating plate.
[0017] Through the rotation of the imbalance shafts, the imbalance masses situated thereon each produce a centrifugal force vector that rotates in a plane that is perpendicular to the axis of rotation of the imbalance shaft. If the axes of rotation of the imbalance shafts are situated at an angle to one another on the soil contact plate, the force vectors of the imbalance masses correspondingly also act in different planes. Depending on the controlling of the imbalance shafts, force actions in various directions can be produced that bring about a corresponding movement of the soil contact plate.
[0018] Of course, imbalance masses can also be provided whose axes of rotation are situated coaxially or parallel to one another. Thus, various mixed arrangements are conceivable in order to achieve a desired travel, directional, and compaction behavior of the vibrating plate.
[0019] In addition, it is possible to provide imbalance masses having different masses. Such a specific embodiment takes into account for example the recognition that in the majority of cases the vibrating plate is used in forward and backward travel operation, while rotation, as well as curved and oblique travel, are the exception, or require smaller forces. Correspondingly, the imbalance masses used for forward and backward travel should have larger masses than do the imbalance masses that are intended to bring about only curved or lateral travel.
[0020] The lower mass can also be fashioned so as to have a plurality of soil contact plates that are charged by the vibration exciter device. In this way, the vibrating plate has the possibility of adapting to uneven terrain. In addition, individual soil contact plates can be used for the forward movement or steering of the vibrating plate as a whole, while other soil contact plates are used solely for soil compaction.
[0021] It is particularly advantageous if the axes of rotation of the imbalance masses also do not stand at an angle of 90° to one another, so that the term “at an angle” refers to angles between 0° and 90°, or between 90° and 180° (0≦α≦90; 90≦α≦180). The axes of rotation of the imbalance masses are then situated obliquely to one another in such a way that at least some of the imbalance masses produce force components both in the forward direction (main travel direction X) and in the lateral direction.
[0022] Advantageously, a phase adjustment device is allocated to each of at least some of the imbalance masses, in order to enable adjustment of the phase position of the allocated imbalance mass relative to the phase positions of the other imbalance masses. Through adjustment of the phase positions, the direction and the magnitude of the resultant force vectors can be modified in order to achieve the desired force action. This makes possible the required steerability and lateral mobility of the vibrating plate.
[0023] It is particularly advantageous if one of the imbalance masses is regarded as a reference imbalance mass, to which a separate phase adjustment device is not allocated, while a separate phase adjustment device is allocated to each of the other imbalance masses. In this way, the phase positions of these imbalance masses can be individually adjusted relative to the reference imbalance mass.
[0024] Because the reference imbalance mass does not require a separate phase adjustment device, it can be driven directly by a drive, thus keeping the mechanical outlay low.
[0025] In a particularly advantageous specific embodiment of the present invention, the axes of rotation of the imbalance masses are situated in a star-shaped [or: stelliform] arrangement relative to one another; here the angles between the axes of rotation can have the same angular size or different angular sizes.
[0026] Thus, at least four imbalance masses, or imbalance shafts bearing same, can be provided on the lower mass, whose phase positions relative to one another can be adjusted with the aid of at least three separate phase adjustment devices (the reference imbalance mass requiring no phase adjustment device).
[0027] It is particularly advantageous if the axes of rotation of the imbalance masses intersect essentially in one point. As explained below, this enables a particularly simple, purely mechanical drive, and is thus not absolutely necessary, even given a star-shaped arrangement of the axes of rotation of the imbalance masses.
[0028] Preferably, the axes of rotation of the imbalance masses are situated such that the force vectors produced by the imbalance masses during their rotation act in different planes. Only then is it also possible to achieve force components transverse to the longitudinal direction of the vibrating plate, in order to enable the vibrating plate to travel in the lateral direction as well. Here, the force vectors produced by at least some of the imbalance masses during their rotation should act in planes that are at angles to one another, rather than being parallel to one another.
[0029] Advantageously, those imbalance masses that are adjacent to one another with respect to their centers of gravity, i.e. that have relatively little distance between them in comparison with the other imbalance masses, are driven so as to rotate in opposite directions to one another. This opposite rotation of the imbalance masses, which usefully have the same mass, makes it possible to adjust the force vector resulting therefrom in a known manner.
[0030] Of course, the term “imbalance mass” is being used here in a generalized sense, and does not presuppose that the imbalance mass has to be formed by a single unified mass element. Rather, an imbalance mass can also be formed by a plurality of partial imbalance masses. However, it is presupposed that the partial imbalance masses on the same imbalance shaft rotate with the same rotational speed and phase position to one another. In contrast, different imbalance masses must be capable of being adjusted at least with respect to their phase position to one another, or must be capable of rotation in opposite directions.
[0031] In a particularly advantageous specific embodiment of the present invention, a plurality of individual exciters are provided, each of which has at least one of the imbalance masses and an imbalance shaft that bears the respective imbalance mass. The individual exciters are capable of being controlled individually with respect to the rotational speed and/or the phase position of the imbalance mass. In this way, small units can be provided in the form of the individual exciters, which in the simplest case have only a single imbalance shaft. The phase position, and if warranted also the rotational speed, of this imbalance shaft can be controlled individually, i.e. independently of the rotational speed or the phase position of other imbalance shafts. The overall vibration exciter device then has at least four of these individually controllable individual exciters, at least two of the individual exciters standing at an angle to the rest of the individual exciters.
[0032] The phase position of the imbalance shaft relates to its rotational position relative to the other imbalance shafts that work together with it.
[0033] Preferably, the upper mass has a drive for driving the vibration exciter device. The drive can for example supply the hydraulic drive energy for hydraulic motors, each of which drives one or more imbalance shafts on the lower mass.
[0034] Thus, for example each of the individual exciters can have a motor that rotationally drives the imbalance shaft.
[0035] In a particularly advantageous specific embodiment of the present invention, each of the individual exciters has a hydraulic motor that is capable of being driven by the drive situated on the upper mass, e.g. an internal combustion engine having a hydraulic pump. Alternatively, the motor can also be an electric motor.
[0036] With the just-described individual drivability of the individual imbalance shafts, in which the mutual relative position or phase position is not ensured by a positive coupling, it is useful to acquire the position of each imbalance shaft in at least one position, using a position sensor. In this way, on the one hand each of the imbalance shafts can be driven individually by the motor allocated to it, while on the other hand the actual position of the imbalance shaft is monitored constantly or at regular intervals via the position sensor. The position sensor should acquire the position of the imbalance shaft (or imbalance mass) in at least one position, i.e. should acquire the position once during a rotation of the imbalance shaft, from which the rotational speed of the imbalance shaft can be determined, and intermediate positions can also be interpolated. Of course, the position sensor can also be fashioned such that it permanently acquires the rotational position of the imbalance shaft, and thus its rotational speed. The precise recognition of the rotational position is important so that the phase position of the imbalance shaft can be derived therefrom.
[0037] With the aid of a central control device, the individual exciters can be coordinated so that each individual exciter achieves its individually pre-specified target rotational speed and/or target phase position. The central control device evaluates a desire on the part of the operator, and/or that is pre-specified by an operating or driving program, in order to achieve the desired behavior of the soil contact plate.
[0038] In another specific embodiment of the present invention, the imbalance shafts that bear the respective imbalance masses are coupled to one another by a gear mechanism, and are capable of being driven via a common drive. The gear mechanism enables a positive coupling, so that the relative phase position of the individual imbalance shafts or imbalance masses to one another is known at all times and can be maintained. The phase modification devices then need merely carry out the required modifications of the phase position relative to a defined, known initial phase position.
[0039] Advantageously, the imbalance shafts are situated in a star-shaped pattern around a central axis that is vertical relative to the soil contact plate, in such a way that the axes of rotation of the imbalance masses intersect the central axis. The gear mechanism has two central bevel gears that are situated on the central axis coaxially one over the other and that are oriented toward one another and are driven by the drive. Each of the imbalance shafts bearing an imbalance mass has allocated to it a drive bevel gear that meshes with one of the central bevel gears in order to drive the respective imbalance shaft. With the exception of one of the imbalance shafts, which bears the reference imbalance mass, the other imbalance shafts should be provided with a phase adjustment device in the flow of torque between the drive bevel gears and the respective imbalance mass, in order to enable modification of the rotational position of the imbalance mass, or of the imbalance shaft bearing it, relative to the other imbalance masses.
[0040] With the aid of the central bevel gears, a central drive is provided from which the imbalance shafts extending away from the central axis in a star-shaped pattern can obtain their drive energy. In this way, using a minimum number of gears a gear mechanism can be realized that distributes the drive energy from a single drive to the various imbalance shafts.
[0041] It is particularly advantageous if one of the drive bevel gears meshes with one of the central bevel gears, while the next (seen in the circumferential direction of the central bevel gears) drive bevel gear meshes with the other central bevel gear. The drive bevel gears should be situated between the central bevel gears. Due to the alternation of the sides at which the drive bevel gears mesh with the respectively allocated central bevel gear, it is possible to achieve a positively coupled rotational movement, in opposite directions, of the adjacent imbalance shafts.
[0042] In another specific embodiment, only one bevel gear is situated on the vertical central axis as a central bevel gear. The respectively desired change of direction from one shaft to the adjacent shaft is achieved by a reverse gear that is allocated to every second shaft. Planetary drives have proven particularly suitable for this. In such drives, the direction of rotation can be achieved by blocking the ring gear or the pinion cage that bears the planet gears. The desired phase adjustment is then possible in a known manner by rotating the blocked element (ring gear or pinion cage).
[0043] These and additional advantages and features of the present invention are explained in more detail below on the basis of examples, with the aid of the accompanying Figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 shows a schematic side view of a vibrating plate according to the present invention;
[0045] FIG. 2 shows a top view of a soil contact plate having a vibration exciter device according to a first specific embodiment of the present invention, in a vibrating plate according to the present invention;
[0046] FIG. 3 shows a schematic section through an individual exciter used in the vibration exciter device of FIG. 2 ;
[0047] FIG. 4 shows a top view of a soil contact plate having a vibration exciter device according to a second specific embodiment of the present invention;
[0048] FIG. 5 shows a top view of a soil contact plate having a vibration exciter device according to a third specific embodiment of the present invention;
[0049] FIG. 6 shows examples of arrangements of imbalance shafts;
[0050] FIG. 7 shows a schematic top view of a soil contact plate in a fourth specific embodiment of the present invention;
[0051] FIG. 8 shows a section through the top view of FIG. 7 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0052] FIG. 1 shows a schematic side view of a vibrating plate for soil compaction, having a lower mass 1 and an upper mass 2 . Lower mass 1 is elastically coupled to upper mass 2 via a spring device 3 , so as to be capable of motion. Spring device 3 can have e.g. rubber elements that are attached between lower mass 1 and upper mass 2 .
[0053] Lower mass 1 has a soil contact plate 4 that stands in contact with the soil that is to be compacted and that bears a vibration exciter device 5 . Vibration exciter device 5 produces vibrations that are introduced into soil contact plate 4 and that are used on the one hand for soil compaction, and on the other hand for steering and propulsion of the vibrating plate.
[0054] A drawbar 6 for operator guidance is attached to upper mass 2 . Alternatively, or in addition, the vibrating plate can also be remotely controlled, so that no drawbar 6 is required.
[0055] In some circumstances, upper mass 2 also has as a component a drive, e.g. an internal combustion engine, that produces the energy required to drive vibration exciter device 5 . The energy is transmitted mechanically (e.g. via a belt drive), hydraulically (using a hydraulic pump), or electrically (using a generator driven by the drive) to vibration exciter device 5 , where imbalance shafts are driven rotationally in a known manner.
[0056] In the case of a mechanical transmission of the drive energy, it is sufficient to couple the drive side of the belt drive to at least one of the imbalance shafts that is connected via a gear mechanism to the other imbalance shafts. For the case (explained in more detail below on the basis of FIGS. 7 and 8 ) of an arrangement of a drive motor having a vertical driven shaft, it is possible to provide a compensating coupling between the vertical driven shaft coming from the motor and a drive shaft to which there is attached at least one central bevel gear (explained in more detail below). In this way, the central bevel gear can be driven directly by the motor.
[0057] In the case of a hydraulic transmission of energy, the hydraulic pump on the upper mass is used to produce a hydraulic pressure that sets the respective imbalance shafts into rotation via one or more hydromotors on the lower mass. In the case of an electrical transmission of energy, the electrical energy produced by the generator is transmitted to electric motors that set the imbalance shafts coupled to them into rotation.
[0058] FIG. 2 shows a schematic representation of a top view of soil contact plate 4 , on which four individual exciters 7 are arranged at angles to one another, forming vibration exciter 5 .
[0059] The two front (seen in the direction of travel X) individual exciters 7 are arranged at an obtuse angle to one another, while individual exciters 7 situated one after the other form acute angles to one another with regard to their axes of rotation 17 .
[0060] FIG. 3 shows a sectional view of the schematic design of an individual exciter 7 .
[0061] An imbalance shaft 9 is rotationally mounted in a tube-shaped housing 8 . Imbalance shaft 9 bears an imbalance mass 10 .
[0062] Imbalance shaft 9 is rotationally driven by a hydraulic motor 11 . Hydraulic fluid is supplied to hydraulic motor 11 via a hydraulic line 12 from a hydraulic supply (not shown). The hydraulic supply can be situated essentially on upper mass 2 in the vibrating plate. A component of the hydraulic supply is e.g. a diesel, gasoline, or electric unit that drives a hydraulic pump. The hydraulic pump produces a hydraulic pressure in a hydraulic fluid that can be stored in a hydraulic storage device. In addition, a hydraulic supply container must be provided for collecting and storing the hydraulic fluid. Due to the strong vibrations in lower mass 1 , it is useful for most of the components of the hydraulic supply to be situated in upper mass 2 , which is decoupled in terms of vibration from lower mass 1 . In this way, it is then further required only to create a connection of the hydraulic supply to hydraulic motor 11 , using hydraulic line 12 .
[0063] Downstream from hydraulic motor 11 there is situated a hydraulic valve 13 that acts as an actuating element that controls the flow of hydraulic fluid to hydraulic motor 11 , and thus influences the rotational speed of hydraulic motor 11 . Of course, hydraulic valve 13 can also be situated upstream from hydraulic motor 11 .
[0064] At an end of imbalance shaft 9 situated opposite hydraulic motor 11 , there is situated a position sensor 14 . Position sensor 14 (e.g. a device for acquiring the angle of rotation) is able to acquire the position of imbalance shaft 9 in at least one position. This can take place for example optically, magnetically, inductively, or capacitively. From the possibility of acquiring the position of imbalance shaft 9 at least one time during a rotation thereof, the rotational speed and the phase position of imbalance shaft 9 can be determined. In addition, it is straightforwardly possible to determine the position of imbalance shaft 9 with sufficient precision at any time using interpolation over time.
[0065] The position of imbalance shaft 9 is important because imbalance mass 10 carried by it produces a strong centrifugal force effect during rotation. The centrifugal force of imbalance mass 10 works together with the centrifugal forces of the other individual exciters 7 ( FIG. 2 ) that belong to the vibration exciter device, thus producing an overall resultant force effect that determines the movement behavior of soil contact plate 4 charged by individual exciters 7 . Soil contact plate 4 can move in the desired manner only when both the rotational speeds of imbalance shafts 9 and also their phase positions are precisely coordinated to one another.
[0066] The vibration exciter device according to the present invention has at least four of these individual exciters 7 that are situated on soil contact plate 4 in a suitable manner. Possible specific embodiments are described below.
[0067] Individual exciter 7 shown in FIG. 3 also has a controller 15 that evaluates the signal produced by position sensor 14 and determines at least the rotational speed and/or the position of imbalance mass 10 relative to a particular point in time (phase position).
[0068] In addition (as explained in more detail below), controller 15 receives a target value signal 16 that prespecifies the required target rotational speed or target phase position. Controller 15 controls hydraulic valve 13 in accordance with this signal in order to achieve the desired rotational speed and phase position of imbalance shaft 9 or imbalance mass 10 , with the aid of hydraulic motor 11 .
[0069] As shown in FIG. 2 , according to the present invention at least four individual exciters 7 , each having an imbalance shaft 9 and an imbalance mass 10 borne thereby, are to be arranged in a suitable manner. “In a suitable manner” here means that the axes of rotation 17 of at least two of the imbalance masses 10 or imbalance shafts 9 must stand at an angle to the axes of rotation 17 of the other imbalance masses 10 . In the example shown in FIG. 2 , it can be seen that two pairs of individual exciters 7 are situated such that the axes of rotation 17 of their respective imbalance masses 10 are situated parallel to one another and axially offset from one another. Imbalance shafts 9 or imbalance masses 10 that stand parallel to one another, or axially offset to one another or coaxially to one another, are not regarded as “standing at an angle” to one another. An angled arrangement presupposes that the axes of rotation 17 of two imbalance shafts 9 have an angle to one another other than 0° or 180°. This is the case for each of two pairs of individual exciters 7 in the specific embodiment according to FIG. 2 . The arrangement shown in FIG. 2 is also regarded as “star-shaped,” although the axes of rotation 17 of individual exciters 7 do not intersect in one point.
[0070] Controllers 15 of individual exciters 7 can be coupled to one another via a central control device (not shown). The central control device specifies the target value signals 16 for the separate individual exciters 7 . Each controller 15 then ensures, for the individual exciter 7 allocated to it, that imbalance shaft 9 behaves in the desired manner. The target value signals 16 specified by the central control unit can be distinguished for each of the individual exciters 7 . Essential distinguishing parameters include target rotational speed, target phase position, and target direction of rotation. The modification of the direction of rotation is optional, and requires additional constructive outlay in the realization of hydraulic motor 11 or of hydraulic valve 13 . In the normal case, no modification of the direction of rotation will be required.
[0071] Alternatively, an individual exciter can also be provided that does not have an individually allocated controller 15 . In this case, the signals from position sensors 14 of the various individual exciters 7 are sent to a central controller (not shown) that evaluates all the signals from all the individual exciters 7 . The central controller then correspondingly carries out individual controlling of each hydraulic valve 13 in order to achieve the desired behavior of imbalance shaft 9 individually for each individual exciter 7 .
[0072] The central control unit or central controller contains suitable operating or travel programs with which the travel and vibration behavior of the vibrating plate desired by the operator and specified via operating elements (remote control, operating lever, buttons) can be converted into control specifications for the individual exciters. If, for example, the operator wishes to carry out a transition from standing compaction of the vibrating plate to forward travel, the central control unit or central controller brings about an adjustment of the phase position in at least one of the individual exciters 7 , causing a change in the direction of action of the resultant overall force.
[0073] For reliable normal operation, it is desirable for imbalance shafts 9 to rotate with exactly the same rotational speed, as far as possible. Because, however, the position of imbalance shafts 9 is also constantly monitored, deviations in the rotational speed can be corrected at any time in order to maintain the desired phase position between imbalance shafts 9 . A progressive deviation of the rotational speed is thus excluded.
[0074] FIG. 4 shows another specific embodiment of the present invention, in the form of differently arranged individual exciters 7 on soil contact plate 4 . In the center, six individual exciters 7 are arranged in a star-shaped pattern around a central axis (vertical axis) in such a way that the axes of rotation 17 of the individual imbalance shafts intersect in a point 18 . In addition, additional individual exciters 19 are situated on soil contact plate 4 , each producing, with their imbalance shafts, force actions in main travel direction X or in the opposite direction in order to support the travel motion of the vibrating plate. With the aid of individual exciters 7 , arranged in a star-shaped pattern, it is possible, by producing a yaw moment about the vertical axis running through point 18 , to steer the vibrating plate or to move it in a direction transverse or oblique to main direction of travel X. With corresponding controlling, it is thus possible to cause the vibrating plate to travel over the ground in any direction, with any orientation.
[0075] FIG. 5 shows another specific embodiment of the present invention, in which the individual exciters 7 are arranged on soil contact plate 4 in such a way that the axes of rotation 17 of the respective imbalance shafts are oriented parallel, perpendicular, or at an angle to main direction of travel X. As a result, it is possible to achieve travel characteristics similar to those of the vibrating plate according to FIG. 4 . In the selection of the arrangement, almost any possibilities are available to someone skilled in the art, because, due to the hydraulically driven and individually controllable individual exciters 7 , he is not bound to a mechanical coupling. Rather, he can situate individual exciters 7 , each representing a complete unit, arbitrarily on soil contact plate 4 . The controlling, in the form of the central control unit or central controller, is then to be programmed in a manner that takes into account the arrangement of the individual exciters 7 or 19 .
[0076] FIG. 6 shows, in a schematic top view, further possibilities for the arrangement of individual exciters 7 on soil contact plate 4 . For simplification, individual exciters 7 are depicted only as lines that coincide with the axes of rotation of the imbalance shafts or imbalance masses.
[0077] In FIG. 6 a , correspondingly, the imbalance shafts of some of the individual exciters 7 are arranged in parallel, axially offset, coaxially, and/or at an angle to one another.
[0078] In FIG. 6 b , in addition to the “normal” individual exciters 7 , reinforced individual exciters 20 are provided that preferably rotate with the same rotational speed and that have imbalance shafts having larger (in terms of mass) imbalance masses. Correspondingly, reinforced individual exciters 20 are symbolically shown not as lines but as elongated boxes.
[0079] Reinforced individual exciters 20 can be used predominantly to achieve a reinforced compaction effect or a more rapid forward and backward travel. Correspondingly, the normal individual exciters 7 , or the exciters having smaller imbalance masses, are provided for the steering of the vibration plate. The imbalance shafts provided in reinforced individual exciters 20 , having larger imbalance masses, can however be replaced by “normal” individual exciters 7 if, for example, a plurality of individual exciters 7 are provided one after the other and parallel to one another.
[0080] In FIG. 6 c , five individual exciters are arranged on soil contact plate 4 , i.e. four “normal” individual exciters 7 and a reinforced individual exciter 20 whose imbalance mass has twice the mass of an imbalance mass of an individual exciter 7 . Individual exciters 7 , 20 , whose axes of rotation are perpendicular to main direction of travel X, are responsible for the propulsion or rearward travel of the vibrating plate, while the two exciters 7 , whose axes of rotation extend in direction of travel X, bring about transverse travel or steering of the vibrating plate.
[0081] Similar to FIG. 2 , FIG. 7 shows a schematic top view of soil contact plate 4 , on which four individual exciters are placed in a star-shaped arrangement. In contrast to the specific embodiment of FIG. 2 , however, here the individual exciters 7 are not driven hydraulically, but rather are mechanically coupled to one another positively via a gear mechanism 21 .
[0082] FIG. 8 shows a sectional representation of the vibrating plate of FIG. 7 , along section line A-B.
[0083] In the center of the star-shaped arrangement of individual exciters 7 there extends a vertical central axis 22 about which a drive shaft 23 rotates. On drive shaft 23 there are attached two central bevel gears that are situated coaxially one over the other and are oriented toward each other, i.e. an upper central bevel gear 24 and a lower central bevel gear 25 . Drive shaft 23 , with the two central bevel gears 24 , 25 , is driven via a hydraulic motor 26 that is situated thereabove, to which hydraulic fluid under pressure is supplied by the drive situated on upper mass 2 .
[0084] Instead of hydraulic motor 26 , an internal combustion engine can also be provided whose preferably vertical driven shaft is coupled directly to drive shaft 23 via an elastic coupling. In this way, it is possible for the motor to drive drive shaft 23 with central bevel gears 24 , 25 without the intermediate connection of a gear mechanism or hydraulic system.
[0085] Each imbalance shaft 9 of the individual drives 7 has, on its end facing housing 21 , a drive bevel gear 27 . The individual drives 7 can, with their imbalance shafts 9 , be arranged on soil contact plate 4 so as to be alternately somewhat raised and somewhat lowered (offset in each case by the module of the toothing), so that the drive bevel gears mesh, in alternating fashion, with upper central bevel gear 24 and with lower bevel gear 25 . This means that over the circumference of central axis 22 , and thus along the circumference of central bevel gears 24 , 25 , in alternating fashion a drive bevel gear 27 meshes with upper central bevel gear 24 , and the next following drive bevel gear 27 meshes with lower central bevel gear 25 . In this way it is achieved that each pair of adjacent imbalance shafts 9 , regarded along the circumference, rotate in opposite directions.
[0086] Due to the positive coupling of the individual imbalance shafts 9 via gear mechanism 21 , a precise phase position relative to one another of the individual imbalance masses 10 is achieved at all times.
[0087] In order to enable controlling of the vibrating plates, it is necessary to adjust the phase positions of the individual imbalance masses relative to the phase positions of the other imbalance masses. For this purpose, three of the individual exciters 7 have a phase adjustment device. Fourth individual exciter 7 then does not require a phase adjustment device, so that its imbalance mass is designated reference imbalance mass 28 . Reference imbalance mass 28 is coupled to hydraulic motor 26 directly and unalterably via gear mechanism 21 (positive rotational coupling). Accordingly, no modification is possible of the phase position of reference imbalance mass 28 to the motor shaft of hydraulic motor 26 or to drive shaft 23 .
[0088] In contrast, the phase position of the imbalance masses 10 of the other individual exciters 7 can be modified relative to the phase position of drive shaft 23 , and thus relative to reference imbalance mass 28 , with the aid of the respective phase adjustment device. Each of the other individual exciters 7 thus has a phase adjustment device allocated to it individually.
[0089] As phase adjustment devices, e.g. turning sleeves, as known from the prior art (e.g. EP 0 358 744 A1), are suitable. However, other constructions of phase adjustment devices are also conceivable. The important thing is only that it be possible to adjust the phase position of the relevant imbalance shaft or imbalance mass individually, relative to the phase position of central drive shaft 23 .
[0090] The phase adjustment device can have for example an actuator unit 29 via which a modification of the phase position of the imbalance mass inside the respective individual exciter 7 is carried out mechanically, electrically, or hydraulically. Here it is also possible to realize a phase adjustment device via intermediate connection of a planetary drive and targeted blocking or rotation of blocked elements (ring gear, pinion cage).
[0091] The coordination of the phase adjustment devices can be carried out manually by the operator, but can also be carried out by a central control device or central controller as described above.
[0092] The desired travel behavior of the vibrating plate is achieved through the interaction of the various imbalance masses 10 in the individual exciters 7 .
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A vibrating plate for compacting soil comprises an upper mass; a lower mass, which is elastically coupled to the upper mass and which has at least one soil contact plate, and; a vibration generator device that acts upon the soil contact plate. The vibration generator device comprises at least four unbalanced masses that can each be rotationally driven about a rotation axis, the rotation axis of at least two of the unbalanced masses being arranged at an angle to the rotation axes of the other unbalanced masses. One of the unbalanced masses depicts a reference unbalanced mass that does not require its own phase adjusting device. On the other hand, a separate phase adjusting device is assigned to each of the other unbalanced masses, enabling the phase position of these unbalanced masses to be individually adjusted with regard to the reference unbalanced mass.
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CROSS REFERENCE TO RELATED APPLICATIONS
Reference is made to commonly-assigned copending U.S. patent application Ser. No. 14/181,909, filed Feb. 17, 2014, entitled PDMS IMPRINTING STAMP WITH EMBEDDED FLEXURE, by Palone; U.S. patent application Ser. No. 14/085,006, filed Nov. 20, 2013, entitled NON-DEFORMABLE PATTERNED TEMPLATE, by Palone; and U.S. patent application Ser. No. 14/085,042, filed Nov. 20, 2013, entitled METHOD FOR FORMING A NON-DEFORMABLE PATTERNED TEMPLATE, by Palone; the disclosures of which are incorporated herein.
FIELD OF THE INVENTION
This invention relates in general to imprinting with a patterned elastomeric stamp and in particular to deforming the stamp to bring a portion of the stamp in contact with a surface to be stamped.
BACKGROUND OF THE INVENTION
Nanoimprint lithography is a method of fabricating nanometer scale patterns by mechanical deformation of imprint resist and subsequent processing. The imprint resist can be a thermally softened or photo-initiated liquid coating that is cured by heat or UV light during the imprinting. A template is brought into contact with the liquid coating and the liquid is cured. The cured liquid includes an imprint of any patterns formed in the template. Alignment of the template with the substrate is performed prior to curing the liquid as described in U.S. Pat. No. 6,916,584. Adhesion between the resist and the template must be controlled to allow proper release, see U.S. Pat. No. 7,157,036. The subject matter of both patents is incorporated herein.
A nano-pattern “parent” is produced using lithography on a silicon or glass parent. The parent pattern, sometimes called a positive image, is created using durable or environmentally stable materials, for example, a chrome positive created on glass. The pattern is then replicated on a liquid Polydimethylsiloxane (PDMS) layer, sometimes called a child layer or negative image. The PDMS is then cured and the final image is used as a template or stamp to reproduce the image on multiple products. The PDMS child pattern is then replicated onto another liquid layer, for example an epoxy-based negative photoresist (SU-8), re-creating the original positive image. SU-8 can be hardened using a combination of light and heat.
Despite the good properties of PDMS, there is a possibility of mechanical stress and thermal expansion causing errors in the moldable layer. As a result, U.S. Pat. No. 7,704,425 teaches performing all processing steps when using the stamp to transfer a pattern to a substrate at a constant control temperature, which is inconvenient in a manufacturing environment.
Wilhelm (Thesis, Massachusetts Institute of Technology, June 2001) teaches casting the stamp around spring steel. As a result of the stresses, however, and under repeated bends, separation of the elastomer from the substrate or steel will occur resulting in waste and short life for the template. Wilhelm also identifies a significant problem with stamping using a flat fixed stamp with air bubbles. Air bubbles trapped between the stamp and the liquid substrate which receives the pattern transfer, prevents good contact between the stamp and substrate thereby resulting in pattern transfer defect. Wilhelm suggests a stiff bowed stamp as a solution. The bow in the stamp shape can help to push the air bubbles formed out from the center of the stamp. There is, however, a problem, there is too much contact force in the center of the stamp, where the stamp is at maximum height and poor pattern transfer at the edges of the stamp where the stamp is a minimum height. Wilhelm suggests the use of a thin flexible stamp to avoid the pattern transfer issues, but that results in wrinkles and poor pattern transfer.
What is needed is a reinforced elastomeric template or stamp. It must be resistant to mechanical stress and thermal expansion and have excellent durability. For UV curing during the pattern transfer process, the stamp must pass light even with the reinforcing substrate in place. Finally, the stamp must be able to take some curvature during its use to avoid the formation of bubbles and have a well controlled contact profile to avoid loss of quality due to failure to transfer the pattern in areas of excessive or insufficient contact.
SUMMARY OF THE INVENTION
Briefly, according to one aspect of the present invention a system for imprinting includes a polymer stamp having a surface pattern and an imbedded mesh, wherein the mesh is resistant to deformation in the x-direction and y-direction (lateral directions (width and length) of the mesh) and flexible in the z-direction (vertical direction); a means for applying a force to the polymer stamp wherein the force deforms the stamp and brings a portion of the stamp in contact with a surface to be stamped; and wherein increasing the force to brings the entire surface pattern in contact with the surface to be stamped. The structure of the pattern of openings causes the mesh to function as a flexure such that, in one embodiment, the effect of the applied force is to create a linear contact pattern. In another embodiment, the pattern of openings is such that the effect of the force is to create a circular point contact pattern.
In other embodiments, the imbedded mesh can be heated to assist with pattern transfer and curing. The heat can be provided by heating the stamp by conductive heating. In another embodiment, the heat is applied by the force, wherein the force is comprised of a hot liquid or gas under pressure.
The structure of the pattern of openings that causes the mesh to function as a flexure can be concentric arc sections cross-hatch, hexagonal, diamond-shaped, circular, or oval.
The invention and its objects and advantages will become more apparent in the detailed description of the preferred embodiment presented below.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the finished stamp with stable mesh and a surface pattern cast by the mold.
FIG. 2 shows the stable mesh in a circular flexure embodiment.
FIG. 3 shows the stable mesh in a linear flexure embodiment.
FIGS. 4A and 4B show the stable mesh with resistive heating.
FIGS. 5A and 5B show the stable mesh with inductive heating.
FIGS. 6A and 6B show the stable mesh with contact heating.
FIG. 7 shows the replication process flow diagram.
FIGS. 8A and 8B show the flexure behavior when force is applied to the stable mesh with a linear flexure.
FIGS. 9A and 9B show the flexure behavior when force is applied to the stable mesh with a circular flexure.
FIGS. 10A and 10B show the stabilizing effect of the mesh on the PDMS stamp.
FIG. 11 shows the Actinic light is applied though the stable mesh and substrate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be directed in particular to elements forming part of, or in cooperation more directly with the apparatus in accordance with the present invention. It is to be understood that elements not specifically shown or described may take various forms well known to those skilled in the art.
A typical material used in nano-replication is polydimethylsiloxane (PDMS) although other materials may be suitable. The PDMS is typically degassed, then poured onto a precise lithography featured master or parent. These typically include silicon or chrome on glass masters. The PDMS stamp or child now contains the negative featured pattern of the master. Numerous low-cost PDMS child stamps can be replicated from the expensive parent master.
The resulting PDMS stamp is a low durometer polymeric sheet, which may be used as a mold or embossing stamp. The featured pattern is transferred from the PDMS stamp into a material that is thermally softened or photo-initiated, or a combination of both. The PDMS material properties are typical of an elastomer. Maintaining global registration and size with these elastomeric properties is difficult to automate in a manufacturing system. Combining a stable perforated material within the PDMS stamp's thickness results in a stamp that has the desirable properties of a polymer such as flexibility and negates the undesirable properties of a polymer such as poor dimensional stability.
The details on manufacturing a PDMS stamp with the stable mesh embedded therein is described in commonly-assigned copending U.S. patent application Ser. No. 14/085,042, by Palone; the disclosure of which is incorporated herein. Briefly, the process starts with fabricating a stable mesh component with the desired patterned opening geometry, fiducials, and system mounting holes or features. The stable mesh component can be manufactured from most any material that exhibits superior stability compared to PDMS and similar polymers. To form the mesh stabilized stamp a lithographic mold is made that is adapted to constrain and register the master (parent) inverse pattern with the stable mesh component. The stable mesh and feature master are then inserted into the polymer mold.
The stable mesh is perforated with the desired frequency and pattern of openings which the PDMS envelops and locks the stamp to the stable mesh backbone. The manufacturing process is completed by heat or photo curing the polymer and removing the completed stamp assembly with the patterned features in polymer registered to fiducially in stable mesh support. Heating may include radiation, convective, conductive, or resistive heating.
Referring now to FIG. 1 , the finished stamp 30 is shown in a detail view after removal from the mold with the stable mesh 1 and a surface pattern 33 cast by the master parent. FIG. 1 also shows a locating feature, e.g. one of the mounting holes 11 on the sides of the stable mesh that can be used with a post or a clamping feature such as a bolt going through the hole to precise register the stamp when it is used to transfer patterns to a substrate.
FIG. 2 shows a plan view of stable mesh 1 in a circular flexure embodiment. The concentric location of the stamp 30 is also shown. Around the edge of the stamp beyond the pattern of openings is the locating features 11 . The openings, in this case concentric arc sections 15 , are shown throughout the stable mesh inside the mounting portion and provide the desired circular flexure properties to movement of the stable mesh in the z-direction. The concentric arc sections also provide openings to pass actinic light as will be discussed below.
FIG. 3 shows a plan view of stable mesh 1 in a linear flexure embodiment. The central location of the stamp 30 is also shown. Around the edge of the stamp beyond the pattern of openings is the locating features 11 . The openings, in this case a pattern of linear opening 15 , are shown throughout the stable mesh inside the mounting portion and provide the desired linear flexure properties to movement of the stable mesh in the z-direction. Optionally, additional openings 15 ′ can be provided in the flexure material to pass actinic light as will be discussed below.
During the operation of using the polymer stamp 30 to transfer a pattern to substrate as a mold or embossing stamp, the featured pattern is transferred from the stamp to a material that is thermally softened or photo-initiated, or a combination of both. Therefore, it is highly desirable to heat or warm the stamp to its operating temperature, which is usually above room temperature. It is also important to maintain the temperature in a controlled manner during curing of the material that is receiving the transferred pattern. FIGS. 4A and 4B show plan and side views of the stable mesh 1 with electrical connections 18 that will allow the user to pass a current though the metal structure of the stable mesh to resistively heat the stable mesh. Suitable sensors (not shown) and a control system (not shown) can be provided to maintain a constant temperature during operations, e.g. curing.
FIGS. 5A and 5B show plan and side views of the stable mesh 1 with an alternate embodiment for heating. An induction coil is provided to stimulate eddy currents in the metal material of the stable mesh. As is well known, these currents will result in heat generated in the mesh. Suitable sensors (not shown) and a control system (not shown) can be provided to maintain a constant temperature during operations, e.g. curing.
FIGS. 6A and 6B show plan and side views of the stable mesh 1 with an alternate embodiment for heating. It is a common practice to apply pressure to pattern transfer mesh for pattern transfer by a piston or bladder that itself can be heated using heated liquid or gas 24 . The contact with pressure by a hot surface will cause contact heating to occur in the stable mesh. In this case, the use of a constant temperature fluid or can be provided to maintain a constant temperature during operations, e.g. curing.
FIG. 7 describes the operation of the stamp for pattern transfer. The substrate is prepared 110 to receive the pattern, for example by spin coating a curable liquid polymer on the substrate. The stamp is positioned 120 for contact with the substrate. The system is heated and pressure applied 130 to contact the substrate by the stamp. The stamp bends 135 as proscribed by the flexure design on the stable mesh and initial contact 137 is made. The force is increased 140 causing the stamp to further move into contact with the substrate without excessive increase in the pressure or engagement of the stamp with the substrate in the region of initial contact. As this happens bubbles are eliminated or prevented in the contact region. Finally, the entire surface area achieves contact 145 with the substrate and the system is held at a constant temperature for curing. Actinic light is applied 147 though the stable mesh and substrate to assist with curing if needed. After curing is complete, the pressure is removed 150 and the stamp is removed 155 from contact with the substrate leaving behind an inverse pattern on the surface of the substrate.
FIGS. 8A and 8B illustrates the action of steps 130 - 145 when applied to a stamp with an imbedded linear flexure stable mesh in plan and perspective view. FIG. 8A is the plan view with the initial linear contact area 12 and the fully formed contact area 4 indicated. FIG. 8B shows the perspective view at position A-A from FIG. 8A . FIG. 8B shows the initial linear contact region 12 and the shape of the stamp 38 that results from the initial application of pressure 130 , 29 through the linear flexure 15 . The increased force 140 results in the stamp shape 46 and the flexure controlled contact of the stamp surface contact area 4 with the substrate.
FIGS. 9A and 9B illustrate steps 130 - 145 when applied to a stamp with an imbedded circular flexure stable mesh in plan and perspective view. FIG. 9A is the plan view with the initial point contact area 6 and the fully formed contact area 4 indicated. FIG. 9B shows the perspective view resulting from a perspective that goes though the center of the circular mesh. FIG. 9B shows the initial linear contact region 6 and the shape of the stamp 38 that results from the initial application of pressure 130 , 29 through the circular flexure opening 15 . The increased force 140 results in the stamp shape 46 and the flexure controlled contact of the stamp surface contact area 4 with the substrate.
Referring now to FIGS. 10A and 10B , the stabilizing effect of the mesh on the PDMS stamp will now be shown. The stable mesh is strongly resistant to deformation due to changes in temperature or moisture content of the stamp in response to environment or applied heat including radiation, convective, conductive, or resistive heating. Here, deformation refers specifically to changes in dimension or strains in the lateral directions (width and length) of the mesh (x-direction and y-direction). The post structures 5 between the holes of the stable mesh act to constrain and stabilize the polymer material, PDMS for example, of the stamp, also in the lateral directions (width and length). FIGS. 10A and 10B shows how the stamp 30 looks in an extreme close-up view where induced strains are greatly exaggerated for this discussion. In FIG. 10A the stamp is in a unstressed state where the temperature of the stamp is close to room temperature and the polymer is flat and straight as shown for the surface pattern surface 35 . When the stamp, including the polymer and the stable mesh, is heated up, for example, in response to applied radiation, the polymer with a relative large CTE will attempt to expand. The resulting strain is constrained by the stable mesh structures and only very small deviations, such as the dilated surface structure 36 as shown in FIG. 10B will occur above the stable mesh openings 15 . The relatively small openings will greatly limit the maximum extent of the strain of the polymer surface.
FIG. 11 illustrates the action of steps 145 - 155 when applied to a stamp with an imbedded linear flexure stable mesh in perspective view. The entire surface area achieves contact 145 with the substrate and the system is held at a constant temperature for curing. The polymeric stamp 30 is shown in contact with a receiver substrate 40 which has a thermally softened or photo-initiated liquid coating 42 configured to receive the pattern transfer from the stamp. The surface pattern 33 is transferred to the receiver substrate by the application of pressure. Actinic light is applied 147 though the stable mesh and substrate to assist with curing if needed. The receiver substrate 40 is cured while the stamp is in contact by, for example, the application of actinic light from a light source 50 . As shown, the actinic light can pass through the openings in the stabilizing mesh. The mesh is transparent to allow actinic radiation. The ability to cure in place is an important advantage of the stable mesh and allows for the formation of high relief structures by stamping without suffering from reflow. After curing is complete, the pressure is removed 150 and the stamp is removed 155 from contact with the substrate leaving behind an inverse pattern on the surface of the substrate.
As shown, the actinic light can pass through the openings in the stabilizing flexural mesh. The ability to cure in place is an important advantage of the stable flexural mesh and allows for the formation of high relief structures by stamping without suffering from reflow.
The following are additional feature that are not yet claimed: the stable mesh may contain mounting holes for mounting and/or tension; the perforated openings geometries are unlimited, depending on intended function; the perforated opening can vary within the stable mesh, such as the tiled smaller high-density configurations within the macro perforated sheet; the stable mesh openings may consist of geometry patterns, resulting in a defined flexural movement of the stable mesh backbone; combining this with the elastomeric properties of the PDMS, the combination may be used as a pneumatic piston to actuate the stamp, while maintaining spatial accuracy of the embossed pattern; when embossing or molding a photo curable polymer, a minimum open area is required to achieve the proper dose of radiation to cure the embossed substrate; when the stable mesh is made of a metal or reflectively coated plastic, once the radiation passes through the plurality of opening, the reflective surface may aid in cross-linking the polymer by total internal reflection.
It is conceivable to have multiple discrete polymer stamps molded onto the stable mesh backbone, where the solid backbone areas in between the stamp regions block the radiation from hitting the substrate.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the scope of the invention.
PARTS LIST
1 stable mesh
4 contact area
5 structures
6 contact area
11 mounting holes
12 initial linear contact area
15 opening
15 ′ opening
18 electrical connections
24 applied pressure
29 applied pressure
30 finished stamp
33 surface pattern
35 surface pattern surface
36 dilated surface structure
38 stamp
40 receiver substrate
42 photo-initiated liquid coating
46 stamp shape
50 light source
110 substrate prepared
120 stamp positioned
130 heat and pressure applied
135 stamp bends
137 initial contact made
140 force increased
145 surface area achieves contact
147 actinic light applied
150 pressure removed
155 stamp removed
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A non-deformable patterned template includes a stable mesh, wherein the stable mesh is resistant to deformation; a polymer sheet with the stable mesh embedded therein, wherein the polymer sheet is formed using a liquid polymer adapted to receive the stable mesh, and wherein the liquid polymer is cured after the stable mesh has been placed within the liquid polymer; and a surface pattern on at least one face of the polymer sheet.
| 1 |
This application is a continuation of application Ser. No. 780,770 filed 09/27/85.
BACKGROUND OF THE INVENTION
The present invention relates generally to phosphatidyl choline compounds useful as pharmaceuticals which are analogs of 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, also known as platelet activating factor or PAF-acether.
Platelet activating factor (PAF-acether) is a potent mediator of anaphylaxis and inflammation. Among its physiological effects are activation of blood platelets and neutrophils and antihypertensive activity related to effects on smooth muscle cells.
Phospholipase A 2 is a phospholipid-hydrolyzing enzyme which is involved in the physiological response to PAF-acether. Inhibitors of this enzyme are useful in regulating various aspects of phospholipid biochemistry in vivo.
Tence et al., Biochimie 63: 723 (1981), disclose fourteen structural analogs of PAF-acether which are tested for platelet aggregating activity. Although several of the compounds tested were active, none contained a sulfur at the C-1 position nor a nitrogen at the C-2 position of the glycerol. This reference suggests that an ether linkage at position C-1 of the sn-glycerol and a short acyl chain at position C-2 are required for activity.
Hadvary et al., Thrombosis Research 30: 143 (1983), disclose structures of 26 synthetic analogs of PAF-acether and the relative activities of the disclosed compounds in triggering aggregation of rabbit and human platelets. All analogs disclosed were characterized by an ether-alkyl linkage at the C-1 position. Of the compounds tested, only those having short chain ester moieties at the C-2 position were active. Replacement at the C-2 position by formyl as well as by the butyryl esters significantly degraded activity.
Chandrakumar et al., Tetrahedron Letters 22: 2949 (1981), disclose use of serine in a synthetic method for making analogs of PAF-acether. The disclosed method yielded compounds of desired chirality for possible use as phospholipase inhibitors. Synthesis of 1-O-acetoalkyl-2-palmitoylamido-2-deoxy-3-O-phosphorylcholine is disclosed. No results of biological testing are provided.
Betzing et al., European Published Patent Application No. 43,472 (1981), disclose analogs of PAF-acether having a thioether linkage at position C-1 of the glycerolphosphorylcholine nucleus. These compounds exhibited anti-hypertensive activity.
SUMMARY OF THE INVENTION
The present invention provides compounds of the formula ##STR1## and physiologically acceptable salts thereof, wherein
R 1 is C 1 -C 25 alkyl, C 1 -C 25 alkenyl, C 6 -C 30 aryl, or C 7 -C 30 aralkyl or alkaryl; and
R 2 is hydrogen, C 1 -C 25 alkyl, C 6 -C 30 aryl, C 7 -C 30 aralkyl or alkaryl, C 1 -C 25 alkoxy, C 1 -C 25 alkenyloxy, C 6 -C 30 aryloxy, or C 7 -C 30 aralkyloxy or alkaryloxy.
The present invention also provides therapeutic compositions comprising the foregoing compounds, and methods for using the compositions to inhibit phospholipase A 2 activity, alleviate hypertension, and alleviate inflammation in warm-blooded animals.
The present invention also provides a process for preparing the compounds of the invention, comprising
(a) protecting an acid salt of
(L)-methylserate by reaction with an ethyl benzimidate salt in the presence of base to yield a
(D)-2-phenyl-4-carbomethoxy-4,5-dihydro-oxazole ester 3 of formula ##STR2## (b) reducing the ester 3 by treatment with lithium aluminum hydride to provide an alcohol 4 of formula ##STR3## (c) reacting the alcohol 4 with a methanesulfonyl compound to provide a chiral mesylate compound 5 of formula ##STR4## (d) displacing the mesylate group of compound 5 with a sodium alkylthiolate, optionally via a thioacetate intermediate, to provide a thioether 7 of formula ##STR5## (e) reacting the thioether 7 with acetic anhydride to provide a 2-acetamido-3-benzoate, and cleaving the benzoate by base hydrolysis to yield a 3-substituted-thioester-2-acetamido-glycerol 8 of formula ##STR6## (f) phosphorylating the glycerol 8 to provide a cyclic triester phosphate 9 of formula ##STR7## (g) reacting the cyclic triester phosphate 9 with trimethylamine to provide a compound 10 of formula I;
or, in the alternative,
(e') reacting the thioether 7 with sulfuric acid to provide an amino alcohol 11 of formula ##STR8## (f') acylating the alcohol 11 with an R 2 -substituted acylating agent and subjecting the resulting acyl intermediate to base hydrolysis to provide an amino-glycerol 12 of formula ##STR9## (g') phosphorylating the amino-glycerol 12 to provide a cyclic triester phosphate 9a of formula ##STR10## (h') reacting the cyclic triester phosphate 9a with trimethylamine to provide a compound 10 of formula I;
wherein R 1 and R 2 are defined as in claim 1.
The present invention also provides a critical intermediate of the foregoing process, compound 7, having the formula ##STR11##
DETAILED DESCRIPTION OF THE INVENTION
The phosphatidyl choline analogs of formula I above are characterized by a thioether linkage to an alkyl, alkenyl, aryl, aralkyl, or alkaryl moiety at position C-1 of the glycerolphosphorylcholine nucleus, and by an amide linkage at position C-2. The amide bridge can link hydrogen or alkyl, aryl, aralkyl, alkaryl, alkoxy, alkenyloxy, aryloxy, alkaryloxy, or alkaryloxy groups to the glycerolphosphorylcholine nucleus.
As used throughout the specification, either individually or as part of a larger group, "alkyl" means a linear, saturated aliphatic radical. "Alkenyl" means a linear, unsaturated aliphatic radical having one or more carbon-carbon double bonds. "Aryl" means an aromatic radical, e.g., phenyl. "Aralkyl" means a linear aliphatic radical comprising an aryl group or groups. "Alkaryl" means a aryl radical having one or more linear aliphatic substituents. "Alkoxy" means an alkyl radical joined by an oxygen atom to the glycerolphosphorylcholine nucleus. Similarly, "alkenyloxy," "aryloxy," "alkaryloxy," and "alkaryloxy" mean alkenyl, aryl, alkaryl, and alkaryl radicals having an oxygen atom at the point of substitution on the parent molecule.
Preferred compounds within the scope of the present invention are those compounds of formula I wheren R 1 is C 14 -C 18 alkyl or C 14 -C 18 alkenyl, and R 2 is C 1 -C 25 alkyl, C 1 -C 25 alkoxy, or phenyl. Especially preferred are those compounds wherein R 1 is a 9Δ-C 18 H 35 alkenyl group and R 2 is methyl or phenyl; R 1 is a C 18 H 37 alkyl group and R 2 is methyl, methoxy or a C 17 H 35 alkyl group; and R 1 is a C 16 H 33 alkyl group and R 2 is methyl, methoxy, phenyl, or a C 17 H 35 alkyl group.
SUMMARY OF SYNTHETIC PROCEDURES
Processes for preparing compounds of formula I are illustrated and summarized below: ##STR12##
The objective of the first series of reactions in the general synthetic scheme is synthesis of intermediates allowing substitution of various alkyl-, alkenyl-, and aryl-thioethers at position R 1 of the final chiral phospholipid compounds of formula I. This series of reactions is illustrated in Scheme 1, above, using (L)-methylserate hydrochloride 2 as starting material. The amino alcohol of 2 is first protected by reaction with ethyl benzimidate hydrochloride 1 in the presence of base (triethylamine), providing (D)-2-phenyl-4-carbomethoxy-4,5-dihydro-oxazole 3.
To introduce the upper side chains, two routes were devised so that both saturated (R 3 ) and unsaturated (R 4 ) alkyl chains could be accommodated. To prepare saturated thioethers, ester 3 is reduced with lithium aluminum hydride in diethyl ether to provide alcohol 4. Alcohol 4 is then mesylated with methanesulfonyl chloride to give the versatile chiral mesylate compound 5. The mesylate group of compound 5 is directly displaced with saturated sodium alkylthiolates by adding the alkyl mercaptans and the mesylates 5 to freshly prepared sodium methoxide in methanol, converting compound 5 into thioether 7. To prepare derivatives of compound 7 having unsaturated thioether substituents at position R 1 , preparation of thioacetate 6 is necessary. Compound 6 is obtained by incubating mesylate 5 with potassium thioacetate in acetonitrile and dimethylsulfoxide. The acetate is hydrolyzed by adding freshly generated sodium methoxide in methanol. The addition of unsaturated alkyl mesylates to the reaction mixture provides thioether 7.
With synthetic routes to a variety of alkyl-, alkenyl-, aryl-thioethers complete, amino substitution is addressed as illustrated in Scheme 2, below. In this series of reactions, the protection of phenyl-4,5-dihydro-oxazole is removed and substitution is performed simultaneously. ##STR13##
This is accomplished by adding acetic anhydride to an aqueous acetic acid solution of 7 and refluxing for about 2 hours to generate product 2-acetamido-3-benzoate. Cleavage of the benzoate by base hydrolysis (LiOH) provides the requisite 3-(alkyl, alkenyl, aryl)-thioester-2-acetamido-glycerol 8 in good yield.
The (alkyl, alkenyl, aryl)-thioester-2-acetamido-glycerol 8 is phosphorylated in tetrahydrofuran with 2-chloro-2-oxo-1,2,3-dioxaphospholane in the presence of triethylamine. The resulting cyclic triester phosphate 9 is then exposed to excess trimethylamine for 48 hours at about 65° C., yielding the desired acetamido phospho-lipid 10.
Alternative procedures for amino substitutions are shown in Scheme 3, below. ##STR14##
As indicated in Scheme 3, the protection of phenyl-4,5-dihydro-oxazole 7 is removed with sulfuric acid to give amino alcohol 11. Acylation of amino alcohol 11 with a variety of acylating agents (ClCO 2 CH 3 , ClCOR 2 , HCO 2 COCH 3 ; R 2 =alkyl, alkenyl, aryl) followed by selective base hydrolysis (LiOH) provides the corresponding substituted amino-glycerols 12. Elaboration to the phospholipids 13 proceeds in the same manner described for converting 8 to 10 in Scheme 2.
SYNTHETIC EXAMPLES
The following examples describe synthetic procedures employed in production of particular compounds within the scope of formula I. Unless otherwise indicated, all parts and percentages are by weight and all temperatures are reported in degrees Celsius (°C.).
The following abbreviations are employed in the examples:
NMR: Nuclear magnetic resonance spectroscopy
IR: Infrared spectroscopy
HRMS: High resolution mass spectrometry
FAB-MS: Fast atom bombardment, mass spectrometry
EA: Elemental analysis
Particular intermediates or products are identified by reference to the numbered compounds in the general synthetic procedures summarized above. Physical data for various compounds produced by procedures substantially corresponding to the description contained in each example are provided following individual examples. The following key identifies particular compounds:
______________________________________ ##STR15##First Suffix R.sup.1 Second Suffix R.sup.2______________________________________A 9Δ-C.sub.18 H.sub.35 none CH.sub.3B C.sub.18 H.sub.37 I C.sub.17 H.sub.35C C.sub.16 H.sub.33 II CH.sub.3 OD C.sub.8 H.sub.17 III HE C.sub.6 H.sub.13 IV Ph______________________________________
EXAMPLE 1
Synthesis of Compounds of Formula I
A. Preparation of Ethyl benzimidate hydrochloride (1)
Dry (distilled from sodium) ethanol (9 g) was added to freshly distilled benzonitrile (10 g). The resulting mixture was cooled to 0° and then saturated with anhydrous hydrogen chloride gas. This mixture was then allowed to stand for 18 hours, during which time tan colored crystals formed. These crystals were taken up in ether and washed several times with 2N NaOH, followed by aqueous extraction to give an oil. This oil was dissolved in dry (over sodium and benzophenone) ether (20 mL), cooled to 0°, and then exposed to anhydrous hydrogen chloride. After 2 hours, white crystals were obtained (9.4 g, 55% yield) with a melting point consistent with ethyl benzimidate hydrochloride (1) (J. Org. Chem. 30:699 (1965)).
B. Preparation of (D)-2-phenyl-4-carbomethoxy-4,5-dihydro-oxazole (3)
Ethyl benzimidate hydrochloride (1) (4.73 g) was dissolved in dry (distilled over calcium hydride) dichloromethane (250 mL). 1-Methylserate hydrochloride (2) (4.33 g) was introduced to this solution followed by dropwise addition of triethylamine (7.8 mL) which had been dissolved in dichloromethane (10 mL). The resulting reaction mixture was stirred for about 24 hours at about 23° and then concentrated in vacuo. The residue was dissolved in water (100 mL) and then extracted with ether (4×100 mL). The resulting organic extracts were combined, washed with saturated sodium chloride, and then dried over magnesium sulfate. Filtration and concentration in vacuo supplied only the desired product (D)-2-phenyl-4-carbomethoxy-4,5-dihydro-oxazole (3) (5.0 g, 87% yield).
(3): [α] 25 =+142.5°±0.8° (c=1.02, cyclohexane); +125.1°±0.8° (c=1.17, ethanol), +113.8°±0.8° (c=1.06, methanol); NMR (300 MHz CDCl 3 ): 8.00 (d, j=6 Hz, 2H, phenyl), 7.23 (m, 3H, phenyl), 5.00 (dd, j=7.0 Hz, 5.0 Hz, 1H, CHN), 4.70 (m, 2H, CH2 O ), 3.80 (s, 3H, OCH 3 ); IR (CHCl 3 ): 2920 (s) 2850 (s), 1740 (s), 1640 (s, C═N), 1370 (s), 130 (m), 1050 (s), 900 (m).
C. Preparation of (D)-2-phenyl-4-hydroxymethyl-4,5-dihydro-oxazole (4)
Crude (D)-2-phenyl-4-carbomethoxy-4,5-dihydrooxazole (5.0 g) (3) was dissolved in dry (distilled over sodium and benzophenone) diethyl ether (200 mL). This solution was cooled to 0° and kept under a nitrogen atmosphere while lithium aluminum hydride (0.44 g) was slowly added over a period of about 30 minutes. The resulting reaction mixture was then permitted to warm to about 23°, and then stirred for an additional 4 hours. Complete conversion had occurred as shown later by thin layer chromatography (TLC) analysis. The reaction mixture was then recooled to 0°, quenched by addition of sodium sulfate decahydrate (5.0 g), stirred for 1 hour, filtered and concentrated in vacuo to provide the desired (D)-2-phenyl-4-hydroxymethyl-4,5-dihydro-oxazole (4) (3.5 g, 81% yield).
(4): [α] 25 =+53.4°±0.8° (c=1.03, methanol); NMR (90 MHz, CDCl 3 ): 8.00 (m, 2H, phenyl), 7.35 (m, 3H, phenyl), 4.65 (s, 1H, OH), 4.50 (m, 3H, CH2O, CHN), 3.80 (m, 2H, CH2O); IR (neat): 3400 (bs, OH), 2900 (s), 1645 (s, C═N), 1360 (s), 1060 (s), 700 (s).
D. Preparation of mesylate (5)
Methanesulfonyl chloride (1.25 mL) and triethylamine (3.1 mL) was added, under nitrogen, to a dichloromethane solution containing (D)-2-phenyl-4-hydroxymethyl-4,5-dihydro-oxazole (2.6 g) (4) which had been cooled to 0°. After two hours, when the reaction was complete as shown by thin layer chromatography of a sample (r f =0; 5% acetone in CH2Cl2), it was quenched by addition of water (100 mL). Isolation of (5) was achieved by extracting the aqueous phase with dichloromethane (3×100 mL) and then washing the combined organic fractions successively with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The resulting organic fraction was dried (magnesium sulfate) and concentrated in vacuo to provide the crude mesylate (5) (3.74 g, 100% yield) which was routinely used directly in the next step.
5: NMR (360 mHz, CDCl 3 ): 7.95 (m, 2H, phenyl), 7.45 (m, 3H, phenyl), 4.62 (m, 1H, CHN), 4.55 (m, 1H, CH2O), 4.40 (m, 3H, CH2O), 3.05 (s, 3H, CH 3 ); IR (CHCl 3 ): 2980 (m), 2960 (m), 2900 (m), 1645 (s), 1570 (m), 1450 (m), 1360 (s), 1170 (s), 1060 (m), 970 (s).
E. Synthesis of thioacetate (6)
Crude mesylate (2.55 g) (5) was dissolved in dry (distilled over calcium hydride) dimethylsulfoxide (50 mL) and maintained under an argon atmosphere. Potassium thioacetate (5.7 g) was introduced to this reaction mixture at about 23° and then the reaction mixture was heated and maintained at 45° for three hours. At this time the reaction was complete as shown by thin layer chromatography (5% methanol in chloroform). After cooling to about 23°, the reaction mixture was diluted with diethyl ether (200 mL) and quenched with water (100 mL). The resulting organic layer was successively washed with water (3×50 mL), saturated sodium bicarbonate solution (2×50 mL); and saturated sodium chloride solution (50 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5% methanol in chloroform) to provide pure thioacetate (6) (2.03 g, 86% yield).
6: NMR (90 MHz, CDCl 3 ), 7.90 (m, 2H, phenyl), 7.40 (m, 3H, phenyl), 4.50 (m, 2H), 4.05 (m, 1H, CHN), 3.20 (d, j=6 Hz, 2H, CH2S), 2.35 (s, 3H, CH 3 CO); IR (CHCl 3 ): 2910 (s), 1695 (s, COS), 1645 (s, C═N), 1380 (s), 1140 (s), 1055 (s).
E. Preparation of (D)-2-phenyl-4-octadec-9-enylthiomethyl)-4,5-dihydro-oxazole (7A)
Freshly cut sodium (0.7 g) was added to anhydrous methanol (50 mL) at 0° under a nitrogen atmosphere. When the sodium was completely dissolved (about 2 hours), a methanol solution (200 mL) containing thioacetate (5.0 g) was added and the mixture was stirred for 0.5 hours at 0°. Oleic mesylate (10.0 g) was added to the reaction mixture, which was then slowly warmed (1 hour) to 70° and maintained at 70° for 24 hours. The reaction mixture was then cooled to about 23° and diluted with dichloromethane. After three extractions with dichloromethane, the organic fractions were combined and washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and then concentrated in vacuo to give a crude residue. Silica gel chromatography (R f =0.45, 15% ethyl acetate in hexane) provided 8.1 g (86% yield) of the desired compound 7A, (D)-2-phenyl-4-(octadec-9-enyl-thiomethyl)-4,5-dihydro-oxazole.
7A: NMR (360 MHZ, CDCl 3 ): 7.95 (m, 2H, phenyl), 7.33 (m, 1H, phenyl), 7.25 (m, 2H, phenyl), 5.38 (m, 2H, olefin), 3.83 (m, 1H, CH2O), 3.63 (m, 1H, CH2O), 3.23 (m, 1H, NCH), 2.60 (d, j=8 Hz, 2H, CH2S), 2.35 (t, j=7.0 Hz, 2H, CH2S), 1.95 (m, 4 h), 1.5-1.15 (m, 24H), 0.87 (t, j=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3000 (s), 2910 (s), 2850 (s), 1645 (s, C═N), 1420 (s), 1230 (s), 1190 (s), 1040 (m), 925 (m).
F. Preparation of (D)-2-phenyl-4-(octadecylthiomethyl)-4,5-dihydro-oxazole (7B)
Freshly cut sodium metal (0.28 g) was added slowly to anhydrous methanol (35 mL) at 0° under a nitrogen atmosphere. After the sodium was completely dissolved (0.5 hour at 0° C. then 1 hour at room temperature), the reaction mixture was recooled to 0° C. and octadecylmercaptan (2.86 g) and (D)-2-phenyl-4-(methanesulfonyl hydroxymethyl)-4,5-dihydro-oxazole (5) (2.40 g) were added sequentially. The reaction temperature allowed to warm to about 23° over a period of about 1 hour, and then increased to 75° and maintained at 75° for 6 hours. The reaction was then complete, as determined by thin layer chromatography (R f (7B)=0.45, 15% ethylacetate in hexane). The reaction was diluted with dichloromethane (100 mL) and quenched with water (50 mL). Extraction of the combined dichloromethane extracts (2×50 mL) with saturated sodium chloride solution, followed by drying over magnesium sulfate, filtration, and concentration in vacuo afforded crude 7B. Silica gel chromatography provided the pure (D)-2-phenyl-4-(octadecylthiomethyl)-4,5-dihydro-oxazole (7B) in a good yield (2.8 g, 67% yield).
7B: m.p.=78°-79°, [α] 25 =-2.3±2.0 (C=0.98, cyclohexane); NMR (360 MHz, CDCl 3 ): 7.95 (m, 2H, phenyl), 7.40 (m, 3H, phenyl), 4.50 (m, 2H, CH2O), 4.30 (m, 1H, CHN), 3.00 (dd, J=13 Hz, 3 Hz, 2H, CH2S), 2.60 (t, J=6 Hz, 2H, CH2S), 1.60 (m, 2H, CH2CH2S), 1.30-1.20 (m, 30H), 0.88 (s, 3H, CH 3 ); IR (CHCl 3 ): 3000 (s), 2920 (s), 2850 (s), 1645 (s, C═N), 1420 (s), 1230 (s), 1190 (s), 1040 (m), 925 (m).
7C: (71% yield); NMR (300 MHz, CDCl 3 ), 7.90 (m, 2H, phenyl), 7.40 (m, 3H, phenyl), 4.50 m, 2H, CH2O), 4.25 (m, 1H, CHN), 3.00 (dd, J=13 Hz, 3 Hz, 2H, CH2S), 2.60 (t, J=7.0 Hz, 2H, CH2S), 1.60 (m, 2H, CH2CH2S), 1.40-1.20 (m, 26H), 0.90 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3005 (s), 3000 (s), 2910 (s), 2850 (s), 1645 (s, C═N), 1420 (s), 1230 (s), 1190 (s), 1040 (m), 925 (m).
7D: (55% yield); NMR (360 MHz, CDCl 3 ): 7.95 (m, 2H, phenyl), 7.40 (m, 3H, phenyl), 4.50 (m, 2H) CH2O), 4.30 (m, 1H, CHN), 3.00 (dd, J=14 Hz, 2 Hz, 2H, CH2S), 2.60 (t, J=7.0 Hz, 2H, CH 2 S), 1.60 (m, 2H, CH 2 CH 2 S), 1.40-1.20 (m, 10H), 0.90 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 2910 (s), 2850 (m), 1645 (s, C═N), 1450 (m), 1360 (m), 1060 (m), 980 (m).
7E: (50% yield), NMR (360 MHz, CDCl 3 ): 7.95 (m, 2H, phenyl), 7.40 (m, 3H, phenyl), 4.50 (m, 2H, CH 2 O), 4.30 (m, 1H, CHN), 3.00 (dd, J=4.0 Hz, 14.0 Hz, 2H, CH 2 S), 2.60 (t, J=7.5 Hz), 2H, CH 2 S), 1.60 (m, 2H, CH 2 CH 2 S), 1.40-1.20 (m, 6H), 0.90 (t, J=7.0, 3H, CH 3 ); IR (CHCl 3 ): 2980 (s), 2920 (s), 2850 (m), 1645 (s), 1470 (m), 1360 (s), 1300 (m), 1260 (m), 1080 (m), 1060 (m), 1030 (m), 960 (m).
F. Preparation of (D)-2-acetamido-3-octadecylthioglycerol (8B)
Freshly distilled acetic anhydride (20 mL) and water (5 mL) were added to a glacial acetic acid (40 mL) solution of (D)-2-phenyl-4-(octadecylthiomethyl)-4,5-dihydro-oxazole (7B) (0.54 g) at about 23°. The reaction mixture was stirred overnight (about 18 hours) at about 23°, but very little product formed as observed by thin layer chromatography. The reaction mixture was then refluxed for 3 hours at 100°, which resulted in the complete (as determined by thin layer chromatography) consumption of the starting material 7B. The reaction mixture was then diluted with dichloromethane (200 mL), and the organic fraction was extracted with water (5×100 mL), saturated sodium bicarbonate (3×50 mL), water (2×50 mL) and then saturated sodium chloride solution. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo to give crude 2-D-acetamido-3-octadecylthio-glycerol-benzoate (4.45 g). The crude (D)-2-acetamido-3-octadecylthio-glycerolbenzoate was diluted with tetrahydrofuran (10 mL) and exposed to 1N lithium hydroxide (10 mL) at about 23° for about 18 hours. The reaction mixture was then concentrated to remove the tetrahydrofuran and the aqueous solution extracted with dichloromethane (5×50 mL). The combined organics were washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo. Pure (D)-2-acetamido-3-octadecylthio-glycerol (8B) was obtained by silica gel chromatography (R f =0.36, 5% methanol in chloroform) and provided 264 mg, (61% yield).
8B: [α] 25 =+15.2°±2.0° (C=1.00, ethanol); NMR (360 MHz, CDCl 3 ): 6.08 (bd, J=6.0 Hz, 1H, NH), 4.05 (m, 1H, NCH), 3.80 (dd, J=4.0, 12.0 Hz, 1H, CH2O), 3.80 (dd, J=4.0, 12.0 Hz, 1H, CH 2 O), 3.70 (bd, J=12.0 Hz, 1H, CH 2 O), 2.72 (m, 2H, CH 2 S), 2.54 (t, J=8,0 Hz, 2H, CH 2 S), 1.75-1.20 (m, 32H), 0.88 (t, J=7.0 Hz, 3H, CH 3 ); IR (neat): 3440 (bw, NH), 3280 (bs, OH), 2910 (s), 2850 (s), 1735 (s, CON), 1380 (s), 1215 (s), 710 (s).
8A: (50% yield); NMR (90 MHz, CDCl 3 ), 6.10 (bs, 1H, NH), 5.40 (m, 2H, CH═CH), 4.05 (m, 2H, CHN), 3.80 (m, 2H, CH 2 O), 2.75 (d, J=6 Hz, 2H, CH 2 S), 2.70 (m, 2H, CH 2 C═), 2.60 (t, J=7.5, 2H, CH 2 S), 2.00 (s, 3H), CH 3 ); IR (CDCl3): 3400 (bs, OH, NH), 2910 (s), 2920 (s), 1670 (s, CON), 1600 (m), 1500 (m), 1480 (), 1420 (s), 1200 (s).
8C: (82% yield); NMR (90 MHz, CDCl 3 ), 6.15 (m, 1H, NH), 4.00 (m, 1H, CHN), 3.75 (m, 2H, CH 2 O), 2.70 (d, J=7.0 Hz, 2H, CH 2 S), 2.50 (t, J=7.0 Hz, 2H, CH 2 S), 2.00 (s, 3H, CH 3 ), 1.80-1.00 (m, 28H), 0.90 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ), 3500 (bs), 3000 (s), 2970 (s), 2930 (s), 1675 (s, CON), 1600 (m, ), 1510 (m), 1425 (m), 1200 (s), 1040 (s).
8D: (93% yield); NMR (90 MHz, CDCl 3 ): 6.20 (bd, 7.0 Hz, 1H, NH), 4.00 (m, 1H, CHN), 3.80 (m, 2H, CH 2 O), 3.30 (bm, 1H, OH), 2.70 (d, 6.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.0 Hz, 2H, CH 2 S), 2.00 (s, 3H, CH 3 CO), 1.80-1.10 (m, 12H), 0.95(t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3400 (bs, OH, NH), 3000 (s), 2920 (s), 2850 (s), 1665 (s, CON), 1500 (s), 1460 (m), 1380 (m), 1270 (w), 1045 (s).
8E: (64% yield); NMR (90 MHz, CDCl 3 ): 6.10 (bd, J=7.0 Hz, 1H, NH), 4.00 (m, 1H, CHN), 3.85 (m, 2H, CH 2 O), 3.50 (bm, 1H, OH), 2.70 (d, J=7.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.0 Hz, 2H, CH 2 S), 2.00 (s, 3H, CH 3 CO), 1.80 -1.10 (m, 8H), 0.95 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3400 (s), 3000 (s), 2950 (s), 2920 (s), 2850 (s), 1665 (s, CON), 1500 (s), 1460 (m), 1380 (m), 1040 (m).
G. Preparation of 3-Octadecylthio-2-acetamidophosphatidylcholine (10B)
Anhydrous triethylamine (distilled from calcium hydride) (0.4 mL) was added to a dry (distilled from benzophenone/sodium) tetrahydrofuran (20 mL) solution containing 3-octadecylthio-2-acetamido-gyclerol (8B) (1.5 g) at 0° under nitrogen. The resulting mixture was maintined at 0° and 2-chloro-2-oxo-1,2,3-dioxaphospholane (0.41 g) in dry tetrahydrofuran (5 mL) was added. The reaction mixture was then stirred and permitted to warm to about 23° during the next 24 hours. Thin layer chromatography showed that starting material 8B had been completely converted into the desired cyclic phosphate [R 4 (9)=0.25, R f (8B)=0.10; 10% methanol in chloroform]. The crude cyclic phosphate 9 was isolated by diluting the reaction mixture with tetrahydrofuran (20 mL), which was then filtered through a bed of magnesium sulfate and the resulting solution was concentrated in vacuo. The residue was dissolved in dry (distilled from calcium hydride) acetonitrile (10 mL) and transferred to a dry Carius tube. The reaction mixture was cooled to -78° with liquid nitrogen. While frozen, anhydrous (distilled through potassium hydroxide) trimethylamine (1 mL) was added, and the contents were sealed under vacuum. The reaction mixture was next permitted to warm to about 23°, and then the selaed tube was heated to 65° and kept at that temperature for 48 hours. The sealed tube was cooled and opened and the contents were evaporated in vacuo. The residue of the tube was subjected to medium pressure liquid chromatography (R f (10B)=0.15; chloroform, methanol, water; 65:25:4) and afforded 3-octadecyl-2-acetamido phosphatidylcholine (10B) (0.54 g, 33% yield).
10B: m.p. 198°-202°, [α] 25 =+6.8°±0.8°, (C=1.03, methanol); NMR (360 MHz, 10% CD 3 OD/CDCl 3 ): 4.25 (m, 2H, CH 2 OP), 4.08 (m, 1H, NCH), 4.06 (m, 1H, CH 2 OP), 3.98 (m, 1H, CH 2 OP), 3.59 (m, 2H, CH 2 N), 3.22 (s, 9H, N(CH 3 ) 3 ), 2.68 (d, J=7.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.0 Hz, 2H, CH 2 S), 1.98 (s, 3H, CH 3 CO), 1.57 (m, 2H, CH 2 ), 1.40-1.20 (m, 30H), 0.88 (t, J=7.0 Hz, 3H, CH 3 ); IR (KBr, cm -1 ): 3400 (bs, NH, OH), 2920 (s, sat. CH), 2850 (s, sat. CH), 1655 (s, CON), 1550 (m, CONHR), 1245 (s, P═O), 1090 (s, POC); FAB-MS (glycerol): 1133 (10%, 2M.H+), 567 (22%, M.H+), 384 (8%, C 23 H 46 NOS+), 185 (100%, C 5 H 15 NO 4 P.H+); EA for C 28 H 57 N 2 O 5 PS.2H 2 O: calcd.: C 55.97%, H 10.23%, N 4.66%, S 5.34%, P 5.16%); found: C 56.82%, H 9.81%, N 4.94%, S 5.73%, P 5.25%.
10A: (38% yield); m.p.=190°-200°, [α] 25 =+12.2°±0.8°, (C=1.10, methanol); NMR (360 MHz, 10% CD 3 OD/CDCl 3 ), 5.35 (m, 2H, CH═CH), 4.38 (m, 2H, CH 2 OP) 4.05 (m, 2H, NCH, CH 2 OP) 3.95 (m, 1H, CH 2 OP), 3.69 (m, 2H, CH 2 N), 3.22 (s, 9H, N(CH 3 ) 3 ), 2.68 (d, J=7.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.0 Hz, 2H, CH 2 S), 2.02 (m, 4H, CH 2 C═), 1.97 (s, 3H, CH 3 CO), 1.57 (m, 2H, CH 2 ), 1.40-1.20 (m, 22H), 0.88 (t, J=7.0 Hz, 2H, CH 2 S); IR (neat, cm -1 ): 3400 (BS, NH, OH), 2920 (s, sat. CH), 2850 (s, sat. CH), 1650 (s, CON), 1555 (s, CONHR), 1240 (s, P═O), 1090 (s, POC); HRMS: calculated for C 25 H 43 NOS, 381.3065; found 381.3052, M+--C 5 H 24 O 4 NP; FAB-MS (glycerol): 565 (M+H)+; EA for C 28 H 59 O 5 N 2 PS.2H 2 O: calcd.: C 55.79%, H 10.53%, N 4.65%, S 5.32%, P 5.14%; found: C 56.42%, H 10.30%, N 4.39%, S 5.82%, P 5.12%.
10C: (58% yield); m.p. 185°-190° dec.; [α] 25 =+8.2°±0.8°, (C=1.05, methanol); NMR (360 MHz, 10% CD 3 OD/CDCl 3 ): 4.25 (m, 2H, CH 2 OP), 4.08 (m, 1H, NCH), 4.06 (m, 1H, CH 2 OP), 3.98 (m, 1H, CH 2 OP), 3.59 (m, 2H, CH 2 N), 3.22 (s, 9H, N(CH 3 ) 3 ), 2.70 (m, 2H, CH 2 S), 2.56 (t, J=7.0 Hz, 2H, CH 2 S), 2.00 (s, 3H, CH 3 CO), 1.57 (m, 2H, CH 2 ), 1.40-1.20 (m, 28H), 0.88 (t, J=7.5 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3300 (bs, NH, OH), 2920 (s, sat. CH), 2850 (m), 1665 (s, CON), 1560 (m), 1450 (m), 1240 (s), 1080 (s).
10D: (53% yield); m.p. 129°-130° dec.; [α] 25 =12.7°±0.8°, (C=1.15; methanol); NMR (300 MHz, 10% CD 3 OD/CDCl 3 ), 4.25 (m, 2H, CH 2 O), 4.07 (m, 2H, CH 2 O), 3.97 (m, 1H, CHN), 3.60 (m, 2H, CH 2 N), 3.20 (s, 9H, (CH 3 ) 3 N), 2.70 (d, J+7.0 Hz, 2H, CH 2 S), 2.55 (t, J=7 Hz, 2H, CH 2 S), 1.95 (s, 3H, CH 3 CO), 1.58 (m, 2H, CH 2 CH 2 S), 1.40-1.20 (m, 10H(m 0.90 (t, J-7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ):3220 (bs, OH, NH), 2920 (s, sat. CH), 2850 (m), 1655 (s, CON), 1550 (m), 1465 (m) 1220 (s), 1080 (s), 970 (m); EA for C 18 H 39 N 2 O 5 PS.2H 2 O: calcd.: C 46.74%, H 9.37%, N 6.06%, S 6.93%, P 6.70%; found: C 44.66%, H 9.63%, N 6.29%, S 7.69%, P 6.41%.
10E: (50% yield); m.p. 60°-61° dec.; [α] 25 =+11.1°±0.8°, (C=1.14, methanol); NMR (360 MHz, 10% CD 3 OD/CDCl 3 ): 7.80 (bd, J=6.0 Hz, 1H, NH), 4.20 (m, 2H, CH 2 OP), 4.00 (m, 3H, CH 2 OP, CHN), 3.55 (m, 2H, CH 2 N), 3.10 (s, 9H, N(CH 3 ) 3 ), 2.80 (d, J=6.0 Hz, 2H, CH 2 S), 2.45 (t, J=7.0 Hz, 2H, CH 2 S), 1.95 (s, 3H, CH 3 CO), 1.50 (m, 2H, CH 2 CH 2 S), 1.35-1.10 (m, 6H), 0.80 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3240 (bs, NH, OH), 3950 (s, sat. CH), 3920 (s, sat. CH), 2850 (m), 1650 (s, CON), 1550 (m), 1460 (m), 1420 (w), 1370 (m), 1220 (s), 1080 (s), 1050 (m), 960 (s); FAB-MS, EA for C 16 H 35 N 2 O 5 PS.2H 2 O: calcd.: C 44.23%, H 9.05%, N 6.45%, S 7.38%, P 7.13%; found: C 46.18%, H 9.18%, N 7.24%, S 8.23%, P 7.55%.
H. Preparation of (D)-2-amino-3-(octadecyl)-glycerol (11B)
To a dioxane (5 mL) solution of (D)-2-phenyl-3-(octadecyl-thiomethyl)-4,5-dihydro-oxazole (7B) (5.3 g) was added 6N sulfuric acid (10 mL). After refluxing for 48 hours, the reaction mixture was cooled and combined with saturated sodium chloride solution (50 mL). The aqueous fraction was extracted with diethyl ether (5×100 mL) and the combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo, (R 4 (11)=0.25, 10% methanol in chloroform) to provide pure 11B (3.56 g, 83% yield).
11B: (83% yield); NMR (360 MHz, CDCl 3 ): 3.65 (dd, J=10.0, 4.0 Hz, 1H, CH 2 O), 3.41 (dd, J=10.0, 7.0 Hz, 1H, CH 2 O), 3.00 (m, 1H, NCH), 2.65 (dd, J=4.3, 13.5 Hz, 1H, CH 2 S), 2.52 (t, J=7.0 Hz, 2H, CH 2 S), 2.45 (dd, J=13.5, 8.0 Hz, 1H, CH 2 S), 1.80 (bs, 2H, NH 2 ), 1.58 (m, 2H, CH 2 ), 1.40-1.20 (m, 30H), 0.88 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3420, (bs, OH, NH), 3000 (s), 2920 (s), 2850 (s), 1460 (s), 1380 (w), 1080 (s).
11C: (35% yield); NMR (300 MHz, CDCl 3 ): 3.60 (m, 2H, CH 2 O), 3.00 (m, 1H, CHN), 2.60 (m, 2H, CH 2 S), 2.40 (m, 2H, CH 2 S), 1.40-1.00 (m, 28H), 0.85 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3600 bm, NH), 3420 (bs, OH, 3000 (s), 2920 (s), 2850 (s), 1460 (s), 1375 (w), 1210 (s), 1090 (s).
I. Preparation of 3-hexadecylthio-2-carboxymethylamideglycerol (12CII)
Methylchloroformate (0.63 mL) was added to a dry (distilled over calcium hydride) dichloromethane (25 mL) solution of 3-hexadecylthio-2-amino-glycerol hydrochloride (11) (2.0 g) at 0° under a nitrogen atmosphere. Anhydrous triethylamine (1.9 mL) was added slowly to the resulting slurry at 0°. After 1 hour, the reaction mixture was allowed to warm to room temperature. The reaction was complete in 1 hour; at that time it was diluted with dichloromethane (200 mL) and quenched with water (50 mL). The combined organic fractions were extracted 4 times with dichloromethane (100 mL), then washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography (R f (12CII)=0.35, 5% acetone in dichloromethane) and provided pure 12CII (1.6 g, 79% yield).
12CII: NMR (90 MHz, CDCl 3 ): 5.20 (bm, 1H, NH), 3.90 (m, 1H, CHN), 3.75 (m, 2H, CH 2 O), 3.65 (bm, 1H, OH), 2.70 (d, J=7.0 Hz, 2H, CH 2 S), 2.50 (t, J=7.0 Hz, 2H, CH 2 S), 1.80-1.10 (m, 28H), 0.85 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3580 (bm, NH), 3420 (bs, OH), 3000 (m), 2920 (s), 2850 (s), 1710 (s, CO 2 N), 1510 (s), 1460 (m), 1340 (w), 1050 (s).
12BII: (53% yield); NMR (90 MHz, CDCl 3 ): 5.30 (bm, 1H, NH), 3.85 (m, 1H, CHN), 3.70 (m, 2H, CH 2 O), 3.45 (m, 1H, OH), 2.75 (d, J=7.0 Hz, 2H, CH 2 S), 2.50 (t, J=7.0 Hz, 2H, CH 2 S), 1.70-1.10 (m, 32H), 0.80 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3600 (bs, NH), 3430 (bs, OH), 3000 (s), 2920 (s), 2850 (s), 1700 (s), 1505 (s), 1460 (s), 1350 (m), 1050 (s).
J. Preparation of (D)-2-octadecyl-3-octadecylglycerol (12BI)
Stearic anhydride (10 g) was added to a solution (5 mL) of 7B (1.0 g) in tetrahydrofuran at about 23° under nitrogen. The components were completely mixed, then para-toluenesulfonic acid monohydrate (0.5 g) was added and the resulting reaction mixture was heated 3 hours at 120°. The solvent was removed by evaporation, leaving a brown solid which was diluted with ether (200 mL) and extracted 3 times with saturated sodium bicarbonate solution (50 mL). The organic phase was then shaken successively with water (50 mL), and saturated sodium chloride solution (50 mL), and then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (R f =0.75, 25% ethyl acetate in hexane) to provide the required amide benzoate contaminated with excess stearic anhydride. The mixture was diluted with tetrahydrofuran (50 mL) and combined with excess 1N lithium hydroxide (50 mL) solution and permitted to stir 24 hours at about 23°. The tetrahydrofuran was removed by evaporation (in vacuo). The resulting aqueous phase was shaken with ether (3×100 mL) and the combined organic layers were repeatedly extracted with 2N sodium hydroxide solution (4×50 mL). The resulting organic phase was washed with water (50 mL), saturated sodium chloride (50 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (R f (12BI)=0.45, 5% methanol in chloroform) supplied pure 12BI (0.23 g) in 17% yield.
12BI: NMR (360 MHz, CDCl 3 ): 4.00 (m, 1H, NCH), 3.72 (dd, J=12.0, 5.0 Hz, 1H, CH 2 O), 3.62 (dd, J=12.0, 5.0 Hz, 1H, CH 2 O), 2.70 (t, J=8.0 Hz, 2H, CH 2 S), 2.54 (t, J=8.0 Hz, 2H, CH 2 S), 2.20 (5, J=8.0 Hz, 2H, CH 2 CO), 1.65-1.20 (m, 62H), 0.88 (t, J=7.2 Hz, 6H, CH 3 ); IR (CHCl 3 ): 3430 (bs, OH, NH), 2930 (s), 2850 (s), 1660 (s, CON), 1510 (s), 1465 (s), 1360 (m), 1300 (m).
K. Preparation of 2-phenacylamino-3-hexadecathiomethylglycerol (12CIV)
Aqueous 1N hydrochloric acid (25 mL) was added to 7C (1 g) and the resulting mixture was refluxed for 3 hours. The mixture was then cooled and neutralized (pH=7.0) by adding saturated sodium carbonate solution. It was then extracted with dichloromethane (3×100 mL). The combined organic fractions were washed with water (100 mL) and saturated sodium chloride and then dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL) and the resulting solution was combined with 1N lithium hydroxide solution (5 mL) at about 23°. The reaction mixture was incubated for 1 hour, quenched with saturated ammonium chloride solution (25 mL), and then extracted with diethyl ether (3×100 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (R f (12CIV)=0.35, 5% acetone in dichloromethane) to afford purified amide alcohol 12CIV (0.9 g, 85% yield).
12CIV: NMR (300 MHz, CDCl 3 ): 7.80 (m, 2H, phenyl), 7.50 (m, 3H, phenyl), 6.80 (m, 1H, NH), 4.30 (m, 1H, CHN), 3.80 (m, 2H, CH 2 O), 2.90 (m, 2H, CH 2 S), 2.60 (t, J=7.0 Hz, 2H, CH 2 S), 2.40 (bm, 1H, OH), 1.80-1.10 (m, 28H), 0.90 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3420 (bm, NH, OH), 3000 (w), 2920 (s), 2850 (s), 1665 (s), 1580 (m), 1520 (s), 1480 (s), 1460 (m), 1080 (m), 880 (w).
L. Synthesis of Phospholipids of the 13 Series
Phospholipids 13 were prepared from corresponding glycerols 12 by procedures substantially similar to those described for conversion of 3-octadecylthio-2-acetamido-glycerol (8B) to 3-octadecylthio-2-acetamidophosphatidylcholine (10B) in part I, above
13CIV: (20% yield), m.p.=170°-175° dec.; [α] 25 =21.5°±0.8°, (C=1.27, methanol); NMR (300 MHz, 10% CD 3 OD/CDCl 3 ): 8.40 (bd, J=5 Hz, NH), 7.80 (m, 2H, phenyl), 7.35 (m, 3H, phenyl), 4.30 (m, 2H, CH 2 OP), 4.20 (m, 2H, CH 2 OP, CHN), 4.05 (m, 1H, CH 2 OP), 3.45 (m, 2H, CH 2 N), 3.15 (s, 9H, N(CH 3 ) 3 ), 2.75 (d, J=7.5 Hz, 2H, CH 2 S), 2.50 (t, J=7.0 Hz, 2H, CH 2 S), 1.60 (m, 2H, CH 2 CH 2 S), 1.40-1.20 (m, 28H), 0.90 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3300 (bs, OH, NH), 3000 (m), 2920 (s), 2850 (s), 1660 (s, CON), 1570 (m), 1450 (m), 1420 (m), 1080 (s), 970 (s), EA for C 31 H 57 N 2 O 5 PS.2H 2 O: calcd: C 58.46%, H 9.65%, N 4.40%, S 5.03%, P 4.86%; found: C 59.55%, H 9.34%, N 4.36%, S 5.81%, P 5.15%.
13BII: (63% yield); m.p. 215°-220° dec; [α] 25 =+7.1°±0.80°, (C=1.07 g, methanol); NMR (360 MHz, 10% CD 3 OD/CDCl 3 ): 4.27 (m, 2H, CH 2 OP), 4.05 (m, 1H, CH 2 OP), 3.98 (m, 1H, CH 2 O), 3.85 (m, 1H, NCH), 3.65 (s, 3H, OCH 3 ), 3.63 (m, 2H, CH 2 N), 3.23 (s, 9H, N(CH 3 ) 3 ), 2.70 (d, J=7.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.5 Hz, 2H, CH 2 S), 1.57 (m, 2H, CH 2 ), 1.40-1.20 (m, 30H), 0.88 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3250 (bs, NH, OH), 2920 (s), 2850 (m), 1705 (s, CO 2 N), 1460 (s), 1390 (w), 1085 (s), 970 (m); EA for C 28 H 59 N 2 O 6 PS.2H 2 O: calcd: C 54.34%, H 10.26%, N 4.53%, S 5.18%, P 5.01%; found: C 53.82%, H 10.20%, N 4.31%, S 5.70%, P 5.12%.
13CII: (63% yield ); m.p.=220°-223° dec.; [α] 25 =+6.8°±0.8°, (C=1.03, methanol), NMR (360 MHz, 10% CD 3 OD, CDCl 3 ): 4.25 (m, 2H, CH 2 OP), 4.05 (m, 1H, CH 2 OD), 3.98 (m, 1H, CH 2 OP), 3.84 (m, 1H, NCH), 3.65 (s, 3H, OCH 3 ), 3.62 (m, 2H, CH 2 N), 3.32 (s, 9H, N(CH 3 ) 3 ), 2.70 (d, J=6.0 Hz, 2H, CH 2 S), 2.55 (t, J=7.0 Hz, 2H, CH 2 S), 1.57 (m, 2H, CH 2 ), 1.40-1.20 (m, 26H), 0.88 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3300 (bs, NH, OH), 2930 (s), 2860 (m), 1750 (s, CO 2 N), 1450 (s), 1390 (w), 1090 (s), 970 (m).
13BI: (17% yield); m.p.=165°-170°; [α] 25 =+7.5°±0.2°, (1.20, methanol:chloroform, 1:4); NMR (300 MHz, CDCl 3 ): 7.80 (m, 1H, NH), 4.20 (m, 2H, CH 2 OP), 4.00 (m, 2H, CH 2 OP, CHN), 3.90 (m, 1H, CH 2 OP), 3.50 (m, 2H, CH 2 N), 3.10 (s, 9H, N(CH 3 ) 3 ), 2.80 (d, J=7.0 Hz, 2H, CH 2 S), 2.50 (t, J=7.0 Hz, 2H, CH 2 S), 2.10 (t, J=7.0 Hz, 2H, CH 2 CO), 1.50 (m, 2H, CH 2 CH 2 S), 1.50-1.10 (m, 63H), 0.80 (t, J=7.0 Hz, 3H, CH 3 ); IR (CHCl 3 ): 3250 (bw, NH, OH), 2920 (s), 2850 (s), 1660 (m, CON), 1550 (w), 1460 (m), 1370 (w), 1080 (s), 970 (m), EA for C 44 H 91 N 2 O 5 PS.2H 2 O: calcd: C 63.88%, H 11.58%, N 3.93%, S 3.88%, P 3.74%; found: C 63.24%, H 11.67%, N 3.20%, S 4.51%, P 3.93%.
Utility
The product compounds of the present invention (Formula I) selectively induce significant reductions in the blood pressure of experimental animals in which hypertension is a spontaneous and chronic condition. In addition, the compounds of the invention have been demonstrated to significantly inhibit the inflammatory response caused by a noxious agent when applied topically just prior to the noxious stimulant. This evidence clearly indicates the utility of the compounds of Formula I in various pharmaceutical formulations for use in human and/or veterinary applications.
The compounds of the invention can be administered intravenously, intramuscularly, intraperitoneally, or topically to a warm-blooded animal following dispersal or solution in a pharmaceutically suitable diluent or vehicle.
For the purpose of this invention, a warm-blooded animal means a member of the animal kingdom having a homeostatic mechanism; the term includes mammals and birds.
I. EXAMPLES 2-8
Antihypertensive Activity
The compounds of this invention can be administered in the treatment of hypertension by any means resulting in contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration can be parenteral, i.e., intravenous.
Appropriate and effective dosages of the compounds of Formula I to be administered in treating of hypotension will be determined by the age, health, and weight of the recipient; the extent of disease; nature of of concurrent treatment, is any; frequency of treatment; and the nature of the effect desired.
Usually, a daily dosage of active ingredient compound will be from about 0.1 to 100 milligrams per kilogram (mg/kg) of body weight. Ordinarily, from 0.2 to 60, and preferably 1.0 to 40 mg/kg per day in one or more applications is effective to obtain the desired results. For the more potent compounds of the invention, e.g. 10A, daily dosages range from about 0.1 to 20 mg/kg, preferably 0.2 to 20 mg/kg, and more preferably from 0.5 to 5 mg/kg.
EXAMPLE 2
The antihypertensive activity of 3-octadecylthio-2-carbomethoxyamidophosphatidylcholine (compound 13BII) was demonstrated by tests conducted using the spontaneous hypertensive rat (SHR). In this procedure, anesthetized rats were dosed intravenously with graded dose levels the test compound on a cumulative dose schedule. The test compound was administered in an aqueous 0.25% methylcellulose vehicle at a volume to body weight ratio of 1 mL/kg. Arterial blood pressure was continuously recorded directly through an arterial cannula and a polygraph. That dose of compound producing a reduction in mean blood pressure of 30 mm Hg, or ED 30 , was then determined. In this manner, an ED 30 of 2.00 mg/kg was determined for compound 13BII.
EXAMPLES 3-8
The antihypertensive activity of other compounds within the scope of the present invention was determined by methods substantially similar to those reported in Example 2, above, except that intravenous dosage levels of 2 and 12 mg/kg were employed. The results of these tests are indicated in Table I, below. The designation "prolonged" indicates a hypotensive response lasting from 15-30 minutes. The following designations are employed to indicate the magnitude of hypotensive response:
TABLE I______________________________________Blood Pressure Responses to Analogsof Platelet Activating Factorin Spontaneous Hypertensive RatCom- Dosage Re-Ex. pound R.sup.1 R.sup.2 (mg/kg) sponse Duration______________________________________3 10A 9Δ--C.sub.18 H.sub.35 CH.sub.3 2 ++ pro- longed4 10B C.sub.18 H.sub.37 CH.sub.3 2 ++ pro- longed5 13CII C.sub.16 H.sub.33 CH.sub.3 O 2 ++ pro- longed6A 13BII C.sub.18 H.sub.37 CH.sub.3 O 2 ± --6B 13BII C.sub.18 H.sub.37 CH.sub.3 O 12 ++ pro- longed7A 10D C.sub.8 H.sub.17 CH.sub.3 2 NE --7B 10D C.sub.8 H.sub.17 CH.sub.3 12 ++ pro- longed8A 13CIV C.sub.16 H.sub.33 Ph 2 NE --8B 13CIV C.sub.16 H.sub.33 Ph 12 ± --______________________________________ ++: Pronounced decrease in blood pressure (>50 mm Hg) +: Moderate decrease in blood pressure (35-50 mm Hg) ±: Threshold decrease in blood pressure (25-35 mm Hg) NE: No effect observed
II EXAMPLES 9-10
Topical Anti-inflammatory Activity
Topical application of tetradecanoyl phorbol acetate (TPA) to murine skin results in an inflammatory reaction characterized by edema, a dense cellular infiltration 4-6 hours later, and an epidermal hyperplasia 24 hours following application. (Kuehl et al., Nature 265:170 (1977). One of the earliest events characteristic of the epidermal response to TPA is release of prostaglandin E 2 (PGE 2 ). PGE 2 is produced and released in response to activation of phospholipase A 2 and release of arachidonic acid. (Ashendel et al. Biochem. Biophys. Res. Comm. 90:623 (1979); Bresnick et al., Cancer Letters 7: 121-125, (1979); Furstenberger et al., Biochem. Biophys. Res. Comm. 92:749 (1980)). Various antiinflammatory agents inhibit this reaction; the most potent are the corticosteroids. (Viaje et al., Cancer Research 37:1530 (1977)). Cyclo-oxygenase inhibitors also inhibit this reaction (Viaje et al., Cancer Research 37:1530 (1977).
To evaluate the antiinflammatory activity of certain compounds within the scope of the present invention, TPA was applied topically to ear epidermal tissue of male CF1 mice 4-6 weeks old. One μg of TPA in acetone was applied topically to one ear, while acetone only was applied to the contralateral ear of each mouse. Test compounds to be evaluated as antiinflammatory agents were applied to both ears in acetone just prior to application of TPA. Four hours after the application of the TPA, the animals were sacrificed, and 6 mm disks of tissue were excised from each treated ear and weighed. The relative amount of edema was then assessed by determining the difference in mass between control and TPA-treated tissue samples. The results obtained are set forth in Table II, below:
TABLE II______________________________________Topical Antiinflammatory Activityof Analogs of Platelet Activating Factor Ear VolumeExample Compound R.sup.1 R.sup.2 Reduction (%)______________________________________ 9 13CIV C.sub.16 H.sub.33 Ph 5710 10B C.sub.18 H.sub.37 CH.sub.3 10______________________________________
III. EXAMPLES 11-19
Inhibition of Phospholipase A 2
Inhibition of porcine pancreatic PLA 2 was measured by a modification of the assay used by Hirata et al., Proc. Natl. Acad. Sci. USA 77:533 (1980). The enzyme-substrate reaction was run in a total volume of 0.1 mL with the enzyme at a final concentration of 19 units/mL (0.025 ug protein/mL) which gave approximately 4000-8000 dpm of activity in a buffer containing 25 mM Tris, 25 mM glycylglycine, 25 mM CaCl 2 and 0.75 mM EDTA (tetra sodium salt), pH 8.5. Compounds to be tested as inhibitors were added to an aliquot of enzyme and incubated for 2 minutes, and then the substrate, [arachidonyl-1- 14 C] L-1-palmitoyl-2-arachidonyl phosphatidylcholine was added to provide a final concentration of 14.0 uM (80,000 dpm). The reaction was allowed to proceed for five minutes at 37°, and then halted by freezing the mixture in a dry ice-ethanol slurry. The arachidonic acid product was separated from unreacted substrate using silica gel columns.
All reactions were run in duplicate. Compounds to be tested were dissolved in 0.2M Tris-Cl, pH 8.5 or dissolved in DMSO and then diluted with Tris-Cl buffer (maximum DMSO concentration, 7%). An approximation of IC 50 (the concentration of compound which inhibits the phospholipase activity by 50 percent) was determined for each compound from a semilog plot of percent inhibition versus the final inhibitor concentration. The results of these determinations are set forth in Table III, below:
TABLE III______________________________________Inhibition of Phospholipase A.sub.2Activity by Analogs of Platelet Activating FactorExample Compound R.sup.1 R.sup.2 IC.sub.50 (M)______________________________________11 10A 9Δ--C.sub.18 H.sub.35 CH.sub.3 6.0 × 10.sup.-712 10B C.sub.18 H.sub.37 CH.sub.3 5.2 × 10.sup.-713 10C C.sub.16 H.sub.33 CH.sub.3 1.1 × 10.sup.-614 10D C.sub.8 H.sub.17 CH.sub.3 9.0 × 10.sup.-615 10E C.sub.6 H.sub.13 CH.sub.3 9.8 × 10.sup.-516 13BI C.sub.18 H.sub.37 C.sub.17 H.sub.35 5.5 × 10.sup.-717 13BII C.sub.18 H.sub.37 CH.sub.3 O 1.9 × 10.sup.-518 13CII C.sub.16 H.sub.33 CH.sub.3 O 1.8 × 10.sup.-519 13CIV C.sub.16 H.sub.33 Ph 1.4 × 10.sup.-6______________________________________
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1-Thioether-1-acylaminophosphatidylcholine compounds are structural analogs of platelet activating factor and useful for inhibition of phospholipase A 2 , reduction of blood pressure, and alleviation of inflammation.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional application serial No. 60/368,511 attorney docket no. DP-306101 filed Mar. 29, 2002, the contents of which are incorporated herein by reference thereto.
TECHNICAL FIELD
[0002] The present disclosure relates to horn contact mechanisms and more particularly the present disclosure relates to horn contact mechanisms for use with driver's side air bag modules.
BACKGROUND
[0003] Vehicles are supplied with driver's side airbag modules; generally the driver's side airbag module is located in the center of the steering wheel. This is also the same location where a horn-activating switch has traditionally been mounted. Thus, when driver's side airbags were first introduced, the horn-activating switch was moved from the center to another location on the steering wheel to make room for the airbag. The horn-activating switches were often mounted on the steering wheel spokes or rim. However, many drivers preferred that the horn-activating switch be located at the center of the steering wheel.
[0004] Eventually, the horn-activating switch was adapted for mounting on the underside of the airbag module cover between the inflatable airbag and the cover of the module. This type of switch allowed the horn-activating switch to be placed in its traditional position. Such horn-activating switches react to a user-applied force to the cover in an effort to sound the horn. For example, a floating horn system where the entire airbag moves as force is applied to actuate the horn. However, such existing horn mechanisms contain contact points that are exposed to environmental conditions. These contact points are used to activate the horn by completing an electrical circuit. These exposed contact points can corrode when exposed to environmental conditions. In turn, this corrosion leads to the inability to complete the electrical circuit and blow the horn.
[0005] In addition, positive stack up tolerances between horn mechanism components can lead to greater distances of module travel before horn contact is made. The distance between the contact points of the horn mechanism can become greater than the gap between the driver airbag module and the steering wheel. As a result, there could be “no-blow” condition of the horn. Also, the greater distance between contact points can lead to increased horn efforts. Negative stack up tolerances between horn mechanism components can lead to less distances of module travel before horn contact is made. This can lead to inadvertent horn blows, constant horn actuation, and reduced horn efforts.
SUMMARY
[0006] The above discussed and other drawbacks and deficiencies are overcome or alleviated by an enclosed contact horn mechanism. An enclosed contact horn mechanism comprising: a pin having a first end and a second end; a base plate located near the first end; and a device located between the first end and the base plate; the device, the first end, and the base plate creating an enclosed contact area, wherein the device is movable so that the base plate may contact the first end.
[0007] An enclosed contact horn mechanism comprising: a pin having a first end and a second end, the second end being configured for securing an airbag module to a portion of a steering wheel. The module also has a base plate located near the first end and a device located between the first end of the pin and the base plate. The device, the first end, and the base plate creating an enclosed contact area, wherein the device is configured so that the base plate may contact the first end.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] [0008]FIG. 1 is a perspective view of a mounting side of a portion of a driver's side air bag module with a horn contact mechanism;
[0009] [0009]FIG. 2 is another perspective view of a portion of a DAB illustrated in FIG. 1;
[0010] FIGS. 3 A- 3 B illustrate operational aspects of the horn contact mechanism of the present disclosure along lines 3 - 3 of FIG. 1;
[0011] [0011]FIG. 4 is perspective view of a portion driver's side air bag module secured to an armature of a steering wheel;
[0012] [0012]FIG. 5 is a block diagram showing a driver's side driver air bag module connected to a power source and a horn;
[0013] [0013]FIG. 6 is a top plan view of a steering wheel with a driver's side air bag module;
[0014] [0014]FIG. 7 is a view along lines 7 - 7 of FIG. 6;
[0015] FIGS. 8 A- 8 E illustrate a backing plate constructed in accordance with the present disclosure;
[0016] FIGS. 9 A- 9 D illustrate a base plate constructed in accordance with the present disclosure;
[0017] FIGS. 10 A- 10 C illustrate an insulator constructed in accordance with the present disclosure;
[0018] FIGS. 11 A- 11 B illustrate a contact pin constructed in accordance with the present disclosure;
[0019] FIGS. 12 A- 12 B illustrate a washer constructed in accordance with the present disclosure;
[0020] FIGS. 13 A- 13 B illustrate a coil constructed in accordance with the present disclosure;
[0021] [0021]FIG. 14 is a cross-sectional view of an alternative embodiment of the present disclosure; and
[0022] [0022]FIG. 15 is a cross-sectional view of another alternative embodiment of the present disclosure.
DETAILED DESCRIPTION
[0023] Referring to FIG. 1, a portion of a driver's side air bag module (module) 10 having a horn contact mechanism 11 is illustrated. Module 10 has among other elements a backing plate 12 (See also FIGS. 8 A- 8 E) and a base plate 14 (See also FIGS. 9 A- 9 D). Both backing plate 12 and base plate 14 have a large center opening 16 and smaller connection openings 18 surrounding center opening 16 . Connection openings 18 are used to secure an inflator (not shown) to module 10 . A portion of the inflator is received within opening 16 . Backing plate 12 has four raised areas 20 located at each corner 22 of backing plate 12 . Raised areas 20 define an area 21 for receiving a portion of the horn contact mechanism. Area 21 is sufficiently large enough to house portions of the horn contact mechanism which will be discussed in more detailed below. Each raised area 20 has a pin opening 24 with three grooves 26 or areas located around the periphery of pin opening 24 . Of course, the number and configuration of grooves or openings 26 may vary. A pin 30 extends through pin opening 24 . Pin 30 is made of a material that can conduct electricity and is preferably steel. Pin 30 serves a dual purpose of securing the driver's side airbag (DAB) to the steering wheel and providing a contact portion of horn contact mechanism. In an exemplary embodiment Pin 30 remains fixedly secured to an armature of a steering column while driver's side air bag module 10 moves upon an actuation force provided by a vehicle operator. The movement of driver's side air bag module 10 causes a portion of the pin to become in contact with another portion of the driver's side air bag module in order to complete the electrical circuit of the horn switch.
[0024] An insulator 32 (See also FIGS. 10 A- 10 E), which is preferably made from plastic or other nonconductive material, is disposed about a base 34 (see FIG. 3) of pin 30 . Alternatively, insulator 32 is positioned within area 21 of raised area 20 . Insulator 32 has three features or bumps 36 that fit within grooves or openings 26 . Of course, the number of features 36 may vary along with the number of openings 26 . A coil 40 (See also FIGS. 13 A- 13 B) surrounds pin 30 and fits over insulator 32 . Coil 40 is configured to provide a biasing force between insulator 32 and a portion of the steering wheel armature 80 (See FIGS. 3A, 3B, 4 and 7 ) that pin 30 is secured to. Coil 40 may also be connected directly to insulator 32 . A locking spring 42 secures four of pins 30 to a portion of an armature 80 (See FIGS. 3 A- 3 B and 4 ). Locking spring 42 is configured to make contact with grooves located on a portion of pin 30 . Accordingly, locking pin 42 secures pins 30 and driver's side air bag module 10 to an armature 80 of a steering wheel.
[0025] Referring now to FIG. 2, base plate 14 has a plurality of slots 50 located at each corner 22 of base plate 14 . Slots 50 line up under raised areas 20 (see FIG. 1) of backing plate 12 when backing plate 12 and base plate 14 are assembled. In particular, there are three slots 50 located at each corner 22 and each of the three slots 50 aligns with each groove 26 in pin opening 24 (see FIG. 1). Slots 50 are shaped so that there is a first end 51 that is larger than a second end 52 of each slot 50 .
[0026] Referring to FIG. 3, a side view of pin 30 assembled with backing plate 12 and base plate 14 is illustrated. A sealing means or device, such as a urethane washer 60 , having a central opening is located in a cavity 61 between a first end 62 of pin 30 and base plate 14 . First end 62 has a flange 64 that is wider than width of a main body 66 of pin 30 . Main body 66 and insulator 32 are configured to allow insulator 32 to move with respect to pin 30 as a force is being applied to the air bag module. First end 62 also has an extension or contact point 70 , which protrudes outwardly from a portion of first end 62 . Extension 70 protrudes a distance that is greater than the thickness of a side 68 of washer 60 . Thus, if washer 60 is flattened against first end 62 , extension 70 extends through the central opening of washer 60 .
[0027] Pin 30 and washer 60 are inserted into insulator 32 prior to securement of backing plate 12 to base plate 14 . Insulator 32 fits over flange 64 and extends up along main body 66 of pin 30 . Insulator 32 has three features or hooked ends 72 (only one shown) that depend away from insulator 32 and extend past washer 60 when insulator 32 is assembled with pin 30 and washer 60 . Hooked ends 72 are configured to be inserted into and through first end 51 of slots 50 (see FIG. 2) of base plate 14 . In order to secure insulator 32 to base plate 14 insulator 32 is then rotated so that hooked ends 72 slide in slots 50 so that hooked ends 72 are located at second end 52 of slots 50 (see FIG. 2). This movement of insulator 32 secures pin 30 , washer 60 , and insulator 32 to base plate 14 . In addition, and through the securement of insulator 32 and a device such as washer 60 cavity 61 is an enclosed contact area, which is located between first end 62 of pin 30 and base plate 14 . The enclosed contact area is completely enclosed by washer 60 , pin 30 , and base plate 14 . Thus, extension 70 , which in the position illustrated in FIG. 3B, contacts base plate 14 and is located within the enclosed contact area and is not exposed to the elements.
[0028] Backing plate 12 is then assembled so that pins 30 are inserted through pin openings 24 located at raised areas 20 (also see FIG. 1). Raised areas 20 are configured so that backing plate 12 is seated against insulator 32 . As such, a portion of both pin 30 and insulator 32 are located within pin opening 24 . Pin opening 24 is smaller than flange 64 of pin. Backing plate 12 also helps to secure insulators 32 to base plate 14 . This also provides additional strength to insulators 32 . Coil 40 is then inserted over pin 30 and insulator 32 .
[0029] Referring again to FIG. 1, bumps or features 36 are configured to fit within grooves or openings 26 , which holds insulator 32 in place so that insulator 32 does not rotate and allow hooked ends 72 to release from slots 50 . Backing plate 12 and base plate 14 are secured to each other when an inflator (not shown) of the driver's side air bag module is secured to the backing plate 12 and base 14 , which occurs at small connection openings 18 .
[0030] Referring to FIGS. 3 and 4, pins 30 are attached to a steering wheel armature (armature) 80 through locking spring 42 . Locking spring 42 fits into a notch 82 at a second end 84 of pin 30 . Locking spring 42 has ends 86 that are located under armature 80 . In addition, locking spring 42 also hooks under an extension 88 of armature 80 . Extension 88 is located approximately half way between two pins 30 (see FIG. 4). As such, locking spring 42 secures pins 30 to armature 80 . Armature 80 contains power leads for the horn system, initiation of the air bag, and for power controls on the steering wheel.
[0031] Referring now to FIG. 5, base plate 14 is electrically connected to a power source 90 through a lead so that base plate 14 is “hot” or provided with an electrical current. In addition, pin 30 is electrically connected to a horn 92 through armature 80 or other connection means such as an electrical lead. Therefore, the horn circuit is open when the pin 30 is in the position illustrated in FIG. 3A. This is provided by the insulating qualities of insulator 32 and the air gap between extension 70 and base plate 14 . Alternatively, base plate 14 is electrically grounded and contact between pin 30 and base plate 14 is used to complete the horn activation circuit.
[0032] Referring to FIGS. 6 and 7, module 10 is located at a steering wheel 100 . Module 10 is located within an inside area 102 of steering wheel 100 . A deployable cover 104 as is known in the art is located over module 10 .
[0033] Referring now to FIGS. 1 - 7 , horn contact mechanism 11 operates as follows. A driver pushes on cover 104 of steering wheel 100 . As the driver pushes on cover 104 , a force is applied to module 10 in the direction of arrow 106 . As a result, base plate 14 and backing plate 12 move and compress coils 40 located at each pin 30 . As base plate 14 and backing plate 12 move, insulator 32 also moves with base plate 14 , which causes base plate 14 to compress washer 60 . Washer 60 flattens so that extension 70 comes into contact with base plate 14 . When extension 70 contacts base plate 14 , the electrical circuit for horn 92 is complete and horn 92 is activated. Horn 92 is grounded at armature 80 . When the driver stops pressing on the steering wheel, coil 40 forces module 10 back to its starting position and extension 70 is no longer in contact with base plate 14 and horn 92 is no longer activated.
[0034] Although four contact mechanisms are shown in the aforementioned Figures it is contemplated that the driver's side air bag module can be constructed with more or less than four mechanisms and not all pins need to be configured as a horn contact mechanism.
[0035] Alternatively, washer 60 could be removed and module 10 would operate in the same manner as described above. In that embodiment, extension 70 is still located in the enclosed contact area, and extension 70 is completely enclosed by insulator 32 , pin 30 , and base plate 14 . In either embodiment, extension 70 remains fully enclosed.
[0036] Referring to FIG. 14, an alternative embodiment for enclosed contact horn mechanism 11 is illustrated. This embodiment is similar to the one described in FIGS. 1 - 7 ; however, air bag module 10 is constructed without backing plate 12 .
[0037] Referring to FIG. 15, an alternative embodiment for enclosed contact horn mechanism 11 is illustrated. This embodiment is also similar to the one described in FIGS. 1 - 7 . Extension 70 extends from base plate 14 into cavity 61 , which is an enclosed contact area in which a first end 112 of extension contacts pin 30 . Extension 70 may be part of base plate 14 , or may be connected to base plate by welding or other such manner known in the art. Insulator 32 surrounds extension 70 , except at a first end 112 . This embodiment operates as follows. A driver exerts a force on base plate 14 , which moves and compresses coils 40 located at each pin 30 . As base plate 14 moves, insulator 32 and extension 70 also move with base plate 14 , which causes first end 112 of extension 70 to come into contact with pin 30 . When extension 70 contacts pin 30 , the electrical circuit for horn 92 (see FIG. 5) is complete and horn 92 is activated. Horn 92 is grounded at armature 80 . When the driver stops pressing on the steering wheel, coil 40 forces base plate 14 back to its starting position. Extension 70 is no longer in contact with base plate 14 and horn 92 is no longer activated.
[0038] Module 10 having an enclosed contact horn mechanism 11 provides for cavity 61 , which is also the enclosed contact area, and provides that the contact area for horn 92 , which occurs at extensions 70 , is not susceptible to environmental conditions. Consequently, extensions 70 will not corrode, which provides for improved horn blow activation. In addition, module 10 provides for all contact surfaces to occur within one assembly located at module 10 . The design also provides in-line contact points and reduces the amount of stack tolerances. As such, module 10 is also less susceptible to inadvertent horn actuation.
[0039] While this invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.
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An enclosed contact horn mechanism includes: a pin having a first end and a second end; a base plate located near the first end; and a device located between the first end and the base plate; the device, the first end, and the base plate creating an enclosed contact area, wherein the device is movable so that the base plate may contact the first end.
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[0001] This application claims priority from German patent application serial no. 10 2008 002 383.3 filed Jun. 12, 2008.
FIELD OF THE INVENTION
[0002] The invention relates to a method of controlling a hybrid drive train of a motor vehicle which is designed with serial arrangement of the internal combustion engine, a clutch, an electric motor operating as engine and generator, and a drive transmission having an output drive connection to the drive axle of the motor vehicle, wherein during thrust operation of the motor vehicle a change occurs from an electric driving mode with the internal combustion engine shut off, the clutch disengaged and an electric motor in engine operation into a combination driving mode with an internal combustion engine in thrust operation, the clutch engaged and an electric motor in engine operation, or into an internal combustion driving mode with an internal combustion engine in thrust mode, the clutch engaged and an electric motor shifted to a disconnected state, in that the clutch is engaged and the torque of the internal combustion engine is temporarily increased.
BACKGROUND OF THE INVENTION
[0003] A parallel-operating hybrid drive train with serial arrangement of components in the aforementioned manner is possible in different embodiments.
[0004] Known from DE 103 46 640 A1, for example, is one such hybrid drive train in which the electric motor is arranged coaxially about the input shaft of the driving transmission, the rotor of the electric motor is attached directly to the input shaft of the driving transmission in a non-rotational manner, and the driving transmission is designed as an automatic planetary transmission.
[0005] Described in DE 100 12 221 A1 is a hybrid drive train with a primary drive train and a secondary drive train. In the primary drive train which corresponds to the hybrid drive train under consideration herein, the relevant electric motor is arranged axis-parallel to the input shaft of the drive transmission and the rotor of the electric motor is in a drive-connection with the input shaft of the drive transmission by means of an input transmission stage with high translation ratio (i EK >1) designed as a pair of spur gears. The drive transmission is designed preferably as an automatic planetary transmission. The discussion below relating to the torque and the rotational speed of the electric motor transmission in this kind of arrangement of the electric motor applies accordingly to the reduced values applied to the output element of the input transmission stage and/or to the input shaft of the drive transmission.
[0006] In the above referenced invention the drive transmission is designed preferably as an automatic load-shift transmission, such as an automatic planetary transmission, a double clutch transmission or a stepless transmission. The drive transmission, however, can also be designed as an automatic shift transmission with countershaft design in which shifting processes are associated with an interruption in traction power.
[0007] In addition, a start-up element can be provided directly in front of the drive transmission. For example, a hydraulic torque converter can be connected upstream to an automatic transmission in a known manner which is bridged in standard drive mode, that is, outside of start-up and backing processes, by means of an engaged lock-up clutch. A start-up clutch or start-up and shifting clutch designed as dry clutch, in particular as membrane spring clutch or as wet clutch, in particular as laminar clutch which is normally engaged, can be connected upstream to a stepless transmission and to an automatic shifting transmission. The same also applies to a double clutch transmission, which is known to consist of two input shafts each with an associated start up and shifting clutch. Alternatively, a start-up element can also be integrated into the drive transmission, for example, by placement of a start-up clutch associated with the input shaft within the transmission housing of the drive transmission or in that a load-bearing, friction shift element of a drive transmission, designed as automatic transmission, is constructed as a start-up clutch.
[0008] This kind of hybrid drive train offers the possibility of operating a motor vehicle, if necessary, in a purely internal combustion drive mode, in a purely electric drive mode, or in a combination drive mode. In the internal combustion drive mode the clutch is engaged, the electric motor is disconnected and the motor vehicle is driven in traction mode solely by means of the drive torque of the internal combustion engine, and in the motor-braking mode—potentially in addition to the braking torque—the motor vehicle is decelerated by additional braking devices, such as an operating brake or a retarder, supported by the drag torque of the internal combustion engine then running in motor-braking mode. In the electric drive mode, the clutch is disengaged, the internal combustion engine is switched off and the motor vehicle is being driven in traction mode solely by the torque of the electric motor operating then as an engine, and in motor-braking mode—perhaps additionally supported by other brake features in addition to the braking torque—the vehicle is decelerated by the drag torque of the electric motor then operating as generator.
[0009] In combination drive mode, the clutch is disengaged and the motor vehicle is driven in traction mode by the sum of the drive torques of the internal combustion engine and of the electric motor, and in motor-braking mode—perhaps additionally supported by other brake features in addition to the braking torque—the vehicle is decelerated by the sum of the drag torque of the internal combustion engine and by the electric motor then operating as generator.
[0010] In addition to the hybrid drive modes under consideration here, the internal combustion engine and the electric motor can also be operated, if necessary, with a different direction of power flow, so that the generated torques are partly cancelled out. For example, in certain operating phases of traction mode, it may be useful to operate the electric motor as a generator, opposite to the effect of the drive torque of the internal combustion engine, for instance, in order to recharge a drained electric power supply or to operate the internal combustion engine at an optimum operating point. Likewise, in certain operating phases of motor-braking it may be useful to operate the electric motor as an engine, opposite to the effect of the drag torque of the internal combustion engine, for instance, to keep the internal combustion engine above a critical rotational speed limit.
[0011] Based on the large number of different operating characteristics of the potential embodiments of this kind of hybrid drive train, known control methods usually are postulated on at least one determination of the power of the electric motor and/or on a particular design of the drive transmission. In addition, the known control methods are often restricted to the solving of partial problems occurring in the control of the particular hybrid drive train.
[0012] A method to control a corresponding hybrid drive train is disclosed in DE 43 24 010 C2 which proceeds from a design of the drive transmission as an automatic planetary transmission with a hydraulic torque converter connected immediately upstream. The known method provides that the electric motor be controlled in pure electric drive mode, such that the torque characteristic of an internal combustion engine is simulated. Furthermore, the known method provides that in the motor-braking operation of the relevant motor vehicle the braking moment (drag torque) of the internal combustion engine is supplemented by, or replaced, by a braking torque of the electric motor produced in generator operation.
[0013] A similar method to control a corresponding hybrid drive train is described in DE 101 50 990 A1. This known method also proceeds from the design of the drive transmission as an automatic planetary transmission, but no hydraulic torque converter is connected upstream thereto. This method also provides that the electric motor is controlled in a pure electric drive mode, such that the operating behavior of the internal combustion engine is simulated. In a change from electric drive mode (with idling internal combustion engine and disengaged clutch) into combination drive mode or into internal combustion drive mode, the internal combustion engine is started by engaging the clutch, whereby a soft, that is low-jolt, transition to internal combustion engine power is to be ensured. DE 101 50 990 A1 does not, however, indicate how the clutch and the electric motor are actually to be controlled, in order to achieve this result.
[0014] An additional method to control a corresponding hybrid drive train is known from DE 102 60 435 A1 which proceeds from an embodiment of the drive transmission as an automatic shift transmission, a double clutch transmission or a stepless transmission, having a second clutch (start-up and shifting clutch or start-up clutch) connected immediately upstream. This method provides that in a change from electric drive mode (with internal combustion engine shut off, disengaged first clutch and engaged second clutch) into combination drive mode, the internal combustion engine is started by engagement of the first clutch, whereby during the starting of the internal combustion engine the power output from the electric motor is increased to avoid a drop of torque on the output side, and the second clutch is partly disengaged to avoid torque fluctuations on the output side or is operated at the slippage limit. No additional data, however, is provided in DE 102 60 435 A1 about the actual control of the first clutch and of the electric motor during starting of the internal combustion engine.
[0015] Starting of the internal combustion engine by engaging the clutch located between engine and the electric motor, however, is problematic, since the breakaway torque for cranking of the internal combustion engine and the drag torque (which must be subsequently overcome to accelerate the internal combustion engine up to the rotational speed which allows start-up of the internal combustion engine) are essentially dependent on operating parameters of the internal combustion engine, such as the engine temperature (coolant temperature and oil temperature) and on the maintenance and wear state of the internal combustion engine.
[0016] Thus the breakaway torque and the starting drag torque in old internal combustion engines and/or in internal combustion engines in a poor state of maintenance and repair are much higher than for warmed-up internal combustion engines and/or for internal combustion engines in a good state of maintenance and repair. If the start-up process of the internal combustion engine, in particular the wear on the clutch, is performed without taking account of the relevant operating parameters, there necessarily results different starting times for starting of the internal combustion engine and accordingly different control processes for changing from the electric drive mode into the combination drive mode or into the internal combustion drive mode.
SUMMARY OF THE INVENTION
[0017] Therefore, the object of this invention is to propose an improved method to control a hybrid drive train of the kind described above in which the change from the electric drive mode into the combination drive mode or into the internal combustion drive mode during traction operation of the motor vehicle is possible in an essentially reproducible manner, regardless of the current operating parameters of the internal combustion engine.
[0018] This object is attained in that the engagement of the clutch is regulated at least until a starting rotational speed n Start of the internal combustion engine is reached in such a manner that the acceleration dn VM /dt of the internal combustion engine takes place according to a predetermined progression of rotational speed n VM (t) and that the torque M EM of the internal combustion engine is increased during this time by the same amount as the transferred torque M K of the clutch is increased by the engagement process (dM EM /dt=dM K /dt, (ΔM EM =ΔM K ).
[0019] Accordingly, the method of the invention proceeds from a hybrid drive train of a motor vehicle which is designed as a parallel hybrid drive with a serial arrangement of the internal combustion engine, a clutch, an electric motor operating as an engine and generator, and a drive transmission having an output drive connected to the axle input drive of the motor vehicle. When the motor vehicle is in traction mode, a change should occur from an electric drive mode into a combination drive mode or into an internal combustion mode in a generally smooth and thus comfortable and low-wear manner. The electric drive mode is characterized in that the internal combustion engine is shut off, the clutch is disengaged and the electric motor is being operated as an engine. In the combination drive mode, the internal combustion engine is in traction mode, the clutch is engaged and the electric motor is being operated as an engine. In the internal combustion drive mode, the internal combustion engine is in traction operation, the clutch is engaged and the electric motor is disconnected.
[0020] With the motor vehicle in traction mode, a change from the electric drive mode into combination drive mode or into internal combustion drive mode, like that known from DE 102 60 435 A1, takes place, in that the internal combustion engine is started by engaging the clutch and by a temporary increase in the torque M EM of the electric motor.
[0021] In order to implement the change from the electric drive mode into the combination drive mode or into the internal combustion drive mode independently of the current operating parameters of the internal combustion engine and in an essentially reproducible manner, the invention provides that engaging the clutch is regulated at least until a starting rotational speed n Start of the internal combustion engine is reached, so that an acceleration dn VM /dt of the internal combustion engine is adjusted which corresponds to a predetermined progression of rotational speed n VM (t). In order to thus avoid a drop of torque on the input shaft of the drive transmission and to achieve essentially steady torque progression during this action, the torque M EM of the electric motor is increased by the amount that the transmissible torque M K on the clutch is increased by the engagement process (dM EM /dt=dM K /dt, ΔM EM =ΔM K ). Accordingly, in this phase the transferable torque M K forms the control value which is tracked by the torque M EM produced by the electric motor.
[0022] As a result of the fact that the internal combustion engine is always accelerated and started in the same amount of time independent of the current operating parameters which, like the engine temperature T VM and the current state of maintenance and repair of the internal combustion engine, basically influence the breakaway torque for cranking of the internal combustion engine and the drag torque for subsequent acceleration of the internal combustion engine up to the starting rotational velocity n Start , the corresponding changes of the hybrid drive mode always occur essentially in the same way. This simplifies the control of additional functions of the hybrid drive train and provides passengers within the vehicle with an improved sensation of comfort.
[0023] The predetermined progression of rotational speed n VM (t) of the internal combustion engine is defined preferably as a ramp-like increase in rotational speed with a constant rotational speed gradient dn VM /dt=C, so that a relatively simple control of the clutch actuator is possible by means of an associated clutch characteristic line and the controlled electric motor dependent thereon.
[0024] In order to achieve the lowest possible jolt-profile of torque during the continued shifting to the hybrid drive mode, the invention further provides that after the start of the internal combustion engine, roughly during the same time as the internal combustion engine is accelerated to the rotational speed n EM of the electric motor, the clutch is further engaged and the increase in torque M EM of the electric motor caused by the engine start is decreased again.
[0025] The invention also provides that after the reduction in the increase in torque M EM of the electric motor caused by engine start, the torque M VM of the internal combustion engine is increased to its target value and the torque M EM of the electric motor is decreased in a coordinated manner to its particular target value.
[0026] An essentially steady torque transition is achieved, preferably in that the torque M EM of the electric motor is reduced as a function of the torque M VM of the internal combustion engine to the same amount as the torque M VM of the internal combustion engine is increased (dM EM /dt=−dM VM /dt, ΔM EM =−ΔM VM ). Consequently, in this phase the torque M VM of the internal combustion engine forms the control value, which is inversely tracked by the torque M EM produced by the electric motor.
[0027] In addition it is advantageous to reduce the control effort, that a control parameter of an associated clutch actuator determining the initial torque gradient (dM K /dt) a of the clutch during engagement of the clutch caused by engine start is corrected with each change in the hybrid driving mode as a function of at least one relevant and currently determined operating parameter of the internal combustion engine. The result, then, is that the clutch is engaged by the base controller of the clutch actuator which was used, such that the predetermined progression of rotational speed n VM (t) or the predetermined gradient of rotational speed dn VM /dt is essentially maintained and that very little subsequent regulation is needed.
[0028] In this regard, it appears to be particularly useful that a relevant engine temperature T VM of the internal combustion engine is detected by sensors and that the control parameter of the clutch actuator in the presence of an engine temperature (T VM >T Ref ) greater than a reference temperature T Ref is corrected in the sense of a lower engagement gradient (dM K /dt) a and in the presence of an insufficient engine temperature (T VM <T Ref ), the reference temperature T Ref is corrected in the sense of a higher engagement gradient (dM K /dt) a .
[0029] Likewise, in this regard the shut-down period Δt Abst can be detected, since the last shut-down of the internal combustion engine and the control parameter of the clutch actuator can be corrected in the presence of a shut-down period (Δt Abst >Δt Ref ) greater than a reference time Δt Ref in the sense of a higher engagement gradient (dM K /dt) a , and in the presence of a shut-down period (Δt Abst <Δt Ref ) less than a reference time Δt Ref , in the sense of a lower engagement gradient (dM K /dt) a .
[0030] One particularly advantageous adaptation method to reduce the control effort consists of a control parameter of an associated clutch actuator which determines the intermediate torque gradient (dM K /dt) m of the clutch during the engagement of the clutch caused by engine start, that is determined with each change into the hybrid driving mode and of a deviation from the previously valid control parameter for control of the initial torque gradient (dM K /dt) a of the clutch which is adapted to the currently determined control parameter.
[0031] The adaptation of the formerly valid control parameter can comprise, in a known manner, the correction of the formerly valid control parameter in the direction of the currently determined control parameter or the replacement of the formerly valid control parameter by the currently determined control parameter and also the saving of the control parameter determined in this manner instead of the formerly valid control parameter. Preferably longer-term and irreversibly changed operating parameters of the internal combustion engine, such as the wear state of the internal combustion engine, are implicitly detected and automatically compensated with this procedure.
[0032] Without additional measures, even short-time variable operating parameters such as the engine temperature T VM and the maintenance state of the internal combustion engine are detected and compensated frequently and partly offset with respect to each other. This, however, can be avoided in that the control parameter of the associated clutch actuator which determines the intermediate torque gradient (dM K /dt) m of the clutch is ascertained in connection with at least one current, short-term variable operating parameter, and that the relevant previously valid control parameter is determined as a function of the at least one operating parameter for control of the initial torque gradient (dM K /dt) a of the clutch from a plurality of control parameters parameterized accordingly and is subsequently adapted.
[0033] The determination of the formerly applicable control parameter can take place, for example, when using the current engine temperature T VM as a short-term variable operating parameter, in that the current engine temperature T VM is sensed, and that then the control parameter linked with the nearest engine temperature T VM is chosen as the formerly valid control parameter from the plurality of control parameters having the operating temperature T VM as a parameter or the formerly valid control parameter is determined by interpolation from the control parameters linked with the nearest engine temperatures T VM . Any potentially necessary adaptation of this control parameter for the control of future changes of the hybrid drive mode is then restricted in a favorable manner to other operating parameters, not including the operating parameters involved here (for example, the engine temperature T VM ).
[0034] The change to hybrid drive mode is initiated when a limit torque M EM — Gr is reached or exceeded by the current torque M EM of the electric motor. The reason for this can be an increasing power demand by the driver or a load state of the electric power supply to the electric motor which is falling below a critical level. The level of the limiting torque M EM — Gr is variable and is obtained by subtraction of a start up torque ΔM EM — Start and a control reserve ΔM EM — Res from a maximum torque M EM — max , which is also variable and is basically determined by the current load state of the electric power supply (M EM — Gr =M EM — max −ΔM EM — Start −ΔM EM — Res ).
[0035] The control reserve ΔM EM — Res is a safety reserve and is used to prevent a low discharge of the electric power supply. The start-up torque ΔM EM — Start is reserved for compensation of the increasing clutch torque M K , when starting the internal combustion engine VM, and thus in principle is determined by the breakaway torque and the drag torque of the internal combustion engine VM. Since the current operating state of the internal combustion engine VM is not inherently known very accurately, a start-up torque ΔM EM — Start was reserved up to now for the worst case, that is, for the largest possible breakaway torque and drag torque of the internal combustion engine. This, however, has the disadvantageous result that the capacitance of the electric power supply is not used to the optimum and thus the limiting torque ΔM EM — GR is usually set too low, and thus the change into combination drive mode or into internal combustion drive mode occurs too early.
[0036] To avoid this disadvantage, the invention provides that a torque M EM — Gr of the electric motor causing the change of the hybrid driving mode is determined as a function of at least one relevant and currently detected operating parameter of the internal combustion engine.
[0037] For this, a relevant engine temperature T VM of the internal combustion engine, such as the oil temperature or the coolant water temperature, is detected by sensors and the torque M EM — Gr of the electric motor is increased in the presence of an engine temperature (T VM >T Ref ) above a reference temperature T Ref and is reduced in the presence of an engine temperature (T VM <T Ref ) below the reference temperature T Ref .
[0038] Likewise in this regard, it is possible to detect the shut-down period Δt Abst since the last shut-down of the internal combustion engine, and then the torque M EM — Gr of the electric motor is reduced in the presence of a shut-down period (Δt Abst >Δt Ref ) greater than a reference time Δt Ref and is increased in the presence of a shut-down period (Δt Abst <Δt Ref ) less than a reference time Δt Ref .
[0039] The hybrid drive train from DE 102 60 435 A1 with a second clutch (start up and shifting clutch) connected directly upstream to the drive transmission which uses a known method for damping of occurring torque peaks by partly disengaging the second clutch during the change to the hybrid drive mode or of operating at the slippage limit can also be transferred to differently designed hybrid drive trains.
[0040] Accordingly, in an embodiment of the drive transmission as a double clutch transmission equipped with two shift clutches the invention envisions that the load-bearing shift clutch is kept disengaged up to the slippage limit for damping of torque peaks during the change of the hybrid driving mode. This means that the relevant shift clutch is disengaged at the beginning of the method up to the slippage limit, is held at the slippage limit during the process, and is then fully engaged again at the end of the process. The damping of occurring torque peaks is achieved in that the function of the relevant shift clutch changes briefly into that of an anti-slip clutch during slipping operation and thus smoothes out or filters out the positive torque peaks.
[0041] In one embodiment of the drive transmission as an automatic planetary transmission equipped with friction shift elements, the damping of the torque can be attained in that at least one of the load-bearing friction shift elements is kept disengaged up to the slippage limit for damping of torque peaks during the change to the hybrid driving mode.
[0042] In the presence of a hydraulic torque converter arranged directly in front of the driving transmission and equipped with a lock-up clutch, however, the damping of the torque peaks can be attained in that the lock-up clutch is kept fully disengaged for damping of torque peaks during the change to the hybrid driving mode. This means that the lock-up clutch is fully disengaged at the beginning of the process, is kept disengaged during the process, and is then fully engaged again at the end of the process. The damping of occurring torque peaks in this case is brought about by the elastic, damping transmission properties of the torque converter.
[0043] Now if a gear shift is intended in the time proximity to the change of the hybrid driving mode, then this gear shift process should be carried out simultaneously with the change to the hybrid driving mode, since the torque peaks caused by the shift and the torque peaks caused by the change to hybrid drive mode can be partly eliminated or at least will be perceived by vehicle passengers as a single, comfort-reducing load jolt.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] To illustrate the invention, figures with design embodiments are attached to the description. These figures show:
[0045] FIG. 1 A shifting sequence according to the invention from the electric drive mode into combination drive mode for a hybrid drive train in traction mode of the motor vehicle in the form of the relevant torque- and rotational speed profiles; and
[0046] FIG. 2 A known sequence of shifting from the electric drive mode into the combination drive mode of a hybrid drive train in traction mode of the motor vehicle in the form of the relevant torque- and rotational speed profiles.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0047] In the two diagrams of FIGS. 1 and 2 two different processes are illustrated, based on relevant torque- and rotational speed profiles, which each relate to a hybrid drive train of a motor vehicle that is designed as a parallel hybrid with a serial arrangement of an internal combustion engine VM, a clutch K, an electric motor EM operable as an engine and a generator, and a drive transmission having a drive connection on the output side to a drive axle of the motor vehicle.
[0048] Based on the torque profiles of the internal combustion engine, of the electric motor and of the transmissible torque to the clutch, M VM (t), M EM (t), M K (t), illustrated in part a), and also based on the profiles of rotational speed n VM (t), n EM (t) of the internal combustion engine and of the electric motor illustrated in part b) of the figures, it is clear how in the traction mode of the motor vehicle a change from an electric drive mode, in which the internal combustion engine is shut off, the clutch is disengaged and the electric motor is operating as engine, into a combination drive mode will occur, in which the internal combustion engine is in traction mode, the clutch is engaged and the electric motor is operating at reduced torque as an engine.
[0049] In the generally well-known process according to FIG. 2 , the torque M EM of the electric motor at time t 0 reaches a limiting torque M EM — Gr , so that the change is triggered from the electric drive mode into the combination drive mode. The limiting torque M EM — Gr has fallen so much in comparison to a maximum torque M EM — max determined essentially by the current load state of an associated electric power supply, that the maximum torque M EM — max is neither reached nor exceeded during the following control process.
[0050] The internal combustion engine is first accelerated during the initiation of the change to hybrid drive mode by engaging the clutch and a simultaneous increase in the torque M EM of the electric motor, until the start-up rotational speed n Start necessary to start the internal combustion engine is reached. Since this occurs independently of the current operating state of the internal combustion engine, however, that is, independent of the current breakaway torque for cranking and of the drag torque for subsequent acceleration of the internal combustion engine, always with the same control sequences for engaging of the clutch and for increasing the torque M EM of the electric motor, different torque profiles n VM (t) unavoidably occur, especially during the acceleration of the internal combustion engine.
[0051] Thus in FIG. 2 , part-figure b), n VM ′(t) denotes a relatively steep progression of rotational speed which is adjusted for extremely low breakaway torque and drag torque of the internal combustion engine that exist in an operationally warm internal combustion engine with a good maintenance and repair status. On the other hand, n VM ″(t) illustrates a relatively flat progression of rotational speed which is adjusted for extremely high breakaway torque and drag torque of the internal combustion engine that exist in an operationally cold internal combustion engine with a poor maintenance and repair status. The bandwidth of possible progressions of rotational speed n VM (t) is illustrated in FIG. 2 , sub-figure b) by the shaded region between these two limiting progressions n VM ′(t) and n VM ″(t).
[0052] Once the start-up rotational speed n Start is reached at time t 1 ′ or t 1 ″, the internal combustion engine is then started by internal combustion, passes over from motor-braking into traction mode, and then as its torque M VM ′ or M VM ″ increases, is accelerated to the rotational speed n EM of the electric motor which is reached at time t 2 ′ or t 2 ″.
[0053] At the same time, the clutch is again engaged and the increase in torque M EM ′ or M EM ″ of the electric motor decreases again. Next, the torque M VM of the internal combustion engine increases to its target value and the torque M EM of the electric motor is reduced to its target value.
[0054] In the case of an extremely low breakaway- and drag torque of the internal combustion engine (see profiles of rotational speed and torque n VM ′, M VM ′, M EM ′) the change to hybrid drive mode occurs relatively quickly and is concluded right at time t 3 ′. In the case of an extremely high breakaway- and drag torque of the internal combustion engine (see profiles of rotational speed and torque n VM ″, M VM ″, M EM ″), the change to hybrid drive mode is relatively slow and is not concluded until later at time t 3 ″. The bandwidth of possible progressions of torque, is illustrated in FIG. 2 by the shaded region between these two limiting progressions M VM ′(t) and M VM ″(t), and/or M EM ′(t) and M EM ″(t).
[0055] Depending on the current operating state of the internal combustion engine, starting times of varying length therefore result for starting of the internal combustion engine and accordingly different control processes for changing from electric drive mode to combination drive mode, so that the control of additional functions of the hybrid drive train is impeded and a negative comfort sensation will be perceived by the vehicle passengers.
[0056] Conversely, in the inventive process sequence according to FIG. 1 , a reproducible, that is, always essentially identical control sequence is achieved, regardless of the current operating state of the internal combustion engine.
[0057] In order to attain this advantage, the invention provides, that engagement of the clutch starting at time t 0 is controlled, at least until reaching the starting rotational speed n Start of the internal combustion engine, in such a manner that the acceleration dn VM /dt of the internal combustion engine occurs according to the predetermined profile of rotational speed n VM (t) which in the present case is defined as a ramp-like increase in rotational speed with a constant gradient of rotational speed (dn VM /dt=C) (see FIG. 1 , sub-figure b). During the acceleration of the internal combustion engine to its starting rotational speed n Start , which is reached at time t 1 , the torque M EM of the electric motor is increased to the same extent as the transmissible torque M K on the clutch is increased by the engagement process (dM EM /dt=dM K /dt, ΔM EM =ΔM K ). The transmissible torque M K on the clutch in this phase thus forms the control value which is tracked by the torque M EM generated by the electric motor.
[0058] Since the maintenance of the predetermined profile of rotational speed n VM (t) requires different torque gradients dM K /dt, dM EM /dt on the clutch and on the electric motor, depending on the current operating state, i.e., on the level of the current breakaway- and drag torque on the internal combustion engine, there necessarily result different torque progressions M K (t), M EM (t), M VM (t).
[0059] In the case of an extremely low breakaway- and drag torque on the internal combustion engine at the given acceleration of the internal combustion engine, a relatively low torque gradient dM K /dt results at the clutch. The resulting torque progressions on the clutch, on the electric motor and on the internal combustion engine are denoted in FIG. 1 , sub-figure a), as M K *, M EM *, and M VM *.
[0060] In the case of an extremely high breakaway- and drag torque on the internal combustion engine at the indicated acceleration of the internal combustion engine, a relatively high torque gradient d M K/dt occurs at the clutch. The resulting torque progressions on the clutch, on the electric motor and on the internal combustion engine are denoted in FIG. 1 as M K **, M EM ** and M VM **. The bandwidth of possible torque progressions for the time t 0 to t 1 is illustrated in FIG. 1 by the shaded region between these two limiting progressions M K *(t) and M K **(t), M EM *(t) and M EM **(t), and M VM *(t) and M VM **(t) (see FIG. 1 , sub-figure a).
[0061] The internal combustion engine transitions from motor-braking into traction mode at the internal-combustion start. Then, to achieve the most harmonious and low-jolt output torque profile, the internal combustion engine is accelerated at approximately the same time to the rotational speed n EM of the electric motor, which is reached at time t 2 , the clutch continues to be engaged, and the increase in torque M EM of the electric motor caused by the engine start is again reduced. Next, the torque M VM of the internal combustion engine and the torque M EM of the electric motor are controlled to their particular target values in a coordinated manner, in that the torque M EM of the electric motor is reduced to the same extent as the torque M VM of the internal combustion engine is increased (dM EM /dt=−dM VM /dt, ΔM EM =−ΔM VM ). Thus in this phase, the torque M VM of the internal combustion engine forms the control value which is tracked by the torque M EM produced by the electric motor EM.
[0062] Once the particular target values of torques M VM , M EM are reached at time t 3 , the change to hybrid drive mode is completed. In spite of the torque profiles M K *(t), M EM *(t), M VM *(t) and/or M K **(t), M EM **(t), M VM **(t) having different level or gradient at time t 0 depending on the current operating state of the internal combustion engine, basically identical time profiles of the control processes are obtained, so that a reproducible change from the electric drive mode into the combination drive mode is achieved.
REFERENCE CHARACTERS
[0000]
C Constant
EM Electric motor
i EK Translation of the electric motor
K Clutch
M EM Torque of the electric motor
M EM ′ Torque of the electric motor
M EM ″ Torque of the electric motor
M EM * Torque of the electric motor
M EM ** Torque of the electric motor
M EM — Gr Limiting Torque of the electric motor
M EM-max Maximum torque of the electric motor
M K Transmissible torque of the clutch, clutch torque
M K * Transmissible torque of the clutch, clutch torque
M K ** Transmissible torque of the clutch, clutch torque
M VM Torque of the internal combustion engine, engine torque
M VM ′ Torque of the internal combustion engine, engine torque
M VM ″ Torque of the internal combustion engine, engine torque
M VM * Torque of the internal combustion engine, engine torque
M VM ** Torque of the internal combustion engine, engine torque
n EM Rotational speed of the electric motor
n VM Rotational speed of the internal combustion engine
n VM ′ Rotational speed of the internal combustion engine
n VM ″ Rotational speed of the internal combustion engine
t 0 -t 3 Time points
t 1 ′-t 3 ′ Time points
t 1 ″-t 3 ″ Time points
T Ref Reference temperature
T VM Engine temperature
VM Internal combustion engine
ΔM EM Change in torque of the electric motor
ΔM EM — Res Standard reserve of the electric motor
ΔM EM — Start Starting torque of the electric motor to start the internal combustion engine
ΔM K Change in torque of the clutch
ΔM VM Change in torque of the internal combustion engine
t Time
Δt Time period
Δt Abst Shut-down period
Δf Ref Reference time
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A method of controlling a hybrid drive train of a vehicle having, in series, an internal combustion engine, a clutch, an electric motor and a transmission with an output connected to the drive axle. During traction operation, the vehicle changes from an electric driving mode into a combination driving mode or a combustion engine driving mode, in that the clutch is engaged and the combustion engine torque is temporarily increased. The method includes regulating engagement of the clutch at least until reaching a starting rotational speed of the combustion engine such that the acceleration of the combustion engine occurs according to a predetermined progression of rotational speed and that the torque of the combustion engine is increased by the same amount as the transferable torque of the clutch is increased by the engagement process.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/668,648, filed on Apr. 6, 2005, entitled HANDLE WRAPPER; the prior application is herewith incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is a cover for an elongated handle of a shopping cart, typically used in grocery stores or other similar stores, that provide such a cart for customers, or other similar carts used by the public, such as in airports, for luggage handling situations, where the user of the cart holds a handle of the cart that has previously been used or touched by a prior user. The present cover provides a clean surface, covering the handle so the present user can avoid touching the handle, touched by a previous user which may have been dirtied or contain disease causing bacteria, germs or other harmful matter as a result of prior use.
[0004] 2. Description of the Related Prior Art
[0005] There are many reasons why a second user may desire not to directly touch a handle used by a prior first user including health and sanitary reasons. Some have attempted to provide washing solutions in close proximity to the area where a new user would select a shopping cart. However these washing solutions are wet and messy and require an applicator to apply the washing solution to the handle of the shopping cart. Disposal of the applicator causes for example an unsightly mess. Others have provided covers for the entire cart or portions of the cart. However these covers are bulky, and are not generally disposable. Some companies even provide bacteria shopping cart washers.
SUMMARY OF THE INVENTION
[0006] The present invention is related to shopping carts. Shopping carts were invented in the 1930's with the advent of the supermarket, when shoppers needed more than a hand held bag to carry their groceries. In the 1940's shopping carts acquired most of the features we are familiar with today. In 1947, the carts were first nested. Notwithstanding different materials of wire and plastic, all shopping carts have a handle.
[0007] The present invention is a cover, which preferably may be made of a thin material, such as paper, a paper like material, or of plastic, for placement around the elongated shopping cart handle. The cover is preferably disposable, for one time use by a present user, and is inexpensive.
[0008] Typically, a store such as a grocery store will have hundreds of carts, which are generally stored and located at an entrance of the store. The exact location will most likely be in a convenient setting for shoppers to select a shopping cart when they enter the store. Since shopping carts are generally substantial in construction, of steel and wire or heavy plastic materials, they are re-used continuously by the store. When shopping, a user will push the cart through the store, up and down aisles, while loading goods into the cart. The shopper will hold and direct or steer the cart, using the cart's elongated handle, which is usually an integral part of the cart. Thus each user, typically holds the handle with their hands, contacting it—usually with uncovered hands—to push and steer the cart. Each user holds the handle many times as the cart is moved from location to location throughout the store during the shopping process.
[0009] It is often considered to be unhealthy to hold a handle when another person has touched and in most cases recently touched or come in contact with the handle. Additionally, external elements, such as the weather, outside matter etc. come in contact with the handle. Thus there is a rapid spread of germs from the handle, transferred from one person—a first cart user—to another person—a second cart user.
[0010] There is also provided a dispenser of the present invention at or near a storage area. The covering of the handle is accomplished with a sheet of paper or other material, cut to size, so that the covering, can be easily applied to the shopping cart handle. The coverings are dispensed from a roll of coverings that may or may not be within a dispenser container. In this manner, when a new user is about to use the shopping cart, this second cart user can apply a covering to the handle that was previously touched by a prior user or users of the cart. The new user thus has a clean area to touch when holding the handle of the shopping cart.
[0011] Thus the present invention also provides for a novel way of dispensing the covers of the present invention for easy removal of the cover from its stored position. After use, the cover is preferably removed from the handle by disengaging the releasable adhesive. The cover is then disposed as any other waste paper or material, preferably in a waste container.
[0012] Whether the covering from the dispenser is sterile or not, the new user can hold the handle without concern of touching and coming in contact with the same handle previously touched by another. This eliminates the transfer of germs and other dirt from an area a prior user came in contact with to a present user.
[0013] The cover may include coatings to limit moisture and/or to kill harmful germs, such coatings may be antimicrobial coatings. Additional coatings may cause the cover to curl, such that the cover will curl around the handle, when placed on the handle. The curl may also be created by the construction of the cover material, as is known in the art.
[0014] These and other aspects and features of the invention are described in more detail below and are illustrated in the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Referring to the drawings which are made a part hereof this application,
[0016] FIG. 1 . is a top view of a portion of a shopping cart showing the handle portion of said cart.
[0017] FIG. 2 . is a sectional view taken along lines 2 - 2 of FIG. 1 . showing a cross-section of a shopping cart the handle.
[0018] FIG. 3 . is a cross sectional view of a portion of a roll of covers of the present invention to be dispensed for use, showing the arrangement of the said covers in end to end relationship.
[0019] FIG. 4 . is a sectional view of a single cover of the present invention showing the first end and the second end, and an adhesive.
[0020] FIG. 5 . is a rear view of a portion of a shopping cart, the present invention, showing how an advertisement printed on the cover of the present invention would be displayed.
[0021] FIG. 6 . is a cross sectional view of a preferred embodiment of the present invention, showing the relationship of the cover with the handle such that the two ends of the cover are positioned below the handle, positioning the advertisement in a preferred position for viewing.
[0022] FIG. 7 is a schematic view of a shopping cart, with a handle.
[0023] FIG. 8 is a sectional view of an alternative embodiment of the cover of the present invention having the adhesive on the second end.
[0024] FIG. 9 is an alternate embodiment showing the covers in a stacked relationship.
[0025] FIG. 10 is a view of the handle 11 with more than one cover 13 around it.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] In the present invention, reference is made to a cart such as a shopping cart 12 as shown in FIG. 7 ., having a handle 11 generally at the rear of the cart and an open storage area 17 to receive items that shoppers are purchasing, generally for short term storage. Cart 12 has wheels 18 , usually three or four wheels so that cart 12 is balanced while being pushed, and guided by the user holding handle 11 . Typically handle 11 will be of plastic or wood, is generally cylindrical and will be supported on a wire structure of cart 12 . A typical handle 11 as shown in FIG. 1 . is supported by a pair of cart arms 12 a and 12 b extending from the cart cage area 12 c. Handle 11 is elongated, generally cylindrical and is threaded on support 12 d of cart 12 . As shown in FIG. 2 , handle 11 has a radius “r” and would have a resulting circumference 2 pi r.
[0027] A cover 13 , also as described herein a wrapper 13 , has a length from one end to another end “A” as shown in FIGS. 3 and 4 . This length “A” is greater than the circumference of handle 12 , preferably 25% to 50% greater, but may be 50% to 100% greater. Cover 13 has a width “B” FIG. 5 slightly less than the width C of handle 11 .
[0028] As shown in FIG. 4 , cover 13 has a first end 16 and a second end 19 . Preferably the length “A” of cover 13 is such that as shown in FIG. 6 , first end 16 overlaps second end 19 . When cover 13 is provided with a curl, known in the art of paper manufacturing, cover 13 will curl around handle 13 and the ends, end 16 will overlap end 19 . Additionally, a releasable adhesive 14 can releasably be used to attach first end 16 of wrapper 13 to second end 19 as shown in FIG. 6 . Though FIG. 6 shows use of adhesive 14 , with or without the adhesive 14 , when the cover 13 has a curl, the ends 16 and 19 will overlap or be in close proximity to each other. Wrapper 13 is constructed and arranged to be secured around handle 11 , by attachment of said first end 16 with said second end 19 by said adhesive 14 . The inside circumference of closed cover 13 is greater than the circumference of handle 11 such that cover 13 rests on handle 11 in a loose manner depending on the actual length A of cover 13 , the amount of open area 20 , under handle 11 will increase or decrease.
[0029] It is not necessary that secured wrapper 13 be tight against handle 11 . It is preferably loosely fitted around handle 11 . Preferably the weighted portion of the ends, first end 16 , and second end 19 , in close attached relationship, would cause the wrapper 13 to align itself, by gravitational pull, such that the heavier, attached portions, in the proximities of first end 16 and second end 19 , would be drawn by gravity to rest such that wrapper 13 was orientated with the first end 19 and second end 19 at the bottom or a lower level in relationship to handle 11 , see FIG. 6 .
[0030] As shown in FIG. 6 , the top of handle 11 is in contact with the inside portion of wrapper 13 when wrapper 13 is secured around handle 11 with first end 16 attached to second end 19 as heretofore described. In this manner, an advertisement 15 , would be in a preferable orientation for the user of a cart to view advertisement 15 . It is also possible that an advertisement 15 can be repeating across the entire exposed area of cover 13 such that the advertisement would be visible no matter what position cover 13 is in.
[0031] In order to easily dispense handle wrapper 13 , it preferably would be placed on a roll as shown in FIG. 3 whereby each handle wrapper 13 would be arranged first end 16 of one wrapper 13 to second end 19 of a second wrapper 13 whereby a user could peel off one handle wrapper 13 at a time. Each handle wrapper 13 would have a first end 16 attached to a second end 19 by adhesive 14 . As shown in FIG. 3 , first end 16 is available for a user to grab and pull causing a roll to rotate, such that first end 16 of a handle wrapper 13 would be grabbed by a user and pulled until handle wrapper 13 disengages from the next handle wrapper 13 to be grabbed. Each handle wrapper 13 is attached to the following handle wrapper 13 in similar fashion, preferably using adhesive 14 .
[0032] In one preferred embodiment, handle wrapper 13 is made of paper. A characteristic of handle wrapper 13 is a memory curl of each handle wrapper 13 so that handle wrapper 13 will, after being removed from the roll as shown in FIG. 3 , conform in a general shape around handle 11 as shown in FIG. 6 . In this manner, when handle wrapper 13 is applied to a handle 11 , it can easily be placed over handle 11 and paper wrapper 13 , because of its memory curl will conform to the handle even if loosely surrounding said handle as shown in FIG. 6 as heretofore described. In an alternate embodiment, it is not necessary to have adhesive 14 , since the memory curl of cover 13 will cause the two ends first end 16 to overlap second end 19 . Because of the memory curl, the cover 13 will remain in said curled position with overlapping ends 16 and 19 , as shown in FIG. 6 , with or without adhesive 14 .
[0033] As an alternate embodiment, the adhesive 14 as shown in FIG. 8 is in the proximity of first end 16 at the outside portion thereof. It is also possible to have the adhesive 14 at the close proximity to second end 19 at the inner side of wrapper 13 . In the alternate embodiment, a similar roll would be arranged as in FIG. 3 but with the adhesive as described in the alternate embodiment and as shown in FIG. 8 .
[0034] In a second alternate embodiment, the preferred wrapper material 13 could be a plastic, a plastic sheet that has a “curl” memory. Said wrapper is material whether paper, plastic or other material, could be of a range of 0.1 mil inches to 20 mils.
[0035] After use, preferably a user will remove the handle wrapper 13 and properly dispose it in a waste can. If the prior user does not do so, the next user can either dispose of the used wrapper 13 or the said next user can use a new wrapper 13 to cover the handle 11 which also has a used cover 13 thereon. There will be sufficient room for subsequent wrappers 13 to cover prior wrappers 13 since the length A of wrapper 13 is greater than the circumference of handle 11 . As shown in FIG. 10 , a handle 11 , with a first prior cover 13 is under a current cover 13 with the prior cover 13 folded at location “F” to allow room for the next cover 13 , as shown in FIG. 10 .
[0036] Although the disclosure set out herein is detailed in order to enable those skilled in the art to practice the invention, the embodiments disclosed herein are to be considered only examples of the invention which may be embodied in other specific structures as well.
[0037] Those skilled in the art will recognize that a number of other modifications to the invention are also possible. Accordingly, the invention should not be deemed limited to the specific embodiments described hereinabove and illustrated in the drawings, but instead only by a fair scope of the claims that follow along with their equivalents.
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The present invention is a paper cover having a curl, for placement on an elongated handle of a shopping cart so that the user of the cart does not have to touch the handle of the cart that may have come in contact with germs or dirt of a prior user, the cover is designed to have a curl such that the paper material will tend to conform to the handle of the cart, the cover may include an antimicrobial material.
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CROSS-REFERENCE TO RELATED APPLICATION(S)
None.
BACKGROUND OF THE INVENTION
The present invention relates to a system and method for storage of, and interfacing with, portable medical devices. In particular, the invention relates to a docking system and method for storing, charging, and transmitting data to and from portable medical devices, including non-invasive blood pressure measurement devices.
There has been a continuing need for devices which will measure blood pressure non-invasively, with accuracy comparable to invasive methods. Medwave, Inc. the assignee of the present invention, has developed non-invasive blood pressure measurement methods and devices which are described in the following United States patents, hereby incorporated by reference: U.S. Pat. No. 5,649,542 entitled CONTINUOUS NON-INVASIVE BLOOD PRESSURE MONITORING SYSTEM; U.S. Pat. No. 5,450,852 entitled CONTINUOUS NON-INVASIVE PRESSURE MONITORING SYSTEM; U.S. Pat. No. 5,640,964 entitled WRIST MOUNTED BLOOD PRESSURE SENSOR; U.S. Pat. No. 5,720,292 entitled BEAT ONSET DETECTOR; U.S. Pat. No. 5,738,103 entitled SEGMENTED ESTIMATION METHOD; U.S. Pat. No. 5,722,414 entitled CONTINUOUS NON-INVASIVE BLOOD PRESSURE MONITORING SYSTEM; U.S. Pat. No. 5,642,733 entitled BLOOD PRESSURE SENSOR LOCATOR; U.S. Pat. No. 5,797,850 entitled METHOD AND APPARATUS FOR CALCULATING BLOOD PRESSURE OF AN ARTERY; and U.S. Pat. No. 5,941,828 entitled HAND-HELD NON-INVASIVE BLOOD PRESSURE MEASUREMENT DEVICE.
As described in these patents, blood pressure is determined by sensing pressure waveform data derived from an artery. A pressure sensing device includes a sensing chamber with a diaphragm which is positioned over the artery. A transducer coupled to the sensing chamber senses pressure within the chamber. A flexible body conformable wall is located adjacent to (and preferably surrounding) the sensing chamber. The wall is isolated from the sensing chamber and applies force to the artery while preventing pressure in a direction generally parallel to the artery from being applied to the sensing chamber. As varying pressure is applied to the artery by the sensing chamber, pressure waveforms are sensed by the transducer to produce sensed pressure waveform data. The varying pressure may be applied automatically in a predetermined pattern, or may be applied manually.
The sensed pressure waveform data is analyzed to determine waveform parameters which relate to the shape of the sensed pressure waveforms. One or more blood pressure values are derived based upon the waveform parameters. The Medwave blood pressure measurement devices include both automated devices for continually monitoring blood pressure (such as in a hospital setting) and hand-held devices which can be used by a physician or nurse, or by a patient when desired.
When multiple hand-held or portable medical devices, such as the Medwave blood pressure measurement devices, are used in a common environment, such as a hospital, it would be convenient to provide a central storage medium for holding the devices, charging the batteries of the devices, as well as communicating with the devices to obtain stored information.
The information obtained from the devices through the docking station may be used in multiple ways. The information can be used by doctors and nurses for remote patient monitoring. The information can be used for billing purposes. Charts and graphs can be generated from the information, such as blood pressure or pulse rate historical data for a patient. The information can be used for sensor management (e.g., displaying sensor usage information, sensor test information and warnings, sensor expiration information and warnings, etc.).
BRIEF SUMMARY OF THE INVENTION
The present invention is a storage device and method for storing a plurality of portable medical devices and gathering and centrally storing a set of patient data gathered from the portable medical devices. In a preferred embodiment, the storage device includes a plurality of bays for receiving and storing the plurality of portable medical devices. Each portable medical device includes an electrical connector. Each bay includes a first electrical connector. The first electrical connector of each bay is configured to interface with the electrical connector of one of the portable medical devices. A second electrical connector is configured to be coupled to a computer. A battery charger is coupled to at least one of the first electrical connectors of a bay for charging a battery of one of the portable medical devices. A switch is coupled to the first electrical connector of each bay and coupled to the second electrical connector for selectively coupling each bay to the computer for data transfer between the bay and the computer.
A preferred method according to the present invention for gathering and centrally storing a set of patient data for each one of a plurality of patients includes applying a plurality of portable medical devices to a plurality of patients to obtain the patient data. The patient data is stored in the plurality of portable medical devices. The plurality of portable medical devices are placed in a docking station coupled to a computer. The stored patient data is transmitted from each portable medical device through the docking station to the computer and stored therein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a non-invasive blood pressure measurement device suitable for use with the present invention.
FIG. 2A is a side view of the blood pressure measurement device of FIG. 1 .
FIG. 2B is a bottom view of the blood pressure measurement device of FIG. 1 .
FIG. 3 is an electrical block diagram of the blood pressure measurement device.
FIG. 4 is a perspective view of a docking station according to the present invention.
FIG. 5 is a schematic diagram of multiple docking stations coupled together.
FIG. 6 is a high level flow diagram illustrating the flow of information in the present invention.
FIGS. 7A and 7B are electrical schematic diagrams of the docking station.
DETAILED DESCRIPTION
Prior to describing the docking system and method of the present invention, a description is provided of a blood pressure measurement device, which is suitable for use in conjunction with the docking system.
FIG. 1 illustrates a blood pressure measurement device being used to measure and display blood pressure within an underlying artery within wrist 12 of a patient. Blood pressure measurement device 10 includes placement guide 13 , main housing 14 , display panel 16 , patient identification toggle 18 , power switch 20 , and sensor interface assembly 22 (best shown in FIGS. 2 A and 2 B).
Using placement guide 13 of measurement device 10 , measurement device 10 is placed at the projection of the styloid process bone perpendicular to wrist 12 . With device 10 , a small amount of force is manually applied to the radial artery, which runs along the styloid process bone. As the force is manually applied, blood pressure waveforms are recorded and the corresponding hold down pressure which is being manually applied is also recorded. Using the shape of the blood pressure waveforms, waveform parameters are generated. These parameters, along with universal coefficients, are used to calculate pressure values which then can be displayed.
Placement guide 13 is connected to housing 14 at the base of housing 14 . Placement guide 13 straddles the styloid process bone, automatically placing sensor interface assembly 22 over the underlying artery. Housing 14 contains all of the electrical components of measurement device 10 . The shape and configuration of housing 14 allows it to hang on the patient's wrist, using placement guide 13 as a type of hook. Housing 14 includes pressure platform 15 , which is a flattened depression directly above sensor interface assembly 22 . In operation, the user (medical personnel) applies pressure on pressure platform 15 with a thumb or finger. The hold-down force from the user's thumb applies a force in an axial direction (i.e., an axial direction with respect to a central cylindrical axis of sensor interface assembly 22 ) to wrist 12 of the patient. The axial force is transmitted from pressure platform 15 of housing 14 to sensor interface assembly 22 .
In a preferred embodiment, display panel 16 simultaneously displays the following values based upon blood pressure measurements: systolic pressure, diastolic pressure, pulse rate, and mean blood pressure. Display panel 16 also preferably provides visual prompting for manually applying a varying hold down pressure.
Power switch 20 is actuated to turn on power to the circuitry within housing 14 . Timing circuitry within housing 14 automatically turns power of f after a predetermined period of inactivity. Actuation of switch 20 , after the unit is turned on, causes display panel 16 to indicate previous readings of blood pressure and pulse rate.
Patient identification toggle 18 is used to organize the recorded blood pressure information with respect to a particular patient. After actuating power switch 20 , the user selects the specific patient for which blood pressure will be measured by pressing patient identification toggle 18 . In one embodiment, display panel 16 displays a patient identification number for the currently selected patient. The patient identification number changes as patient identification toggle 18 is pressed. In one embodiment the user can scroll through a list of 16 patient identification memory locations.
FIG. 2A is a side view of blood pressure measurement device 10 , and FIG. 2B is a bottom view of blood pressure measurement device 10 . As can be seen from FIGS. 2A and 2B, placement guide 13 is generally U-shaped. Placement guide 13 includes hook 23 , pad 25 , and opening 27 . Opening 27 is a generally circular aperture that has a notch 29 near hook 23 . Guide ribs 17 and 19 encircle opening 27 and notch 29 , and meet at the base of hook 23 .
When device 10 is placed on the patient, pad 25 contacts the palm side of the wrist of the patient, while hook 23 wraps around the backside of the wrist. Placement guide 13 is made of a flexible plastic so as to fit all patients, with the styloid process bone fitting into notch 29 of opening 27 . Opening 27 also allows sensor interface assembly 22 to come in contact with the patient's wrist. Pad 25 becomes a pivot point about which force is applied.
Relying on a cantilever type action, device 10 allows the user to apply a force at pressure platform 15 of housing 14 . Housing 14 pivots about pad 25 , and sensor interface assembly 22 applies an axial force to the underlying artery. Sensor interface assembly 22 is pivotally mounted to housing 14 . As pressure is manually applied by moving housing 14 toward the artery, that force is transferred from housing 14 to sensor interface assembly 22 .
Device 10 , with placement guide 13 and the cantilever type action, allows sensor interface assembly 22 to be consistently placed in the proper position, and the hold-down force to be consistently applied in the axial direction with respect to wrist 12 . This improvement greatly simplifies the procedure of applying pressure by the user, because the user no longer controls the direction and angle at which pressure is applied with respect to the patient's wrist.
Instead of having to palpate wrist 12 to identify the location of the radial artery, a user simply places device 10 adjacent wrist 12 so that placement guide 13 hooks onto the patient's wrist with guide ribs 17 and 19 straddling the projection of the styloid process bone. The measurement process is significantly simplified with the present invention.
The force applied to the artery is swept in an increasing fashion so the pressure waveform data from a series of pulses are obtained with different amounts of force being applied. To achieve the desired pattern of variable force, user feedback is preferably provided with device 10 .
In a preferred embodiment, feedback is in the form of a visual counter on display panel 16 . As the user begins to apply pressure, a number is displayed corresponding to the amount of pressure applied by the user. As the user increases the applied pressure, the displayed number proportionally increases. The user (medical personnel) is previously instructed to increase pressure smoothly so that the displayed counter increases one integer at a time, approximately one per second. If the user increases the hold-down pressure too quickly, the displayed counter will also jump quickly through the corresponding numbers to indicate the choppy applied pressure. The user applies greater pressure until device 10 shows the resulting blood pressure measurements on display panel 16 . Preferably, the user applies enough pressure to get the counter up to the number 15, but it could be as low as 4 or 5, or as high as 27 or 28, depending on the patient. If a patient has higher blood pressure, greater applied force will be necessary, and the corresponding ending counter number will be a higher integer.
After the measurement, the user can then view the blood pressure reading. In a preferred embodiment, display panel 16 provides a digital readout of systolic, diastolic, and mean blood pressure, as well as pulse rate. An indication of memory location (by number) corresponding to the patient is also displayed.
As soon as the reading is complete, device 10 is ready to take another reading. There is no need to clear display 16 . Device 10 stores a predetermined number of previous readings (such as the last 10 readings). To review prior readings, patient identification toggle 18 or power switch 20 is pressed. This causes a different reading from memory to be displayed on display 16 .
Alternatively, the feedback to the user can be audible tones and/or visual movable bars. The process of applying force in response to audible tones and/or visual movable bars on display 16 is fully described in U.S. Pat. No. 5,941,828, entitled “Non-Invasive Blood Pressure Sensor With Motion Artifact Reduction”, which is incorporated herein.
As can be seen in FIG. 2B, device 10 includes external connector 30 . External connector 30 is a five pin connector that is used to transmit and receive data, recharge battery 36 (see FIG. 3) contained within housing 14 and provide an alternative power source to device 10 . External connector 30 allows device 10 to be connected to a docking station 100 (shown in FIG. 4) so that its internal battery can be recharged, and the collected blood pressure information can be downloaded to a central system. Device 10 can be used by a nurse or other employee in a hospital setting to collect blood pressure and heart rate information from a series of patients. Docking station 100 is described below with reference to FIGS. 4-7.
FIG. 3 is an electrical block diagram of device 10 . Device 10 includes patient marker switch 18 , power supply circuit 42 , sensor interface assembly 22 , connectors 58 and 60 , amplifiers 62 A and 62 B, analog-to-digital (A/D) converter 64 , microprocessor 68 , display driver and memory circuit 82 , display panel 16 , non-volatile memory 78 and real-time clock 80 . Power supply circuit 42 includes external connector 30 , amplifiers 32 and 34 , rechargeable battery 36 , supply switch 38 , reverse battery protection 40 , switch 20 , integrated power switch 44 , OR circuit 46 , voltage divider 48 , analog regulator 50 and supervisor circuit 52 .
Device 10 can be powered through an external power source, such as docking station 100 . An external power source couples to device 10 through external connector 30 . Power from external connector 30 on the VSUPPLY line causes supply switch 38 to disconnect rechargeable battery 36 from supplying power to supply circuit 42 . Instead, rechargeable battery 36 is recharged using the CHRGR line while the external power source supplies power to supply circuit 42 on the VSUPPLY line. External connector 30 also allows device 10 to receive and transmit data, such as blood pressure information and device serial number, to docking station 100 (see FIG. 4) over the RX (receive) line and TX (transmit) line. The RX and TX lines are coupled to amplifiers 32 and 34 , respectively, which amplify the signals transmitted and received by microprocessor 68 . Amplifiers 32 and 34 are enabled when power is received through the VSUPPLY line, and are disabled when no power is received through the VSUPPLY line. External connector 30 also includes a GND line, which is connected to ground.
Switch 20 is partially a monitoring pushbutton switch. Pressing switch 20 causes OR circuit 46 to turn on integrated power switch 44 . Integrated power switch 44 supplies power to all digital circuits, including microprocessor 68 , display panel 16 and associated display driver and memory circuit 82 . Integrated power switch 44 supplies power to microprocessor 68 , which in turn latches on OR circuit 46 . The turn of f of the circuit is controlled by microprocessor 68 discontinuing a signal to OR circuit 46 . This occurs through a fixed time of no activity.
Analog regulator 50 outputs electrical power which is used to energize analog circuitry, including amplifiers 62 A and 62 B, and analog-to-digital (A/D) converter 64 .
Pressure transducers 56 A and 56 B and nonvolatile memory 54 within sensor interface assembly 22 are connected through connector 58 and connector 60 to circuitry within housing 14 . Transducers 56 A and 56 B sense pressure communicated within sensor interface assembly 22 and supply electrical signals to connector 58 . In a preferred embodiment, transducers 56 A and 56 B are piezoresistive pressure transducers. Nonvolatile memory 54 stores offsets of transducers 56 A and 56 B and other information such as a sensor serial number. Nonvolatile memory 54 is, in a preferred embodiment, an EEPROM.
The outputs of transducers 56 A and 56 B are analog electrical signals representative of sensed pressure. These signals are amplified by amplifiers 62 A and 62 B and applied to inputs of A/D converter 64 . The analog signals to A/D converter 64 are converted to digital data and supplied to the digital signal processing circuitry 66 of microprocessor 68 .
Microprocessor 68 includes digital signal processing circuitry 66 , read only memory (ROM) and electrically erasable programmable read only memory (EEPROM) 70 , random access memory (RAM) 72 , timer circuitry 74 , and input/output ports 76 . A/D converter 64 may be integrated with microprocessor 68 , while some of the memory may be external to microprocessor 68 .
Based upon the pressure data received, microprocessor 68 performs calculations to determine blood pressure values. As each pulse produces a cardiac waveform, microprocessor 68 determines a peak amplitude of the waveform. Microprocessor 68 controls display driver 82 to create the visual counter on display 16 that counts in correlation to the hold down pressure applied by the user. The visual counter guides the user in applying a variable force to the artery.
When a measurement cycle has been completed, microprocessor 68 reorders the cardiac waveforms in increasing order of their corresponding hold down pressure and performs calculations to determine systolic pressure, diastolic pressure, mean blood pressure, and pulse rate. The process of calculating pressure using shape, amplitude, and hold down is described in the previously mentioned Medwave patents, which are incorporated by reference. If patient identification toggle 18 is pressed, a signal is supplied to microprocessor 68 , causing it to toggle to a new pressure reading with a new memory location. In one embodiment, the memory location of that pressure reading is also displayed.
The blood pressure calculations, organized by patient, are preferably time-stamped at the time of calculation using real-time clock 80 , and stored in non-volatile memory 78 , so that the calculations are not lost when power to device 10 is turned off. Non-volatile memory is preferably an EEPROM.
A preferred docking station according to the present invention is illustrated in FIG. 4 . Docking station 100 includes four bays 102 A- 102 D (collectively referred to as bays 102 ) for receiving and holding blood pressure devices 10 . Bays 102 A- 102 D include five-pin connectors 104 A- 104 D, respectively, for interfacing with external connector 30 of a device 10 . Only connector 104 B is visible in FIG. 4, but connectors 104 A, 104 C and 104 D are the same as connector 104 B. Docking station 100 further includes AC adapter 106 , LED indicators 108 A- 108 D (collectively referred to as LED indicators 108 ) and DB-9 connector 112 . LED indicator 108 B is not visible in FIG. 4, but is positioned adjacent bay 102 B similar to the positioning of LED indicator 108 A adjacent bay 102 A. LED indicators 108 are preferably dual color (red-green) LEDs. AC adapter 106 plugs into a wall receptacle for AC power, and outputs a DC voltage through DC connector 110 . DC connector 110 plugs into docking station 100 and provides DC power for the circuitry therein. Alternatively, power for docking station 100 and for recharging devices 10 may be obtained from another source, such as from personal computer (PC) 120 (shown in FIG. 6 ).
Docking station 100 preferably has a modular design, allowing multiple docking stations 100 to be connected together. FIG. 5 shows a diagram of four docking stations 100 A- 100 D (collectively referred to as docking stations 100 ) connected together. When multiple docking stations 100 are coupled together, one docking station 10 A acts as a master, while the remaining docking stations 100 B- 100 D act as slaves. Docking stations 100 are electrically coupled together via bus input connectors 166 A- 166 D (collectively referred to as bus input connectors 166 ), first bus output connectors 156 A- 156 D (collectively referred to as first bus output connectors 156 ) and second bus output connectors 158 A- 158 D (collectively referred to as second bus output connectors 158 ). Bus connectors 156 , 158 and 166 are preferably positioned on the back and both sides of a docking station 100 , allowing the docking stations to be connected side-to-side or back-to-back.
In a preferred embodiment, docking station 100 is connected to a personal computer (PC) 120 as shown in FIG. 6 . After blood pressure and heart rate data are obtained by a blood pressure measurement device 10 , the nurse places device 10 into a docking station 100 , and PC 120 transmits commands through docking station 100 to device 10 via external connector 30 . In response, device 10 outputs stored data through docking station 100 to PC 120 . Concurrently, the rechargeable battery 36 within device 10 is recharged, and power is supplied to device 10 from docking station 100 via external connector 30 , while device 10 is in docking station 100 .
Device 10 outputs pulse rate data and blood pressure data to PC 120 , including systolic blood pressure and diastolic blood pressure. Each set of pulse rate and blood pressure data includes a patient ID number, and a time stamp and a date stamp of the reading. As described above, the patient ID number is a number from 1-16 that is set using patient identification toggle 18 , and allows blood pressure and pulse rate data to be organized within device 10 with respect to particular patients. In a preferred embodiment, a sensor serial number is also output from device 10 to PC 120 , so that blood pressure and pulse rate information can be organized with respect to particular measurement devices 10 . Device 10 may also transmit to PC 120 any other information stored in the device 10 , including mean blood pressure information, usage history information and sensor test information.
PC 120 preferably includes database 122 for all of the patients in the hospital. PC 120 runs a custom software application that associates actual patients with patient ID numbers and serial numbers for devices 10 . Each time PC 120 obtains information from a device 10 stored in docking station 100 , PC 120 stores the information in database 122 . The information obtained from devices 10 may also be stored on an Internet server 124 . The information obtained from devices 10 and stored in database 122 or Internet server 124 may be accessed by other computers, such as computers 126 used by clinical personnel, computers 128 used by administrative personnel and computers 130 used by payers.
The information obtained from devices 10 through docking station 100 may be used in multiple ways. The information can be used by doctors and nurses for remote patient monitoring. The information can be used for billing purposes. Charts and graphs can be generated from the information, such as blood pressure or pulse rate historical data for a patient. The information can be used for sensor management (e.g., displaying sensor usage information, sensor test information and warnings, sensor expiration information and warnings, etc.).
FIGS. 7A and 7B show an electrical schematic diagram of docking station 100 . Docking station 100 includes five-pin connectors 104 A- 104 D (collectively referred to as connectors 104 ), LED indicators 108 A- 108 D (collectively referred to as LED indicators 108 ), battery chargers 140 A- 140 D (collectively referred to as battery chargers 140 ), switches 142 A- 142 D (collectively referred to as switches 142 ), input switch 144 , output switch 146 , serial interface 148 , DB-9 connector 112 , counter 154 , first bus output 156 , second bus output 158 , bay address decoder 160 , board address switch 162 , board address decoder 164 , bus input 166 and DC power supplies +V 1 and +V 2 . Power supplies +V 1 and +V 2 are provided power from DC connector 110 (shown in FIG. 4 ).
Each connector 104 of docking station 100 may be connected to external connector 30 of a blood pressure measurement device 10 . Five lines are connected to each connector 104 —DATAIN, DATAOUT, CHRGR, GND and VSUPPLY. Each DATAIN line connects with the TX line of a device 10 (see FIG. 3 ), and is used for transmitting data from device 10 to docking station 100 . The DATAIN line from each connector 104 is connected to input switch 144 . Each DATAOUT line connects with the RX line of a device 10 , and is used for transmitting data from docking station 100 to a device 10 . The DATAOUT line from each connector 104 is connected to output switch 146 . Each GND line within docking station 100 is connected to the GND line of a device 10 , and is coupled to ground.
Each CHRGR line of docking station 100 connects with the CHRGR line of a device 10 . Each CHRGR line of docking station 100 is also coupled to one of the battery chargers 140 . Battery chargers 140 provide a current source for recharging battery 36 within a device 10 . Battery chargers 140 A- 140 D are coupled to LED indicators 108 A- 108 D, respectively. When a device 10 is first plugged into a bay 102 of docking station 100 , for example bay 102 A, battery charger 140 A detects the presence of device 10 , begins charging device 10 , starts a timer, and uses the RED 1 output line to cause LED indicator 108 A to display a red light. The display of the red light indicates that device 10 is charging. In a preferred embodiment, battery charger 140 A monitors the timer and uses the GREEN 1 and FLASH 1 output lines to cause LED indicator 108 A to display a flashing green light after 15 hours of charging. If device 10 is removed from bay 102 A, and then replaced back in bay 102 A, battery charger 140 A resets the timer. Other battery chargers with different charging times may be used. Battery chargers 140 B- 140 D operate in the same manner as battery charger 140 A.
Each VSUPPLY line of docking station 100 is connected to the VSUPPLY line of a device 10 , and is used to provide power to device 10 . Each VSUPPLY line of docking station 100 is connected to one of the switches 142 . Each switch 142 is controlled by one of the battery chargers 140 . When a device 10 is first plugged into a bay 102 of docking station 100 , for example bay 102 A, battery charger 140 A detects the presence of the device 10 , and closes switch 142 A. Power is then supplied to the device 10 from power supply +V 2 . Supplying power to device 10 from power supply +V 2 guarantees not only that the digital voltage levels are the same in device 10 and docking station 100 (optimizing noise margin and reducing likelihood of latch-up and/or damage), but that the saved pressure readings, pulse rates and other data in device 10 may be obtained even with a fully discharged battery 36 .
When multiple docking stations 100 are coupled together as shown in FIG. 5, one docking station 100 A is a master unit, and the remaining docking stations 100 B- 100 D are slave units. The slave units 100 B- 100 D are similar to the master unit 100 A, with the deletion of counter 154 , serial interface 148 and DB-9 connector 112 . When multiple docking stations 100 are connected together, only the master docking station 100 A connects directly to PC 120 , while the remaining docking stations 100 share a common bus 155 for communicating with PC 120 .
Each docking station 100 includes a first bus output 156 , a second bus output 158 and a bus input 166 , which are each implemented with a 10-pin connector. Each bus line coupled to first bus output 156 is also coupled to a corresponding pin of second bus output 158 and bus input 166 . The bus lines are numbered from 1 to 10. Bus lines 1 - 4 are connected to lines ADDR 0 , ADDR 1 , ADDR 2 and ADDR 3 , respectively. Bus line 5 is connected to input switch 144 . Bus line 6 is connected to output switch 146 . Bus lines 7 and 8 are connected to +V 1 , which is a DC power supply. Bus lines 9 and 10 are connected to ground.
In a preferred embodiment, bus input connector 166 is positioned on the left side of docking station 100 , first bus output connector 156 is positioned on the back side of docking station 100 , and second bus output connector 158 is positioned on the right side of docking station 100 . Other configurations are possible.
Each docking station 100 includes a circuit board for holding and connecting the electronics in FIGS. 7A and 7B. When multiple docking stations 100 are coupled together, each circuit board (and correspondingly each docking station 100 ) is assigned a board address. The board address for each docking station 100 is set with board address switch 162 . Similarly, each bay 102 within a docking station 100 is assigned a bay address. Each circuit board and each bay 102 is assigned one address in the set { 00 , 01 , 10 , 11 }. The lines ADDR 0 and ADDR 1 are used to cycle through the four bay addresses. The lines ADDR 2 and ADDR 3 are used to cycle through the four board addresses.
DB-9 connector 112 of docking station 100 is preferably connected to a serial port of PC 120 , although DB-9 connector 112 may alternatively be connected to any other device that is able to manipulate TX, RX, DTR (Data Terminal Ready), and RTS (Request to Send) lines. In order to access bays 102 , and therefore the blood pressure measurement devices 10 , PC 120 toggles the RTS line, which then toggles the CLK line of counter 154 . Counter 154 generates binary addresses in a sequence of 0 (i.e., 0000) to 15 (i.e., 1111). The first two digits of the four digit binary address represent a board address and are sent out on lines ADDR 2 and ADDR 3 . The last two digits of the four digit binary address represent a bay address and are sent out on lines ADDR 0 and ADDR 1 . The DTR line may toggled by PC 120 in order to reset counter 154 to 0. In this way, the data may be re-synchronized at any time to start from board 00 , bay 00 .
When counter 154 toggles to a new address, the new address goes out to bay address decoder 160 and board address decoder 164 . Board address decoder 164 includes four output lines, each output line corresponding to one of the four possible board addresses. Board address decoder 164 decodes the two digit board address portion of the four digit address and, based on the decoded address, sets one of its four output lines high. If the line set high by board address decoder 164 corresponds to the board address set at board address switch 162 , board address switch 162 sends an enable signal to bay address decoder 160 , allowing bay address decoder 160 to decode the bay address. If the line set high by board address decoder 164 does not correspond to the board address set at board address switch 162 , board address switch 162 maintains its output line low, thereby maintaining bay address decoder 160 in a disabled state.
Bay address decoder 160 includes four output lines, each output line corresponding to one of the four possible bay addresses. When bay address decoder 160 is enabled by board address switch 162 and receives a bay address, bay address decoder 160 decodes the bay address and, based on the decoded address, sets one of its four output lines high. The output lines of bay address decoder 160 are coupled to input switch 144 and output switch 146 . Based on the output of bay address decoder 160 , input switch 144 and output switch 146 couple the DATAIN and DATAOUT lines for the currently selected bay 102 to serial interface 148 and to bus lines 5 and 6 . Serial interface 148 includes amplifiers 150 A- 150 D, which amplify signals on the DATAIN, DATAOUT, DTR/CLR and RTS/CLK lines.
After toggling to a new address, PC 120 sends characters on the DATAOUT line and then waits for a response. If PC 120 does not receive a response within an allotted time, PC 120 assumes that no blood pressure measurement device 10 is present at the current board and bay address, moves on to the next board and bay address, and repeats the process. If a blood pressure measurement device 10 is present at the current board and bay address, the device 10 responds by sending characters to PC 120 on the DATAIN line. In this fashion, PC 120 is constantly scanning bays 102 , looking for blood pressure measurement devices 10 that may be present.
Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.
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A storage device for storing a plurality of portable medical devices includes a plurality of bays for receiving and storing the plurality of portable medical devices. Each portable medical device includes an electrical connector. Each bay includes a first electrical connector. The first electrical connector of each bay is configured to interface with the electrical connector of one of the portable medical devices. A second electrical connector is configured to be coupled to a computer. A battery charger is coupled to at least one of the first electrical connectors of a bay for charging a battery of one of the portable medical devices. A switch is coupled to the first electrical connector of each bay and coupled to the second electrical connector for selectively coupling each bay to the computer for data transfer between the bay and the computer.
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FIELD OF THE INVENTION
The present invention relates to the field of sensors housed in tires and particularly to adaptations used to receive and hold same in position under optimal position.
DESCRIPTION OF THE PRIOR ART
There exist, at the present time, pressure and temperature sensors that are sufficiently compact to be housed in a tire such as those fitted on a motor vehicle.
The mechanical attachment modes of said sensors are varied and make use of three main techniques which are:
strapping of a housing containing the electronics of the sensors on the rim, the housing being pressed into the rim base by a belt most frequently made of metal, the tire thus containing said strapping and said electronics, attachment of a housing directly on a wall of the rim by boring or gluing of the rim, attachment of a housing via the valve hole and the valve itself.
The majority of solutions using the latter technique are subject to tangential stress occurring during acceleration and deceleration of the vehicles to form a major source of fatigue for the seal involved in fitting.
A solution to this problem is described in the document FR 2876322 which proposes an assembly of a detection housing inside a tire of the type attached to the body of a valve and comprising the following elements:
a detection housing receiving the detection components, a valve body, a seal type tightness means ensuring the tightness between the valve body and the rim, a means for holding the valve body in position on the rim, preformed for this purpose with a connection orifice, a connection module of the detection housing with the valve body,
at least one of the elements of said assembly, apart from the tightness means, being preformed so that a part of this element enters the connection orifice so as to rest thereon when the assembly is subjected to tangential stress.
The applicant observed that this type of assembly involved the drawback of requiring a special valve suitable for the required assembly. Another drawback is that the electronic housing is rendered integral to the valve and can only be replaced or undergo a maintenance operation if the valve itself is disassembled from the rim.
DESCRIPTION OF THE INVENTION
On the basis of this statement, the applicant conducted research intended to attach this type of electronic housing on standard valves. Another aim of this research was to render the electronic housing independent from the valve to facilitate maintenance or replacement operations.
This research resulted in the design and production of a device for the attachment on a rim of an electronic detection housing for tires of the type attached to the valve which comprises one part outside the rim and one part inside the rim, said device constituted by a connection module connected, on one hand, to the inner part of the valve and, on the other, to a receptacle preformed to receive said electronic housing, characterised in that said receptacle forms a reception volume open on the side of the tire tread which facilitates the access and operation thereof, while preventing the creation of a Faraday cage between the walls of the rim and the receptacle.
In addition, this feature is particularly advantageous in that it allows the use of a standard valve for the attachment of the housing. In addition, according to the aims of the invention, the housing becomes integral to the receptacle only, is no longer involved in the assembly on the rim and is no longer attached directly to the valve. Therefore, it is no longer necessary to remove the valve to arrange the housing. In this way, only the receptacle and the connection module are liable to be modified according to the applications. The valve used in the attachment device of the invention may thus remain the original valve.
In order to facilitate the detachability of the housing with respect to the receptacle thereof, said receptacle and the housing are preformed to produce a sliding joint.
The applicant envisaged several configurations for the device according to the invention. According to a first configuration, the connection module and the receptacle are made of the same part. According to a non-limitative embodiment, said receptacle is then constituted by a sheet of metal preformed essentially with an opening wherein the valve is inserted during assembly, the valve head resting on the edges of said opening. This opening forms said connection module.
According to second configuration, the connection module is constituted by one or more independent elements of the receptacle. According to a non-limitative embodiment, said connection module is then constituted by a hollow cylinder comprising an inner shoulder and an outer shoulder, the valve being inserted in the cylinder and said valve head resting on the inner shoulder for the purposes of attaching the connection part on the rim, and the receptacle being inserted on the cylinder by means of an orifice provided for this purpose and resting with the edges of said orifice on the outer shoulder.
According to another embodiment of said second configuration, said connection module is essentially constituted by a nut comprising an inner threaded bore screwed onto the valve for the purposes of attaching the connection module on the rim, said nut being preformed with an outer shoulder, the receptacle being preformed with an orifice wherein the nut is inserted such that the outer shoulder rests on the edges of the orifice.
According to another particularly advantageous feature, an attachment flange is attached to said receptacle to ensure that the housing is held in position.
According to another particularly advantageous feature, the housing volume is preformed on the side thereof oriented towards the valve head so as to adopt an offset shape to free, once the housing has been fitted, the volume around the valve head.
The fundamental concepts of the invention described above in the most basic form thereof, other details and features will emerge more clearly on reading the description hereinafter with reference to the appended figures, giving as a non-limitative example, an embodiment of the device according to the invention.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 is a schematic drawing of an exploded perspective view of an embodiment of the device according to the invention,
FIG. 2 is a schematic drawing of a perspective view of the device in FIG. 1 showing the engagement of the housing in the receptacle,
FIG. 3 is a schematic drawing of a perspective view of the device in FIG. 1 showing the housing positioned in the receptacle,
FIG. 4 is a schematic drawing of a perspective bottom view of the device in FIG. 1 , the housing being positioned in the receptacle,
FIG. 5 is a schematic drawing of a cross-sectional view of the device in FIG. 1 ,
FIG. 6 is a schematic drawing of a cross-sectional view of another embodiment of the device according to the invention,
FIG. 7 is a schematic drawing of an exploded perspective view of another embodiment of the device according to the invention,
FIG. 8 is a schematic drawing of a cross-sectional view of another embodiment of the device according to the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
As illustrated in the drawing in FIGS. 1 and 5 , the device referenced D overall performs the attachment on the rim J (partially represented herein by a washer) of an electronic detection housing 100 for tires of the type being attached to the valve 200 which comprises, once fitted, a part 210 outside the rim and a part 220 inside the rim comprising a head 221 .
According to the invention, the device D is constituted by a connection module 300 connected, on one hand, to the inner part 220 of the valve 200 and, on the other, to a receptacle 400 preformed to receive said electronic housing 100 . In this way, the housing is not directly connected to the valve which allows the interchangeability of said housing without removing the valve.
According to the embodiment illustrated, the device also comprises a seal 500 associated with a hollow washer 600 which rests J around the valve hole J 1 .
As illustrated, said receptacle 400 and the housing 100 are preformed to produce a sliding joint.
According to the invention and according to the embodiment illustrated, said receptacle 400 is constituted by a sheet of metal 410 preformed essentially with an opening 411 wherein the valve 200 is inserted and on the edges 412 whereof the valve head 221 rests, said opening forming said connection part 300 . According to the embodiment illustrated, the opening 411 is an orifice produced in the thickness of the sheet of metal 410 and located such that the edge 412 surrounds same completely.
According to the embodiment illustrated, said sheet of metal 410 is provided with a plurality of openings so as to lighten the structure formed, which offers the advantage of reducing stress on the valve 200 .
According to a particularly advantageous feature, the thickness of the sheet of metal is sufficiently small so that the threading conventionally used for the assembly of the standard valve 200 can be used. In this way, the device according to the invention does not require any modification of the assembly existing on a standard valve. Indeed, as illustrated in the drawing in FIGS. 1 and 5 , the elements of the assembly of a standard valve 200 are constituted by the valve 200 and the nut 700 , the device D merely adds a thickness between the inner surface of the rim J and the bearing surface of the valve head 221 . This additional thickness is constituted by the height of the washer 600 and the thickness of the sheet of metal.
In spite of the reduced thickness and the different openings made in the metal sheet, the material of the receptacle formed in this way is selected to form a rigid and non-deformable frame to receive the electronic housing.
As illustrated, the volume of housing 100 is preformed on the side oriented towards the valve head 221 so as to adopt an offset shape 110 to prevent the formation of an obstacle at the air inlet or outlet from the head 221 of the valve 200 . In order to render the housing 100 completely independent from the valve 200 , said receptacle 400 forms a bearing platform 420 for the housing 100 , the surface of said platform and the bearing surface for the valve head 221 proposed by the connection part 300 and the respective distance thereof are defined such that the valve head 221 does not come into contact with said housing 100 .
According to the embodiment illustrated, the sheet of metal forming the receptacle 100 comprises a plane central part forming the platform 420 on two opposite sides whereof two substantially plane lateral parts 430 and 440 rise to form the sides of the receptacle 400 . As illustrated, the ends 431 and 441 of said sides 430 and 440 not connected to the platform 420 are preformed with an internal return to form longitudinal offset volumes with which projecting volumes 120 and 130 of the outer surface of the housing cooperate to form said sliding joint.
As illustrated by the drawings in the figures, to ensure the housing 100 is held in position in the receptacle 400 , the housing and the receptacle are each preformed with an orifice 140 and 450 corresponding once the housing is positioned in the receptacle and whereby an attachment pin 800 is positioned. This pin is fastened inside the orifice 140 produced in the housing 100 .
According to another embodiment not illustrated, another solution to lock said sliding joint in translation comprises preforming said receptacle 100 on the upper face thereof with an offset shape with which a projecting pin preformed on the lower face of the housing cooperates.
According to the non-limitative embodiment illustrated by the drawing in FIG. 6 , said connection part 300 a is an independent part of the receptacle and is constituted by a hollow cylinder comprising an inner shoulder 310 a and an outer shoulder 320 a , the valve 200 being inserted in the cylinder 300 a and said valve head 221 resting on the inner shoulder 310 a for the purposes of attaching the connection part on the rim J, and the receptacle 400 a being engaged on the cylinder 300 a by means of an orifice 410 a provided for this purpose and resting with the edges 411 a of said orifice 410 a on the outer shoulder 320 a . The cylinder 300 a may then slide in the receptacle 400 a.
As illustrated, a compression spring 900 positioned around the connection part 300 a comprises one end 910 resting on the rim J and one end 920 resting on the receptacle 400 a so as to hold the receptacle 400 a in position against the outer shoulder 411 a.
The embodiment illustrated by the drawing in FIG. 8 also shows a solution wherein the connection module forms an intermediate part essentially constituted by a nut 700 c comprising an inner threaded bore screwed onto the valve 200 c for the purposes of attaching the connection module on the rim J, said nut being preformed with an outer shoulder 710 c , the receptacle 400 c being preformed with an orifice 410 c wherein the nut 700 c is inserted such that the outer shoulder 710 c rests on the edges of the orifice 410 c . A spring 900 holds, resting on the rim, the edge of the orifice 410 c provided in the receptacle 400 c against the outer shoulder of the nut 700 c.
The embodiment illustrated by the drawing in FIG. 7 represents an alternative embodiment having features of the first and the second embodiments. In this embodiment, the connection part 300 b is integral to the receptacle 400 b and is constituted by a hollow cylinder comprising an inner shoulder not illustrated, the valve 200 being inserted in the cylinder 300 b and said valve head 221 resting on the inner shoulder for the purposes of attaching the connection part 300 b on the rim J.
In this embodiment and according to a feature of the invention, an attachment flange 460 b is attached to said receptacle 400 b to ensure that the housing 100 b is held in position in the receptacle 400 b . The flange 460 b is fastened on the sides of the receptacle 400 b.
According to all the embodiments, said receptacle 400 forms an open receiving volume on the side of the tire tread.
It is understood that the device described and represented above has been described and represented with a view to a disclosure rather than a limitation. Naturally, various arrangements, modifications and improvements may be added to the example above, without leaving the scope of the invention.
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The invention relates to a device (D) for fastening an electronic detection unit ( 100 ) for tires to a rim (J), this unit being of the type which is fastened to the valve ( 200 ), which valve comprises a part ( 210 ) outside the rim and a part ( 220 ) inside the rim, said device consisting of a connection module ( 300 ) connected on the one hand to the inner part ( 220 ) of the valve ( 200 ) and on the other hand to a preformed receptacle ( 400 ) for accommodating said electronic unit ( 100 ), distinguished in that said receptacle ( 400, 400 a, 400 b ) forms an accommodation volume which is open on the tire tread side. Applications: detection unit fastened to the vehicle wheels.
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BACKGROUND OF THE INVENTION
The instant invention relates to the building construction industry and particularly to the construction of building roofs using a technique in which wide, relatively narrow consecutive sections of the roof, having a support truss along one edge, are consecutively raised and placed in position against the last section that was put in place, so that each section has a truss along one edge, with the other edge being supported by the truss of the previous section of the roof which was installed. Roof sections are in this fashion laid consecutively, each one being attached to the previously installed section until the entire roof, or at least a very wide swath of the roof, has been completed.
When roofs are constructed in this way, each roof section is very wide laterally, relatively narrow, and is quite unwieldy. The wide section is engaged by a forklift which passes its forks beneath the truss, which is on the side of the section toward the forklift, with the ends of the forks having some type of spacer to reach up to the level of the roof section, with a wide spanner bar passing across the spacers to stabilize the section. Because the section of the roof is so wide, and the forks engage beneath the truss which is several feet below the level of the main roof section, the operation is very unstable and somewhat dangerous. The laterally extended length of the roof section has a large moment arm around the forklift, and the instability is aggravated by the fact that main portion of the roof, that is the horizontal roof section, is spaced several feet above the forklift forks because of the need to engage the forks beneath the truss.
Additionally, there is only minimal control of the remote edge of the roof section by the front ends of the forks, which support the spacers, which in turn support a relatively short spanner beam that supports the far edge of the roof section.
There is a need for a rack which mounts on a forklift that would pass through the upper portion of the truss, with tangs supporting the roof section at multiple points along its length, with the tangs being rotatably adjustable about a transverse axis to accurately, horizontally orient the roof section, and create the ability to more positively engage it as it is being positioned.
SUMMARY OF THE INVENTION
The instant invention fulfills the above stated need by providing a specialized rack which is created specifically to elevate and position wide roof sections in a stable and safe manner.
The rack comprises a frame, which in turn comprises a lateral, horizontal tube mounted to the backboard of the forklift. A long beam passes through the tube, extending a considerable distance to each side, and is rotatable within the tube. The beam mounts forwardly extended tangs, which are adjustable in how far forwardly they extend, and the beam itself can be rotated about its axis by means of hydraulic cylinders mounted between radial arms rigidly fixed to the beam and structure on the frame to rotate the tangs.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevation view of a forklift, shown in phantom, with the rack in place;
FIG. 2 is a front elevation view of the configuration of FIG. 1;
FIG. 3 is a top plan view of the configuration of FIGS. 1 and 2, illustrating the forklift diagrammatically in phantom;
FIG. 4 is a section taken along lines 4--4 of FIG. 2 illustrating the details of operation of the hydraulic cylinder beam rotating mechanism;
FIG. 5 is a top plan view of a portion of the rack illustrating the rotating mechanism;
FIG. 6 is a section taken along line 6--6 of FIG. 2 and illustrates how up-rotated tangs stabilize a single beam; and
FIG. 7 is a perspective view of a detail of a slightly modified version of the invention in which the beam is acircular.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The forklift to which the invention is attached is illustrated in phantom in FIGS. 1-3 at 10. As shown in FIG. 5, a forklift has a lifter frame 12 and typically a backboard 14 mounted to the lifter frame. At the bottom of the backboard there are generally a pair of forks 16 although in many applications the forks are omitted.
The instant invention comprises a rack, generally indicted at 18, which is mounted to the backboard 14. Although there are a number of variations of the way in which the rack can be constructed, in the illustrated embodiment it comprises a main heavy-duty laterally extended horizontal tube 20, with a pair of heavy posts 22 welded to the ends of the tube and projecting upwardly as seen from the top in FIG. 5 and from the side in FIG. 6. The main tube 20 is mounted to the backboard by bolts 24 which pass through the backboard and engage heavy brackets 26 which are welded to the tube. Although two bolts and brackets are shown, obviously more could be used if needed to support the load.
The interior of the tube 20 is maintained clear because a transverse cylindrical beam 28 passes through the tube and extends a considerable distance to each side as shown in FIG. 3. Although it is not shown in the drawings, the beam is long enough that in some applications it might be required, or at least be beneficial, to provide stays and guy wires as a superstructure to the beam to support it at its outer ends.
Spaced along the beam in both direction are sockets 30 which are welded to the beam and define cylindrical bores which are longitudinally extended relative to the direction of the forklift. In each of these bores is a forwardly extended tang 32, which is free to slide within the bore, and is locked in place by a set screw 34. Although it may seem tedious to adjust 6 tangs (the number shown in FIG. 3) by manipulating the set screws, ordinarily this would be done only once for a large job, inasmuch as the roof panels that would be installed in a particular job would generally be uniform.
In addition to the tangs being adjustable in their forward extent, they are rotatably adjustable by virtue of the fact that the beam 28 is rotatable about its axis in the tube 20. Rotation is forced by means of hydraulic cylinders 36 which are mounted between the tops of the posts 22 and the ends of radial arms 38 which are welded to the beam 28 on opposite sides of the main tube 20. As is easy to visualize from FIG. 4, operation of the hydraulic cylinders will rotate the tangs concomitantly up or down as shown in phantom.
The rack of the invention is intended to be used for roof panels, one of which is indicated in phantom at 40 in FIG. 3. The roof panel would typically have a truss 42 shown in FIG. 1 which extends across its entire width. The truss is open, and the tangs of the rack would extend beneath the uppermost beam 44 of the truss as shown in FIG. 4. From an inspection of FIG. 4, it can be seen why it is necessary to rotate the tangs upwardly to support the far edge of the roof panel 40 horizontally, because of the inboard beam 44. Of course, the beam may be of different dimensions with different roof panels, and the angle of the lifter frame 12, as shown in FIG. 1, may vary and must be compensated for by rotating the tangs up or down to establish the roof panel horizontally. Upwardly rotated tangs would also be effective in stabilizing a single, thick laminated beam, or a single truss unattached to a roof panel, as the cant of the tangs would tend to throw the member being carried back against the backboard as is well illustrated in FIG. 6.
In practice, very wide prefabricated roof panels such as that shown in FIG. 3 will be consecutively placed between long parallel roof joists which support the outer ends of the roof panels. The roof panels are consecutively put in place, one after the other so that the edge of the roof panel that has no truss is mounted to the edge of the previously installed roof panel, which is the edge having the truss beneath it. It is a very efficient way of making a roof for a large building, and especially a large open building, such as a warehouse or a factory.
It can be easily understood that in some instances it would be desirable or even necessary to vary the spacing between the tangs to accommodate different roof panels and their accompanying trusses. In order to do this, the sockets 30 can be made slidable along the beam 22, where they remain in place under the action of friction, or with the assistance of a set screw or the like. Of course, in order for the sockets to slide along the beam rather that being welded to it, the beam must be acircular, such as the rectangular beam shown in FIG. 7. In FIG. 7, the rectangular beam 46 fairs into a cylindrical portion 48 which rotates freely within the tube 20 to achieve the rotational adjustability of the tangs. In this embodiment, the sockets 50 are themselves rectangular, sliding along the rectangular beam 46. The remaining portion of the socket can be the same. A set screw 52 or an equivalent locking mechanism can be used to secure the socket at any desired spacing along the beam.
Thus, for any particular job, and for any particular type of roof panel, the rack can quickly be adjusted, both in the spacing of the tangs and the extent to which the tangs project forwardly to achieve a safe and secure engagement of the roof panel, holding it just underneath the horizontal portion rather than beneath the truss, providing a safer, stabler, and easier-to-use manner of effecting prefabricated panel roof construction than that provided by previously used techniques and equipment.
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A rack for attachment to the backboard of a forklift has a very long laterally extended beam with forwardly extended, adjustable tangs, the rack being designed primarily for use in engaging wide sections of roof ordinarily having a truss along one long ede with the purpose being to safely and conveniently lift each roof section into place adjacent the previous roof section which was similarly put in place, and so forth, during the construction phase of a building such as a warehouse.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No. 13/169,781, filed Jun. 27, 2011, which is a continuation of U.S. Ser. No. 10/588,166 filed Aug. 7, 2008, and issued as U.S. Pat. No. 7,968,531 on Jun. 28, 2011, which is a national stage filing under 35 U.S.C. §371 of International Application Number PCT/ES2005/70017, filed Feb. 16, 2005, which claims the benefit of priority under 35 U.S.C. §119 of ES Application Number P200400371, filed Feb. 17, 2004. The foregoing applications, and all documents cited therein, are hereby incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The invention relates to a pharmaceutical composition that includes the 2,5-dihydroxybenzenesulfonic acid, and its employment in the preparation of a medicine for treatment of diseases characterized by an intense cell proliferation, vascularization (angiodependent diseases) and more specifically angiodependent diseases also having reduction of the apoptosis, as it is the case for example in cancer or psoriasis.
BACKGROUND
[0003] Malignant tumors are characterized, besides from the uncontrolled cellular proliferation, by their capacity to invade normal peritumoral tissues. Tumor invasion is a complex process developed according to the following consecutive stages: a) adhesion of the tumor cells to proteins of the extra-cellular matrix; b) degradation of the proteins of the extra-cellular matrix by proteases that create extra-cellular spaces that the tumor cells use to, c) migrate through a dynamic and complex mechanism that requires synthesis of new portions of the cytoplasmic membrane and reorganization of the cytoskeleton (Giese A, Westphal M. Neurosurgery 1996; 39: 235-252). The cells that from the tumor mass invade the normal peritumoral-tissue have their genetic program of cellular death disabled and therefore, the tumor cells that migrate to invade the peritumoral intact tissues, elude the apoptosis (Mariani I et al. Clin Cancer Res 7:2480-2489, 2001). When the grouped tumor cells reach 2 to 3 mm 3 volume, the tumor cells synthesize large amounts of angiogenic factors to counteract the hypoxic situation of this primary tumor, (Folkman J. N. Engl J Med 285: 1182-1186, 1971; Carmeliet P, Jain R K. Nature 407: 249-257, 2000; Yancopoulos G D et al. Nature 407: 242-248, 2000) that activate the peritumoral blood vessels so that they form new blood vessels (angiogenesis) that invade the tumor to supply the oxygen and the nutrients and eliminate products from the tumor catabolism. The same cellular processes that occur during the tumor invasion (motility and absence of apoptosis) occur centripetally during tumor angiogenesis. Therefore, the inhibition of the invasive capacity of the tumor cells and of the endothelial cells should produce a delay in tumor growth by inhibiting the tumor expansion, reducing angiogenesis and promoting apoptosis. Therefore, an effective treatment against cancer should inhibit the migration, the angiogenesis and increase apoptosis without producing these effects in normal cells.
[0004] There are numerous anti-tumor and antiangiogenic agents at various stages of clinical development in oncology (Brem S. Cancer Control 6: 436-458, 1999), of which a significant number are peptides that the body uses to counteract the effect of the positive regulators of angiogenesis (Hagerdom M, Bikfalvi A. Crit Rev One Hemat 34: 89-110, 2000). However, when these peptides are compared with compounds with a significantly lower molecular weight, their pharmacological inconveniences become evident. On the other hand, it has been proven that different synthetic compounds containing aromatic rings in their molecular structure and acting as inhibitors of the mitogenic activity induced by growth factors are cytotoxic for quiescent or non tumor cells (Lozano R M J Mol Biol 28 I: 899-9115, 1998). Therefore, there is still need to find compounds with anti-tumor, antiangiogenic and proapoptotic activity with low toxicity for intact, quiescent, non tumor cells. There is presently a great interest for the search of new therapeutic indications for old medicines. In this connection, it has been recently proven that different antibiotics, besides from their antimicrobial activity, have antiproliferative effects, such in the case of rapamycin (Morice M C et al. N Engl J Med 346: 1773-1780, 2002), or of the neomycin (Cuevas P. et al. Neural Res 224: 389-391, 2002); or are useful as anxiolytics such as norfloxacin (fluoroquinolone) (Johnstone T B et al. Nat Med 10; 31-32, 2004).
[0005] Psoriasis is an angiodependent chronic disease that affects 2-3% of the world population and is characterized by epidermic hyperplasia, dermo-epidermic infiltration of inflammatory cells and T lymphocytes, and a very evident development of vascularization, together with a reduction of the cell death due to apoptosis (Kocak M et al, Int J Dermatol 42: 789-793, 2003). Presently, there is no curative treatment for psoriasis. The antipsoriatic treatment may be topical or systemic, depending on the extension and severity of the disease. The mostly used anti psoriatic topical therapy consists of different types of corticoids, but the extended use of these compounds is associated with skin atrophy, stretch marks and telangiectasia (Baker B S, Fry L. Cutis 1999; 64: 315-318). The systemic therapy with immunosuppressant medicines is associated to very severe side effects (Wolina V. et al. Clin Rheumatol 2001: 20: 406-410). For example, the use of cyclosporine for treatment of psoriasis may produce nephrotoxicity (interstitial fibrosis and tubular atrophy), hypertension, hypomagnesaemia, hypercalcemia and hepatic dysfunction (Travis L, Weinberg J M. Drugs of Today 2002; 38: 847-865). The standing use of another immunosuppressant medicine for treatment of psoriasis, tacrolirnus, may produce hypertension, nephrotoxicity and immunosuppression (Jegasothy B V et al. Arch Dermatol 1992; 128: 781-785). It has been recently described that the topic application of the tacrolimus immunosuppressant accelerates carcinogenesis in mouse skin (Niwa Y, Terashima T, Sumi H. B J Dermatol 2003; 149: 960-967). Therefore, there is need for new antipsoriatic compounds proving to be efficient without producing evident side effects such as those associated with the most common anti-psoriatic compounds.
[0006] The 2,5-dihydroxybenzenesulfonic acid is a derivative of the 2,5-dihydroxybenzoic acid, pharmacologically prescribed in the form of different salts (mainly calcium, potassium, and magnesium), which provides stability. The 2,5-dihydroxybenzenesulfonic acid has been used since the 70's as an oral vasculotropic medicine.
[0007] The 2,5-dihydroxybenzenesulfonic acid inhibits platelet aggregation, increase of capilar permeability and blood viscosity in patients with diabetic retinopathy (Bayer J. et al. Dtsch. Mod Wschr 1980; 46: 160-1608; Banarroch L S. et al. Ophthalmic Res 1985; 17; 131-138; Michal M, Giessinger N. Thromb Res 1988; 51: 593-605). The metabolism and the pharmacokinetics of this compound in the human being is known since year 1974 (Benakis A. et al. Therapie 1974; 29: 211-219). Recent experiments have proven that the 2,5-dihydroxybenzenesulfonic acid increases the activity of the endothelial isoform of the nitric oxide synthase [endothelial nitric oxyde synthase (eNOS)] in rat endothelial cells without producing cytotoxic effects (Suscheck C. et al. Bt J Pharmacal 1997; 122: 1502-1508). In addition, the 2,5-dihydroxybenzenesulfonic acid potentiates the in vitro relaxation of human penile arteries (Angulo J et al. Br J Pharmacol 2003; 139: 854-862). There is experimental evidence that the 2,5-dihydroxybenzenesulfonic acid (formulated as a calcium or magnesium salts) possesses in vitro antioxidant activities (Brunet J et al. Fundam Clin Pharmacol 12: 205-212, 1998).
SUMMARY
[0008] The present invention is based on the discovery of new activities of the 2,5-dihydroxybenzenesulfonic acid and/or its salts, associated to their antiproliferative, anti migratory, antiangiogenic and proapoptotic capacity in non quiescent cells, activities that combined, justify their employment as a useful compound for treatment of angiodependent diseases such as the case of cancer, characterized by hyperproliferation, cell invasion and excessive angiogenesis, together with a deficit in cell death due to apoptosis, without causing toxicity for non-tumor intact or quiescent cells. Gliomic tumor cells have been used in experiments because gliomas are very invasive tumors with a significant angiogenic capacity and a significant apoptotic deficit (Merzak A, Pilkington G J. Cancer Metastasis Rev 16: 155-177, 1997).
[0009] The present invention is also based on the proven fact that the 2,5-dihydroxybenzenesulfonic acid and/or its salts possess, in a combined form, antipoliferative, antiangiogenic, and proapoptotic effects and therefore its therapeutic efficacy has been evaluated in chronic psoriatic plaques characterized by epidermic hyperproliferation, acute dermal angiogenesis and apoptotic deficit (Karasek M A, Cutis 64: 319-322, 1999).
[0010] This invention relates then to the search of new treatments for cancer and other angiodependent diseases and it is based on the fact that the 2,5-dihydroxybenzene sulfonic acid and/or its salts have proven their capacity to inhibit growth and migration and induce the apoptosis in in vitro tumor cells as well as the capacity to inhibit the in vivo angiogenesis induced by fibroblast growth factor (FGF). Therefore, due to the combination of these abilities, the mentioned compounds become useful for the treatment of malignant tumors and hematological neoplastic diseases as well as for treatment of other severe vascularization related pathologies (angiodependent diseases).
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIGS. 1A and 1B are graphs depicting treatment with different concentrations of a compound according to one embodiment producing a dose-dependent inhibition of cell proliferation. FIG. 1A depicts 88% inhibition with a concentration of 100 μM of the calcium salt of the 2,5-dihydroxybenzenesulfonic acid. FIG. 1B depicts 74% inhibition with the same concentration of the potassium salt of the 2,5-dihydroxybenzenesulfonic acid;
[0012] FIG. 2A shows the image of a C6 cell culture after 48 hours without treatment; FIG. 2B shows the image of a C6 cell culture after 48 hours of treatment with a concentration of 50 μM of the calcium salt of the 2,5-dihydroxybenzenesulfonic acid; FIG. 2C shows the image of a C6 cell culture after 48 hours of treatment with 100 μM of the potassium salt of the acid;
[0013] FIGS. 3A and 3B are representative graphs depicting the antiproliferative effect of the 2,5-dihydroxybenzenesulfonic acid. FIG. 3A shows the results of treatment with the calcium salt of the 2,5dihydroxybenzenesulfonic acid. FIG. 3B show the results of treatment with the potassium salt of the 2,5dihydroxybenzenesulfonic acid;
[0014] FIG. 4 shows the images of an area of an experiment of a control culture ( FIGS. 4A and 4B ) and of another culture treated with the compound ( FIGS. 4C and 4D );
[0015] FIG. 5 shows histograms of the experiments to evaluate the effect of the 2,5-dihydroxybenzenesulfonic acid in the potentiation of the different cytostatic medicines: Cisplatin (5 μg/ml) ( FIG. 5A ); Vincristine (0.1 μl/ml) ( FIG. 5B ); Paclitaxel (5 μg/ml) (( FIG. 5C ); and 5-fluorouracil (100 μg/ml) ( FIG. 5D );
[0016] FIG. 6 shows images of a representative control experiment ( FIG. 6A ) and another experiment in which the cells were treated during 24 hours with the compound ( FIG. 6B );
[0017] FIG. 7 is a graph representing the percentage data of all the experiments showing that the 2,5-dihydroxybenzenesulfonic acid inhibits up to 64% of migration of tumor cells;
[0018] FIGS. 8A and 8B show the images corresponding to an embryo treated with 3 μg of bFGF+0, 1% heparin ( FIG. 8A ) and another embryo to which 100 μM of a potassium salt solution of the 2,5-dihydroxybenzenesulfonic acid was added on the next day ( FIG. 8B ); and
[0019] FIG. 9 shows images before treatment, at six and at thirteen days after treatment of the same chronic psoriatic plaque located in the extension area of the left elbow treated with the potassium salt of the 2,5-dihydroxybenzenesulfonic acid at 5%.
DETAILED DESCRIPTION
[0020] The 2,5-dihydroxybenzenesulfonic acid formulated in the form of salt is a commercial product (for example, the potassium salt may be acquired at Merck Farma y Quimica SA, Mollet del Vallés, Barcelona) with the following molecular formula:
[0000]
[0000] in which Met=Metal and n is a function of the metal valence used in the salt. Generally n 0 1 or 2 for being the metal cation former of the salt, univalent (K) or divalent (Ca óMg). The new biological activities of the 2,5-dihydroxybenzenesulfonic acid do not depend of the cation bond to the benzene ring because the 2,5-dihydroxybenzenesulfonic acid formulated with any salt has similar effects in the inhibition of cell proliferation, migration and angiogenesis. This invention only describes the activities of the 2,5-dihydroxybenzenesulfonic acid formulated as potassium and calcium salt without forgetting that within the scope of this invention is any pharmaceutically acceptable salt of the compound. The term “pharmaceutically acceptable salts” include metal salts or addition salts which can be used in pharmaceutical forms. The pharmaceutically acceptable salts of the 2,5-dihydroxybenzenesulfonic acid can be obtained from organic or inorganic acids or bases, through conventional methods, by making the appropriate acid or base react with the compound.
[0021] The pharmaceutical compositions containing the 2,5-dihydroxybenzenesulfonic acid can be presented in any adequate administration form, for example, systemic, oral, parenteral, urethral, rectal or topical administration, for which the necessary pharmaceutically acceptable excipients will be included for formulation of the desired form of administration.
[0022] The following examples illustrate and support the invention and should not be considered as limitations of the scope of the invention.
Example 1
Illustrative Assay of the Anti-Proliferative Ability of the 2,5-Dihydroxybenzenesulfonic Acid
[0023] This in vitro study, was carried out in three different triplicate experiments with rat gliomic cells (C6 line). The cells were cultured in a medium formed by DMEM Dulbecco's modified Eagle's Medium (Gibco. Paisley UK), 7.5% of fetal serum (Gibco) 10 units/ml of penicillin (Gibco) and IO ug/ml of streptomycin (Gibco). The cultures were kept in a humid atmosphere at 3 TC. To evaluate the effect of the 2,5-dihydroxybenzenesulfonic acid on the cell proliferation, 2×104 C6 cells per ˜ell were seeded in 24-well (15 mm of diameter) plates. The experimental cultures were treated during 48 hours with different micro molar concentrations (μM) of the compound (calcium or potassium salt of the 2,5-dihydroxybenzenesulfonic acid). The controlled cultures lived 48 hours, without adding the compound. Photographs of the cultures were taken after 48 hours using an inverted microscope and then, the cultures were colored with crystal violet (Merck Farma y Quimica SA. Mollet del Vallés, Barcelona) and processed to determine the number of cells per well, using a spectrum photometric method. As shown in FIG. 1 , treatment with different concentrations of the compound produces a dose-dependent inhibition of cell proliferation, obtaining 88% inhibition with a concentration of 100 μM of the calcium salt of the 2,5-dihydroxybenzenesulfonic acid (A). With the same concentration of the potassium salt of the 2,5-dihydroxybenzenesulfonic acid, a 74% inhibition was obtained (B). The IC 50 is near to 25 μM for the calcium salt and between 40 and 50 μM for the potassium salt. Comparing FIG. 1A with FIG. 1B , it is observed that to obtain the same percentage of inhibition in cell proliferation after treatment with the calcium salt of the compound, a double concentration of potassium salt is necessary to obtain the same effect. This is due to the fact that the calcium salt of the compound contains two active principle moles (2,5-dihydroxybenzenesulfonic acid) that separate from salt in aqueous solution. FIG. 2 shows the image of the C6 cells culture after 48 hours without treatment (A), another image corresponding to the C6 cells culture treated for 48 hours with a concentration of 50 μM of the calcium salt of the 2,5-dihydroxybenzenesulfonic acid (B) and a third one corresponding to a culture of C6 cells treated during 48 hours with 100 μM of the potassium salt of the acid (C). This study shows that the treatment with the compound inhibits proliferation in neoplastic cells and corroborates the antiproliferative effect of the compound observed in normal vascular smooth muscular cells stimulated in vitro with mitogenic factors (Pares-Herbute N et al. Int J Angiol 8: 85-810, 1999). To distinguish if the anti proliferative activity of the 2,5-dihydroxybenzenesulfonic acid is mediated by a cytotoxic or a proapoptotic effect, we conducted different experiments detailed in the following example:
Example 2
Illustrative Assay of the Proapoptotic Ability of the 2,5 Dihydroxybenzenesulfonic Acid
[0024] This assay was carried out with the C6 cells according to the procedure described in example 1. To demonstrate the proapoptotic effect of the analyzed compounds we have used two different methods that detect the intracellular fragmentation of the DNA and the apoptotic nuclei in situ.
Detection of the Intracellular Fragmentation of the DNA.
[0025] The enzymatic immunoassay methods to quantify the DNA fragments associated to histones may be considered suitable to determine the onset of apoptosis (Aragane Y et al. J Cell Biol 1998; 140: 171-182). This method allows to differentiate death due to necrosis from death due to apoptosis since in necrosis the cytoplasmic membrane is fragmented and the DNA appears in the culture medium, while in apoptosis, the fragmented DNA remains in the interior of the cell because the plasma membrane remains intact (Aragane Y et al. J Cell Biol 140: 171-182, 1998).
[0026] Using the Cell Death Detection ELISAP plus kit (Boehringer Mannheim, Mannheim, Germany) in accordance with the manufacturer's instructions, we have determined the fragmentation of DNA in C6 (2×10 3 ) cell cultures at 4, 16, 24 and 48 hours. The controlled cultures did not receive any treatment while from 50 to 200 μM ( FIG. 3A ) of the potassium salt of the 2,5-dihydroxybenzenesulfonic acid were added to the experimental cultures. Experiments were also conducted adding from 25 to 100 μM of the calcium salt of the 2,5-dihydroxybenzenesulfonic acid ( FIG. 3B ). All experiments were performed in triplicate in three different experiments.
[0027] FIGS. 3A and 3B show the following: a) the antiproliferative effect of the 2,5-dihydroxybenzenesulfonic acid is mainly mediated by a proapoptotic activity; b) the cation bonded to the molecule does not determine the activity of the compound because the proapoptotic effect is similar using the calcium or potassium salt of the compound; c) the highest proapoptotic effect is obtained in cells treated with the compound during 48 hours; d) the maximum effect is obtained with a concentration of 25 μM for the calcium salt and 50 μM for the potassium salt, identical to the IC 50 in cellular proliferation studies. Once it is proven that the antiproliferative mechanism of the 2,5-dihydroxybenzenesulfonic acid participates in the cell death due to apoptosis, we quantitatively evaluated such effect through a microscopic study of gliomic cells using the following technique:
In Situ Detection of Apoptotic Nuclei (TUNEL Technique)
[0028] Three independent experiments were made, repeated three times. The C6 cells from controlled cultures and those from cultures treated during 24 hours with the (50 μM and 100 μM of the calcium and potassium salts respectively) were adhered to glass slides and fixed with a 4% paraformaldehyde buffered solution (pH 7.4) for one hour at the laboratory temperature. Afterwards, the cells were washed and permeabilized with a 0.1% solution of Triton X-100. Then the cells were washed before applying the TUNEL technique [(terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (Gavrieli Y, Sherman Y, Bensasson S A. J Cell Biol 119: 493-501, 1992). A kit for in situ detection of apoptotic nuclei (In situ Cell Death Detection Kit Boehringer Mannheim, Mannheim, Germany) was used. The different stages of the technique were followed in accordance with the instructions of the kit manufacturer. Finally, the cells were colored with green light (Fluka, AG, Switzerland). The TUNEL reaction only appears in the apoptotic nuclei.
[0029] Although very similar results were obtained with the calcium and potassium salt of the compound, object of the invention, only the results obtained with the potassium salt of the compound are shown. Cells were counted in 6 different fields in twelve slides where the cells from the 6 control cultures and the 6 cultures treated with the 2,5-dihydroxybenzenesulfonic acid (100 μM) had adhered. The total number of non apoptotic and apoptotic cells was as follows:
[0000]
C6 Cells
Apoptotic Nuclei
Normal Nuclei
Control Cells
138
5954
Treated Cells
3846
354
[0030] The total number of treated cells is lower than the total number of control cells due to the antiproliferative effect of the compound.
[0031] The images of FIG. 4 show an area of an experiment of a control culture (A and B) and of another culture treated with the compound (C and D) in which the TUNEL technique was employed. As shown in the images, only two apoptotic nuclei are observed on the control cells while in the treated cells with the compound object of the invention there are 107 apoptotic nuclei and only 8 normal nuclei (non apoptotic).
[0032] These data show that the 2,5-dihydroxybenzenesulfonic acid is a compound with an important proapoptotic activity useful to induce tumor apoptosis. Given that it has been proven that the 2,5-dihydroxybenzenesulfonic acid inhibits apoptosis in normal human cells (Braber R, Farine J C, Lora G A. Apoptosis 4: 4111-49, 1998), this compound is a strong molecule candidate for treatment of cancer.
[0033] One of the mechanisms involved in the therapeutic failure of chemotherapy and radiotherapy is the inefficacy of these treatments to induce cellular death by apoptosis, mainly due to the hyper expression of antiapoptotic proteins in tumor cells (Sellers W R, Fisher Del. J Clin Invest 104: 1655-1661, 1999; Branch P. et al. Oncogene 19: 3138-3145, 2000). Therefore, the proapoptotic compounds may be of great clinical use as an adjuvant in chemotherapy and radiotherapy treatments.
[0034] Once the proapoptotic effect of the 2,5-dihydroxybenzenesulfonic acid was demonstrated, we evaluated the ability of this compound to increase the antiproliferative effect of the different cytostatic medicines. The following example demonstrates how the 2,5-dihydroxybenzenesulfonic acid is capable of increasing the therapeutic efficacy of the different cytostatic compounds used in oncology such as cisplatin, vincristine, paclitaxel and 5-fluorouracil.
Example 3
[0035] Illustrative Assay of the Ability of the 2,5-Dihydroxybenzene Sulfonic Acid in Potentiation of Chemotherapy
[0036] We used for this study C6 cells cultured in vitro under the same conditions described in example 1. 1×103 cells per well were cultured in 24-well plates. Three types of treatment were made: a) 24 hours after the seeding, the cells were separately treated with each one of the following medicines; cisplatin (5 μg/ml), vincristine (0.1 μg/ml), paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml); b) 24 hours after the seeding, the cells were treated jointly with the 2,5-dihydroxybenzenesulfonic acid (potassium salt, 100 μM) and with each one of the following medicines; cisplatin (5 μg/ml) vincristine (0, 1 μg/ml), paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml); c) at the time of the seeding (Day 0), the cells were pre-treated with the 2,5-dihydroxybenzenesulfonic acid (potassium salt, 100 μM). Next day the cultures were treated also with each one of the following medicines: cisplatin (5 μg/ml) vincristine (0, 1 μg/ml), paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml). The controlled cultures did not receive treatment for 2 days. After 48 hours (day 2), the cells of identical shape to the ones used in example 1 were evaluated in all the cultures. This study was carried out in triplicate independent experiments repeated three times.
[0037] FIGS. 5 (A, B, C, and D) shows the histograms of the experiments performed to evaluate the effect of the 2,5-dihydroxybenzenesulfonic acid in the potentiation of the different 5 cytostatic medicines. Treatment with cisplatin, vincristine and 5-fluorouracil produces an inhibition of 50% in proliferation of C6 cells, while the treatment with paclitaxel obtains 67% of inhibition of the cellular proliferation. The combined treatment of the 2,5-dihydroxybenzenesulfonic acid+the cytostatic medicines (cysplatin, vincristine and 5-fluorouracil) produces an inhibition of 84% in cellular proliferation. The combined treatment with 2,5-dihydroxybenzenesulfonic acid+paclitaxel produces 86% in the inhibition of the cellular proliferation. When cellular cultures are pre-treated with the 2,5-dihydroxybenzenesulfonic acid and afterwards with the following cytostatic medicines: cisplatin, vincristine and 5-fluorouracil, an inhibition of 90% is obtained in the cell proliferation. When paclitaxel is used, the inhibition in cellular proliferation reaches up to 92%.
[0038] The above mentioned results demonstrate that the simultaneous treatment of the 2,5-dihydroxybenzenesulfonic acid with the chemical therapy agents, increases their therapeutic efficacy and besides this chemical potentiation effect is higher when the cells has been pre-treated with the 2,5-dihydroxybenzenesulfonic acid. These data support the use of the 2,5-dihydroxybenzenesulfonic acid as an adjuvant in the treatment associated with chemical therapy and radiotherapy.
Example 4
[0039] Illustrative Assay of the Antimigration Ability of the 2,5 Dihydroxybenzenesulfonic Acid
[0040] This assay was carried out in three different triplicate experiments. To evaluate the ability of the 2,5-dihydroxybenzenesulfonic acid in the inhibition of cellular migration C6 2×10 5 cells cultured in vitro in 20 mm plates were used. A longitudinal lesion was made with a sterile micropipette (day 0) to the control cultures and in cultures treated with 100 μM of the potassium salt of the 2,5-dihydroxybenzenesulfonic acid. Digital photos were taken using a photographic system connected to a luminous microscope and the area of the lesion was delimited using a computerized morphometric program (Moticam. Motic. Barcelona).
[0041] Photographs were taken again after 24 hours, and the borders of the lesion were marked overlapping the first two photos (day 0) with those obtained after 24 hours to calculate the percentage of the injured area covered by the migratory cells. These values were represented as a percentage of the regeneration obtained with the treatment. FIG. 6 shows a typical example of a control experiment (A) and another experiment in which the cells were treated during 24 hours with the compound object of the invention (B). As observed in this Figure, the non treated cells completely regenerate the lesion ( FIG. 6A ) while the cells treated with the compound are not capable of migrating and cover all the area of the lesion ( FIG. 6B ). FIG. 7 that represents the percentage data of all the experiments shows that the 2,5-dihydroxybenzenesulfonic acid inhibits up to 64% of migration of tumor cells.
Example 5
[0042] Illustrative Assay of the Antiangiogenic Ability of the 2,5-Dihydroxybenzenesulfonic Acid
[0043] We used for this assay the chorioallantoic membrane of a chick embryo for testing the activity of antiangiogenic substances in vivo (Zilberberg L. et al. J Biol Chem 2003; 278: 35564-35573). We used a proangiogenic compound, the basic form of the fibroblast growth factor (bFGF) (Meghna U et al. Blood 2003; 102: 2108-2114).
[0044] Fertilized eggs are kept in a incubator at 37° C. with a humidity of 80%. After 4 days, a hole is made in the narrowest end of the egg shell to collect 1 ml of albumin Then, the hole is covered with a paraffin film (Parafilm M Laboratory Film Chicago Ill. USA). This procedure allows creating an air chamber that prevents the embryo to adhere to the upper part of the shell. On day 13 of incubation, the shell is split at the air chamber level to perform the treatment. Twenty embryos are treated with 5 μl of a solution of 3 μg of bFGF+0.1% heparin, soaked in a nitrocellulose paper disc. Afterwards the shell is sealed with a paraffin film. Next day, in half of the embryos (n=10) the shell is uncovered to soak again the nitrocellulose paper disc with 100 μM of potassium salt of the 2,5-dihydroxybenzenesulfonic acid dissolved in physiological saline (5 μl). The hole in the shell is then covered again with a paraffin film. On day seventeen the experiment ends, taking photographs of the nitrocellulose piece for the comparison study.
[0045] FIG. 8 presents two images corresponding to an embryo treated with 3 ug of bFGF+0, 1% heparin (A) and another embryo to which 100 J.!M of a potassium salt solution of the 2,5-dihydroxybenzenesulfonic acid was added on the next day (B) Image A shows how the nitrocellulose disc is invaded by blood vessels while Image B shows a very scarce vascular invasion in the disc. The morphometric quantification of the images of the nitrocellulose discs using a computerized system (Moticam Motic. Barcelona) shows the antiangiogenic effect of the compound (area of the disc covered by blood vessels in embryos treated with bFGF+heparin=35±8.6% vs. area of the disc covered by blood vessels in embryos treated with bFGF+heparin+potassium salt of the 2,5-dihydroxybenzene sulfonic acid=2±1.5%; p<O,OOOI; unpaired student's t-test). Similar effects were obtained using 50 μM of the calcium salt of the compound.
[0046] This experiment shows that the compound object of this invention has an antiangiogenic activity for being capable of neutralizing the angiogenic effect induced by bFGF.
Example 6
Assay on Psoriatic Lesions
[0047] We used for this study the potassium salt of the 2,5-dihydroxybenzenesulfonic acid formulated at 2.5 and 5% in cream for being this type of formulation a usual procedure for topical treatment of skin diseases. The selected concentrations of the salts of the 2,5dihydroxybenzenesulfonic acid are within the range of the concentrations used for treatment of diabetic retinopathies: 6 tablets per day of 500 mg of calcium salt of the 2,5-dihydroxybenzenesulfonic acid (Benakis A et al Therapie 1974; 29: 211-219). As aqueous phase of the cream we have used distilled water. The fatty phase can be constituted by cetylic alcohol, stearic alcohol or vaseline. The span is an efficient emulsifier in the preparation of the cream. Although both formulations (2.5 and 5%) of the product show to be clinically efficient, the best therapeutic benefit is obtained with the concentration at 5%. The following example illustrates the formulation of an efficient cream for the topic treatment of psoriasis, by way of example and not of limitation of the scope of the invention.
[0000] I.—Active Part (potassium salt of the 2,5-dihydroxybenzenesulfonic acid at 5.6%)
II.—Inactive Part (as excipients cetylic alcohol (2.5%), stearyl alcohol (2.5%), liquid vaseline (30%), white soft paraffin (20%), sorbitan oleate (5%) and distilled water (c.s.p 0.100 g).
[0048] The clinical efficacy of the treatment was evaluated according to the index that quantifies the desquamation signs (D), erythema (E) and infiltration (I) to which the following assessment was assigned: (0) absent; (1) slight; (2) moderate and (3) severe (Freeman A K et al. J. Am. Acad Dermat 2003; 48: 564-568). FIG. 9 shows three images: before treatment, six and thirteen days after treatment of the same chronic psoriatic plaque located in the extension area of the left elbow treated with the potassium salt of the 2,5-dihydroxybenzenesulfonic acid at 5%. As can be observed, the topical treatment two times at day with a cream containing the potassium salt of the 2,5-dihydroxybenzene sulfonic acid produces an early (6 days) very notable “clearance” of the plaque with almost total disappearance of hyperkeratosis. The therapeutic efficacy of the cream is more evident at the end of the second week of treatment. The treatment produces a significant reduction of the global values of the DEI index (DEI global pre-treatment=6±1.57 vs. DEI global post-treatment=1±0.58; p<0.0001; unpaired student's r-test).
Figures Captions
[0049] 1. Histogram showing the anti proliferative effect of the treatment with different concentrations of the (A) calcium and (B) potassium salts of the 2,5-dihydroxybenzenesulfonic acid in cultures of C6 cells after 48 hours of treatment. Ordinates: Absorbance at 595 nm; Abscises: concentration: μM.
[0050] 2. Panel A shows the aspect of a control culture of C6 cells after 48 hours. Panel B shows an image of a culture of C6 cells treated during 48 hours with 50 μM of the 2,5-dihydroxybenzenesulfonic acid (calcium salt). Panel C shows a culture of C6 treated during 48 hours with 100 μM of the potassium salt of the 2,5dihydroxybenzenesulfonic acid.
[0051] 3. Representative histograms in which it is observed that the antiproliferative effect of the 2,5-dihydroxybenzenesulfonic acid is not due to necrosis (white histogram) but to apoptosis (lined histogram). A: treatment with the calcium salt of the 2,5-dihydroxybenzenesulfonic acid. B: Treatment with the potassium salt of the 2,5-dihydroxybenzenesulfonic acid. Ordinates: Absorbance at 405 nm; Abscises: time in hours.
[0052] 4. Images of gliomic C6 cells processed with the TUNEL technique for in-situ detection of apoptotic cells. The apoptotic nuclei are shown dark and the nucleus and cytoplasm of the cell of the non apoptotic cells are shown in light color. The arrows indicate apoptotic nucleus. A and B control cells, C and D cells treated with 2,5-dihydroxybenzenesulfonic acid. Photographs Band D correspond to a zoom of the boxes of A and C photographs respectively.
[0053] 5. Histograms demonstrating the potentiating effect on chemotherapy (assessed as an anti proliferative effect) of the 2,5-dihydroxybenzenesulfonic acid, with different cytostatic compounds A) Cisplatin (5 ug/ml); B) Vincristine (0.1 μl/ml); C) Paclitaxel (5 Ug/ml) and D) 5-fluorouracil (100 j-tglml). Ordinates: Absorbance 595 nm; Abscises: white histogram (control); dotted (cytostatic; day 1); lined histogram (2,5-dihydroxybenzenesulfonic acid+cytostatic; day 1); square histogram (2,5-dihydroxybenzenesulfonic acid (day 0)+cytostatic; day 1).
[0054] 6. Photographic images of cellular migration in a control experiment and other experiments where the cells were treated with the 2,5-dihydroxybenzenesulfonic acid (B). The control cells totally regenerate one lesion made during the culture, while the cellular migration of the cells treated with the 2,5dihydroxybenzenesulfonic acid, was unable to fully cover the affected area of the culture. The horizontal lines delimit the initial longitudinal lesion made in the cultures.
[0055] 7. Histogram representing the migratory ability of the C6 cells in controlled cultures (white histogram) and in cultures treated with the 2,5-dihydroxybenzenesulfonic acid (black histogram). The migratory ability is expressed (ordinates) as a percentage of regeneration (percentage of the area covered of a longitudinal lesion made in the cultures)
[0056] 8. Images of two chicken embryos with 17 days of incubation. Panel A corresponds to an embryo treated with 3 μg of bFGF+0, 1% of heparin. Panel B shows the aspect of an embryo treated with 3 μg of bFGF+0.1% de heparin+100 μM of the potassium salt of the 2,5-dihydroxybenzenesulfonic acid. Panel A shows the antiangiogenic effect of the 2,5-dihydroxybenzenesulfonic acid because the nitrocellulose disc used as releasing vehicle of the substance appears almost without any vessels.
[0057] 9. Images of a hiperkeratosic psoriatic plaque located in the rear region of the left elbow. Image A represents the aspect of the psoriatic plaque before initiating treatment. Image B is an aspect of the same plaque after six days of treatment with a cream at 5% containing as an active component the potassium salt of the 2,5-dihydroxybenzenesulfonic acid. Image C shows the aspect of the psoriatic plaque after two weeks of treatment with the potassium salt of the 2,5dihydroxybenzenesulfonic acid formulated at 5%. The numbers shown in the images correspond to the day on which the photographs were taken.
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Provided is the use of 2,5-dihydroxybenzenesulfonic acid in the production of medicaments for the treatment of angiodependent diseases. More specifically, described is the use of the aforesaid compound and, in particular, the calcium and potassium salts thereof, for the treatment of two angiodependent diseases, which present a reduction in the apoptosis, namely cancer and psoriasis. Also described is the antiproliferative, antimigratory, antiangiogenic and proapoptotic capacity of said family of compounds in non-quiescent cells. In addition, described is the potentiating effect of said compounds on known cytostatic medicines in the treatment of tumours and, specifically, on gliomas. Additionally, the therapeutic efficacy of said compounds, based on the combined anti proliferative, antiangiogenic and proapaptotic capacities thereof, in the treatment of chronic psoriatic plaques is provided.
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CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of application Ser. No. 080,813 filed Aug. 3, 1987.
BACKGROUND OF THE INVENTION
There are numerous portable child restraint systems available to the consumer, all of which depend on the seat belt of the automobile or aircraft to hold them in place. Even at best, a child restraint system that depends on the vehicle seat belt to protect the child in the event of a vehicle crash in no way can match the safety and reliability of a restraint system that is made an integral part of the vehicle seat frame. Many states have passed strict laws requiring young children to be in an approved child seat when traveling in a passenger automobile. However, there is no know state requirement for a child seat in a bus or aircraft. The present invention, since it is an integral part of a passenger seat back, can be placed in a bus or aircraft and when stored, provide a comfortable adult seat. At present, many airlines have no infant or child restraint system. If the infant is small, the mother and child buckle together. In case of a survivable crash, the mother's body would obviously crush the child against the seat belt. The present invention, when used in an airliner, would require a person to pay for a seat for an infant, but in a survivable crash, it would guarantee the infant would also have a chance to survive. In addition, if there are no requirements for an infant seat on the aircraft, the seat could be folded up and sold as an adult seat. The same logic would hold true for a bus vehicle. A number of inventors have recognized the advantage of having a child seat being attached to the vehicle. One such invention is U.S. Pat. No. 3,584,481 to G. M. Mast et. al. who describes a child's chair and a infant bed, neither of which have any restraining system. U.S. Pat. No. 3,951,450 to Gambotti claims a child seat folding into the back of the front seat of an automobile with the child riding backwards. U.S. Pat. No. 2,966,201 to Strahler describes a cradle folding into the back seat of an automobile, however, the seat being a removable block on which the child sits. U.S. Pat. No. 4,555,135 to Freeland describes a folding child seat that utilizes the seat bottom to form a seat in which the child rides backwards. pAll of the above patents have the limitation of only a single restraint system, while the present invention has a dual restraint system which is a safety harness and a restraint bar. In addition, the present child restraint system conforms to Federal Motor Vehicle Safety Standard No. 213, latest revision 8/30/84.
SUMMARY OF THE INVENTION
It is a primary objective of the present invention to provide a child restraint system which is an integral part of an adult seat on a vehicle such as an automoile.
It is another objective of the present invention to provide a comfortable child safety seat and padded restraint bar when the child restraint system is unfolded from the adult seat of a vehicle.
It is yet another objective of the present invention to provide a child restraint system that affords greater protection in the event of a crash than a portable child safety seat.
It is still another objective of the present invention to provide a child restraint system that, when folded, will produce a comfortable adult seat.
It is a further objective of the present invention to provide a child restraint system that does not utilize any space in the vehicle when in a folded position.
Briefly, in accordance with the invention, there is provided an integral folding child restraint system that is designed to fit and fold into the back portion of a vehicle seat. When folded, the portion where an adult's back would rest is padded and therefore will be as comfortable as the rest of the back portion of the vehicle seat. When the child safety seat is unfolded, simultaneously a padded restraint bar will unfold with the child safety seat whereby the padded restraint bar can be locked in its up position. The padded restraint bar side tubing has adjustable means and locking means to fit various child body forms. A removable plastic tray is also available that snaps on the restraint bar tubes to hold articles for the entertainment of the child. When unfolded, the child safety seat will rest on the vehicle's seat and the child will be riding in a forward position.
These and other objects, features and advantages of the present invention will become more readily apparent upon detailed consideration of the following description of a preferred embodiment with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a partial "cut away" view of the child restraint system in the unfolded position.
FIG. 2 shows a partial "cut away" view of the child restraint system in the folded position.
FIG. 3 is a front view showing the mechanism of the child restraint system.
FIG. 4 is a top view showing the removable tray fitted on the restraint bar.
FIG. 5 is an isolated section showing part of the mechanism of the child restraint system.
FIG. 6 is a cross section of the channel of part of the mechanism of the child restraint system taken on line 6--6 of FIG. 5.
FIG. 7 shows seat harness webbing which will attach to the child seat mounting frame.
FIG. 8 shows the positioning and locking mechanism of the padded restraint bar.
FIG. 9 is a side view of the pivot and locking mechanism of the padded restraint bar.
FIG. 10 is an end view of the pivot and locking mechanism of the padded restraint bar.
FIG. 11 shows the pivot and holding mechanism of the child safety seat in its down position.
FIG. 12 shows the pivot and holding mechanism of the vertical child safety seat back member.
FIG. 13 shows the pivot and holding mechanism of the vertical child safety seat back member.
FIG. 14 is a perspective view of the child safety seat which also shows the restraint harness.
The novel features which are believed to be characteristics of the invention, both as it's organization and its method of operation, together with further objects and advantages thereof, will be better understood from the following description in connection with the accompanying drawings in which a presently preferred embodiment of the invention is illustrated by way of example. It is to be expressly understood, however, that the drawings are for purposes of illustration and description only, and are not intended as a definition of the limits of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now in detail to the drawings wherein like parts designated by like reference numerals throughout, there is shown in FIG. 1 a partial cut away view of a child restraint system 10 fitted into an adult seat 11 having a child seat mounting frame 12 built into the back of the adult seat 11 mounted in a vehicle (not shown) with the child safety seat 13 pivotally mounted on each side of the child seat mounting frame 12. The integral child safety seat 13 can be built into either side of the adult seat 11 of a land vehicle such as an automobile which would provide room for an adult also to sit on the seat.
It is assumed that the adult seat will contain the required adult seat belts (not shown) which is standard on both an automobile and aircraft. The child safety seat 13, when open, rests on the adult seat bottom 14. A rump support 15 is provided on the child safety seat 13 as shown in FIG. 1 of the drawing. Frame 12 as seen in FIGS. 1, 2 and 3 is a metal plate that is fastened to the same structure (not shown) of the vehicle that holds the vehicle seat secured to the vehicle. The metal plate must be of sufficient strength to take the loads required in Federal Safety Standard No. 213 dated Dec. 13, 1979 with the latest revision being Aug. 30, 1984. The frame 12 can be bolted, welded or fastened to the structure of the vehicle in such a manner that will provide sufficient strength to withstand a survivable crash. The preferred method of fastening, however, is welding since the frame 12 will be an integral part of the vehicle and installed when the remainder of the structure is being initially assembled. The child safety seat 13 has all the members fastened to the mounting frame 12 as shown in FIGS. 1, 2 and 3. A padded restraint bar 16 is shown in its up and locked position with is extended position as 18. In order to provide room to seat a child in the safety seat 13, one may wish to put the restraint bar 16 at position 18. However, after the child is seated, the restraint bar 16 can be positioned closer to the child as shown in FIG. 1.
In order to accomplish this, the tubes 20 and 24 on each side of the padded restraint bar 16 are telescoping with a spring biased locking pin as shown in FIG. 8. In FIG. 8, pin 25 is held in a lock position by spring 27. When it is desired to change the position of the restraint bar 20 and 24, pins 25 are pulled outward against spring tension provided by springs 27 and the end of the restraint bar 29 shown in FIG. 8 is moved in or out as desired. It should be understood that the restraint bar 20 has the same mechanism, shown in FIG. 8, as 24 and therefore to move the restraint bar in and out, both pins 25 must be pulled up simultaneously. A number of positions for the restraint bar 16 are available to adjust to the different anatomies of children.
The pivot mechanism 26 and 28, as most clearly seen in FIG. 3, is a spring biased system that will lock the restraint bar 16 in is up position. As seen in FIGS. 9 and 10, the pivot mechanism 28 is divided into two parts 31 and 33. Part 31 rotates with the tube 24 while part 33 is fixed to plate 12. The pin 35 is spring biased such that when the restraint bar 16 is placed in the up position, the pin 35 will be forced by the spring into a hole in part 33. To release the restraint bar 16, a slight rotation pressure upward will allow the locking pin 35 to be manually released which will further allow the restraint bar 16 to be folded toward the position as described in FIG. 2.
Turning now to FIG. 2, there is seen the child safety seat 13 in is folded position. In order to accomplish this, the restraint bar 16 is released as described above and folded down against padded segment 38 of the seat back. The child safety seat 13 is then lifted off the surface of the adult seat 14 and rotated about pivot points 30 and 32.
The mechanism 34 and 36 as best shown in FIG. 3 holds the seat 13 firmly in either the down or up position. The mechanism that accomplishes this is described in FIGS. 11 and 12. In FIGS. 11 and 12 a spring 37 fixed under tension and a roller 39 are attached to child safety seat 13. A cam 41 is fixed to plate 12 by rod 43. FIG. 11 shows the seat 13 in the down position with the roller 39 in a first detent in cam 41. FIG. 12 shows the seat 13 in its up position with the roller 39 in a second detent in cam 41. It can be seen that the roller 39 which is under tension from the spring 37 will hold seat 13 firm in either the up or down position. The padded restraint bar 16 does not lock in the down position as the seat 13 in the up position holds the restraint bar 16 securely in place. As seen in FIGS. 1 and 3 a padded portion of the child restraint system 38 is supported and attached preferably by fabric loops (not shown) to cross bars 40, 42 and 44 which is also part of the support mechanism pivotally supported by members 52 and 54. Pivot joint 66 as shown in FIG. 1 is a spring biased roller cam mechanism which is shown in FIG. 13. When the members 52 and 54 are in alignment as in FIG. 1, the roller ball 53 in FIG. 13 is forced by spring 55 in a detent in member 54 which provides a stiffening effect to members 52 and also 54. Padded segment 38 is also separated from the remainder of the adult passenger seat at points 48 and 50. The padded restraint bar is first folded down against the padded segment 38. The seat 13 is then raised which pushes vertically against members 54 and 52. This in turn places an upward force on rotating members 73, shown in FIG. 6, such that rotating member 73 can rise vertically in groove 70 as shown in FIG. 5. The rotating member 73 will reach the top of track 70 and continue around the corner as seat 13 continues to be lifted. Since the padded restraint bar 16 is resting against padded segment 38, further rotation of seat 13 will force the padded restraint bar 16 against padded segment 38 and cause pivot joint 66 to break inward as the roller ball 53 in FIG. 13 is forced out of the detent. Continued rotation of seat 13 will pull the rotating member 73 down in groove 70 toward the end of groove 70 which is designated as 74. It can be seen that the padded restraint bar 16 and the seat 13 are simultaneously folded into the cavity in the adult passenger seat. When completely stored, the roller 39 will fall into a detent in cam 41 as shown in FIG. 12. This will hold the seat firmly in place in is up position. When seat 13 is in its folded up position, pivot joint 66 contains another detent that roller ball 53 will fit into. This provides a stiffening effect of members 52 and 54 that allows the seat 13 to be unfolded. When unfolding the seat 13, rotating member 73 will therefore travel up groove 70, go around the corner at the top of groove 70 and as the seat 13 continues to rotate, rotating member 73 will move vertically downward to the end of groove 70. This movement, in turn, will make the members 54 and 52 be in a vertical position as shown in FIG. 1.
In view of the above movements, the unfolding of the seat 13, rotates mechanism 36 which is connected to members 54 and 52 and cause members 52 and 54 to continuously move from a folded position to an unfolded position. Since the padded segment 38 is attached to cross bars 40, 42 and 44 which, in turn, are connected to members 52 and 54, unfolding the seat 13 will simultaneously cause the padded segment 38 or back support to be unfolded. This action will also release padded bar 16 which can be lifted to its up and locked position. Folding member bracket 63 prevents the members 52 and 54 from moving too far forward when seat 13 moves down on the adult seat 14. It can be seen that the padded segment 38 gives a child a comfortable back rest when the child safety seat 13 is in is unfolded position. It can also be seen that the bottom 46 of seat 13 becomes the adult seat back rest when seat 13 is in its folded position. It can be seen from FIG. 3 that there are identical mechanisms on the other side from the one described above and shown in FIG. 1.
FIG. 3 shows a front section cut away and gives good detail of the arms and rods that provide pivotal support to the child restraint system.
FIG. 4 provides a top view of the child restraint system. This figure gives a top view of removable tray 77. Simple spring clips 57 are fitted over the tubular members 20 and 24 of the padded restraint bar 16 and hold the removable tray 77 in place. The removable tray is stored prior to folding of the child safety seat.
FIG. 7 shows a restraint harness made from strong webbing material. A quick release buckle 76 is provided in the event a person desires to move the child quickly to a safer area. The points on restraint harness 79 and 78 tie into the seat frame 12 of an adult 11 by attaching means. The points 80 and 82 tie into the child seat frame 12 by attaching means but at a lower point. The restraint harness 75 attached to frame 12 is shown in FIG. 14. When the child safety seat 13 is folded into its closed position, the restraint harness is tucked into the cavity formed by the rump support 15.
It is well known that a restraint system is mandatory if one is to survive a severe crash in either a land vehicle or aircraft. The child restraint system described by this invention provides maximum protection provided by a restraint system in a vehicle. The child seat 13 is attached to a seat frame 12 which is further attached to the adult seat 11 which is attached to the vehicle. A restraint bar 16 which can be adjusted against the child in addition to the restraint harness 75 will give protection even if the vehicle is in an upside down position. In addition, if the restraint bar 16, harness 75 and child seat 13 are in the folded position, a soft cushion layer 46 and the bottom of the child seat 13 will provide a comfortable back rest for an adult.
It is apparent that the construction of this invention provides for all the required safety features presently thought to be necessary in safe child seating for a land vehicle or aircraft. This is provided in a minimum space with a maximum of simplicity. In addition, the closure of the apparatus in the folded position is complete, giving the vehicle seat almost normal appearance and comfort.
Thus, it is apparent that there has been provided, in accordance with the invention, an integral folding child restraint system that fully satisfies the aims and objectives sat forth above. It is understood that all terms used herein are descriptive rather than limiting. While the invention has been described in conjunction with specific embodiments thereto, it is evident that may alternatives, modifications, and variations will be apparent to those skilled in the art in light of the aforegoing description.
Accordingly, it is intended to include all such alternatives, modifications, and variations that fall within the spirit and scope of the appended claims.
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A child restraint system which is an integral part of and folded into a land vehicle or aircraft adult seat is described. The integral child restraint system may be unfolded from the front portion of the back of an adult seat to form a comfortable child safety seat. A padded restraint bar also unfolds simultaneously with unfolding of the integral child safety seat to further restrain the child in the event of a crash. Also included is a belt restraint system, very similar to an approved portable child seat, attached to the child's safety seat frame. When the integral folding child safety seat is folded into its stored position, a normal padded passenger seat back is formed which is comfortable to an adult passenger sitting in the seat. A detachable tray fitted on the padded restraint bar is also included.
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FIELD OF INVENTION
The present disclosure relates generally to a device for use with fluid dispensing pumps, such as gasoline pumps. More specifically, the invention relates to a device that automates the process of dispensing liquids, such as gasoline, from the pumps by locking the dispensing lever of a pump handle in an open position so that liquid will flow from the pump without the user being required to maintain pressure on the dispensing lever of the pump handle.
BACKGROUND
A fluid dispensing pump, such as a gasoline pump, operates by the user applying upward pressure to, or squeezing, the dispensing lever of the pump handle. Through this squeezing action, the dispensing lever is pushed towards the top of the pump handle. As the dispensing lever is pushed towards the top of the pump handle, the valve controlling the flow from the pump is moved from the “off” position to the “on” position and liquid flows out of the pump, through the pump handle nozzle, and into the user's vehicle. When the dispensing lever is so engaged, the dispensing lever can be said to be in the open position. In the description that follows, reference may be made to gasoline pumps dispensing gasoline. However, the disclosure should not be limited to use on gasoline pump handles as the disclosure is applicable to any pump that operates on similar principles.
Many gasoline pump handles are equipped with automated devices, such as latches, that lock the dispensing lever in the open position. Generally, these automated devices are located on the bottom portion of the gasoline pump handle and operate by applying upward force on the dispensing handle, thereby locking the dispensing handle in the open position. However, many pump handles are not equipped with these devices, or the owners have removed or disabled these devices.
When the pumps handles are not equipped with a device to lock the dispensing lever in the open position, the user is presented with the inconvenience of standing by the pump and manually maintaining the dispensing lever in the open position. Apart from the inconvenience, the user is prevented from attending to other chores normally tended to when purchasing gasoline, such as washing the windows, checking the oil level or checking air pressure in the tires. By being able to accomplish these tasks at the same time that the gas is being pumped into the vehicle, the user's time spent at the gasoline station is greatly decreased. In addition, individuals with physical disabilities effecting their strength or dexterity may be incapable of applying the needed pressure to place and/or maintain the dispensing lever in the open position, forcing the individual to use the more expensive full-service option.
Several attempts have been made to provide devices that automate the process of dispensing gasoline for use with gasoline pumps handles that lack the automated devices. These devices can be divided into two classes. The first class of devices operate by fitting between the bottom portion of the gasoline pump handle and the dispensing lever. Devices in this class operate by applying an upward force on the dispensing lever, thereby locking the dispensing lever in the open position. These include U.S. Pat. No. 4,210,181 to Clevenger, U.S. Pat. No. 4,216,807 to Diamond, U.S. Pat. No. 4,334,560 to Lockwood, and U.S. Pat. No. 4,337,917 to Tesack. These devices suffer from the drawback that they cannot be easily or quickly removed if the user is suddenly required to stop the flow of gasoline. In addition, the devices generally require a substantial amount of manual dexterity to use properly.
The second class of devices operate by simultaneously engaging the top portion of the pump handle and the dispensing lever, locking the dispensing handle in the open position. These devices mimic the natural action of the users hand when squeezing the dispensing lever. These include U.S. Pat. No. 4,287,736 to Hadgis, U.S. Pat. No. 4,690,182 to Knauss, U.S. Pat. No. 4,683,923 to Harris, U.S. Pat. No. 4,846,477 to Hanna, U.S. Pat. No. 5,118,074 to Weissman, U.S. Pat. No. 5,077,850 to Brubaker and U.S. Pat. No. 5,517,732 to Crear. Several of these references disclose devices that can be modified to receive a key ring, allowing the user to attach keys to the device, contemplating that the user will carry the device on their person, making access to the devices more convenient. However, the devices disclosed by these references are bulky and do not lend themselves to storage on the person of the user. Additionally, many of the devices, such as Hadgis (the '736 patent) for example, contain hooked appendages, serrated edged, or other structures that could snag the users clothing, or become entangled with other articles when stored in the users pocket or purse.
None of these difficulties are inherent in the present disclosure. The present disclosure provides for a clip that is capable of locking the dispensing lever of a pump in an open position, and which is capable of being folded into a compact form when not in use. None of the references cited above teach or suggest the use of a clip that can be folded into a compact form. Because the clip can be folded, it is compact enough to be stored conveniently on the person of the user, facilitating its easy access for use. Furthermore, there are no rough edges or other appendages to snag clothing and to become entangled with other articles, making access to and use of the present invention more convenient.
SUMMARY
The present disclosure comprises a generally U-shaped clip that is designed to engage the dispensing lever of a fluid dispensing pump, such as a gasoline pump, and lock the dispensing lever of the pump handle in the open position. In one embodiment, the clip comprises a shank, with a first and a second upwardly turning leg at each end thereof, and a first and a second arm pivotally attached to the first and the second legs, respectively.
The clip is constructed so that the first and second arms are pivotally attached to the first and second legs, respectively. By virtue of the pivotal attachment, the first and second arms fold inwardly onto the shank of the clip to significantly reduce the size of the clip. This compact size allows the user to keep the clip in their pocket or purse for ready access when needed. When folded, the second arm rest on the shank and the first arm rest on top of the second arm. The arms can be pivotally attached by any means that allows the arms of the clip to fold inwardly towards the shank of the clip, but a preferred means is to use rivets. The length of the first and second legs is such that when second arm is folded inwardly towards the shank, the first arm will rest on top of the second arm when the first arm is folded inwardly towards the shank.
The clip operates by simultaneously engaging the top of the pump handle with the first arm and the dispensing lever with the second arm. The space between the first and second arms is determined by the length of the shank, and is such that while the first and second arms are engaging both the top of the pump handle and the dispensing lever, the dispensing lever is locked in an open position. The length of the shank can be varied so that the clip can be used with pump handles of various dimensions.
The clip can be constructed of any material, but a preferred material is high-strength plastic. Additionally, the clip may be constructed with a rib design to further impart strength to the clip without increasing the overall thickness of the clip.
In a preferred embodiment, the clip is manufactured with a hole through the thickness of the shank. A ring or similar device can be Attached to the clip by being passed through the hole, allowing the user to attach keys or other articles to the clip. A feature of the clip so constructed is that the user can quickly remove the clip and restore the dispensing handle to the closed position by pulling on the ring or attached articles and stop the flow of fuel from the nozzle when desired.
Therefore, it is an object of the disclosure to provide a clip for automating the process of dispensing liquids, such as gasoline, by locking the dispensing lever of a pump handle a in an open position so that liquid will flow from the pump without the user being required to maintain pressure on the dispensing lever of the pump handle.
Another object of the disclosure to provide such a clip that is capable of being folded into a compact form when the clip is not in use.
It is a further object of the disclosure to provide such a clip constructed out of plastic, or other lightweight material.
It is a further object of the disclosure to provide such a clip that is capable of receiving a ring or similar device, allowing the user to attach keys or other articles to the clip.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of one embodiment of the clip in its non-folded form.
FIG. 2 is a front view of one embodiment of the clip in its non-folded form.
FIG. 3 is a front view of one embodiment of the clip in its folded form.
FIG. 4 is a perspective view showing one embodiment of the clip being applied to a standard gasoline pump handle.
FIG. 5 is a perspective view showing one embodiment of the clip in use on a standard gasoline pump handle.
DESCRIPTION
The invention can be best understood by reference to the accompanying drawings presented in FIGS. 1 through 5. FIGS. 1 and 2 show a perspective side and front view, respectively, of a one embodiment of the clip of the present disclosure. The clip 10 is of generally a U-shape and is composed of a shank 14 , a first 16 and second 17 upwardly turning leg at each end of shank 14 , a first arm 18 and second arm 20 pivotally attached to the first 16 and second 17 upwardly turning legs, respectively. In the embodiment illustrated in FIGS. 1-5, one of the legs, in this case first leg 16 , is of greater length than the other leg, in this case second leg 17 . This is to facilitate folding of the clamp into a compact form as discussed below. However, in alternate embodiments, the length of each leg can be the same or substantially the same, and still be capable of being folded into a compact form. A means for receiving a key ring 24 or similar device may also be incorporated into the clip. As illustrated best in FIGS. 1-3, the means may be a hole 22 placed along the shank 14 . The hole 22 may be through the thickness of the shank 14 itself, or it may be through a portion 29 appending from the shank 14 (as illustrated in FIGS. 1 - 3 ). The hole 22 may be placed anywhere on the shank 14 , but a preferred position is on the shank 14 adjacent to one of the legs, illustrated in this case adjacent to the second leg 17 .
The first arm 18 and the second arm 20 are pivotally attached to the first leg 16 and second leg 17 , respectively. The means for the pivotal attachment can be any one that allows the first arm 18 and second arm 20 fold inwardly toward the shank 14 (as illustrated in FIG. 3 ), such as rivets, pins, ball and joint connections, dowels or small screws (the screws either being secured by nuts or self-securing). However, a preferred method for pivotal attachment is through the use of a rivet 26 . It is preferred that both the first arm 18 and the second arm 20 fold inwardly towards the shank 14 as illustrated in FIG. 3 .
The clip 10 contains a means for maintaining the shank 14 , first leg 16 , second leg 17 , first arm 18 and second arm 20 in a generally U-shaped configuration during use of the clip 10 . The means can be through a locking mechanism, springs, or angularities created by the pivotal attachment of the first 18 and second 20 arms to the first 16 and second 17 legs. However, a preferred means is through the use of angularities created by the pivotal attachment. As can be seen in FIGS. 1-3, the first arm 18 and second arm 20 are prevented from free rotation about their attachment point (in this case rivet 26 ) by the angle created by their attachment to the first leg 16 and second leg 17 . The angle is such that the first arm 18 and second arm 20 will not rotate past a point where they are generally parallel to the first leg 16 and second leg 17 . In this manner, the first arm 18 and second arm 20 will be able to keep the dispensing lever of a pump handle in the open position. In a preferred embodiment, the clip 10 has the following dimensions. The length of the first arm 18 is approximately 32 centimeters and the length of the second arm 20 is approximately 35 centimeters. The width of the clip from the midpoint of the first leg 16 to the midpoint of the second leg 17 is approximately 55 centimeters and the width of the clip from the outer edge of the first leg 16 to the outer edge of the second leg 17 is approximately 73 centimeters. The attaching means (illustrated as portion 29 ) is placed approximately 46 centimeters from the outer edge of the first leg 16 . These dimensions are suited for a clip designed for use with a standard gasoline pump handle and may be varied to fit other types of pump handles, with the selection of such dimensions being within the skill in the art.
FIG. 3 shows a perspective view of one embodiment of the clip 10 of the present disclosure in its folded form. As is illustrated by this figure, by virtue of their pivotal attachment to the first leg 16 and second leg 17 , first arm 18 and second arm 20 can pivot inwardly towards the shank 14 . In its folded configuration, the second arm 20 lies on top of and in the same plane as the shank 14 . In its folded configuration, the first arm 18 lies on top of and in the same plane as the second arm 20 . The clip 10 may contain certain depressions and protrusions to facilitate the folding of the clip 10 . As illustrated best in FIGS. 1-3, the interior surface of shank 14 has a depression 30 to receive spine 32 on the second arm 20 . Second arm 20 also has a depression 34 to receive a spine 36 on first arm 18 . As used herein, the term spine should be interpreted encompassing any projection that is complementary to a depression described above. The placement and number of these depressions and spines is variable and alternate configurations are possible, with the configuration described in FIGS. 1-3 being illustrative only. The length of the first leg 16 and second leg 17 is selected such that when the first arm 18 pivots inwardly, it will lie against the second arm 20 when the second arm 20 is in its fully folded configuration, and the second arm 20 will lie against the shank 14 .
The clip 10 can be constructed out of any material, including but not limited to aluminum, plastic, or even reinforced paper cardboard, but the preferred material is high-strength plastic. Several methods are known in the plastics manufacturing art to produce the clip 10 , but a preferred method is injection molding. Through the use of this high-strength plastic the clip 10 can be manufactured so that it is durable, lightweight and possesses sufficient rigidity and strength to operate as intended.
As illustrated best in FIG. 1, the clip 10 may comprise a rib structure 40 to impart increased strength to the clip 10 . It is desired to manufacture the clip 10 so its components are as thin as possible, while still retaining the strength and rigidity to operate as intended. As stated above, in one embodiment, the clip 10 is manufactured from high-strength plastic. To impart extra strength to the clip 10 , it may be manufactured so that the shank 14 , the first leg 16 , second leg 17 , first arm 18 and second arm 20 incorporate the rib structure 40 . This rib structure 40 is preferably a ridge of plastic running down roughly the middle of the component parts of the clip 10 . The rib structure 40 increases the strength of the clip 10 , allowing the thickness of the component parts to be reduced, while still retaining the necessary strength and rigidity to function as intended.
FIGS. 4 and 5 show clip 10 of the present invention in use on a standard gasoline pump handle. The clip 10 engages the pump handle 100 by simultaneously engaging the top portion 102 of the pump handle 100 and the dispensing lever 104 . As illustrated in FIGS. 4 and 5, the first arm 18 engages the top portion 102 , while the second arm 20 engages the dispensing lever 104 . Through this action, the dispensing lever 104 is locked in an open position allowing gasoline to flow from the pump through pump handle nozzle 106 into the users vehicle or other storage container. The length of shank 14 is constructed so that when the first arm 18 engages the top portion 102 and second arm 20 engages the dispensing lever 104 of the pump handle 100 , the dispensing lever 104 is held in an open position (as is obvious, the orientation of the clip 10 on the pump handle 100 may be reversed). The user is able to apply the clip 10 to the pump handle 100 using one hand. Furthermore, ring 24 provides a quick and efficient method to quickly remove clip 10 in situations that require the immediate shut-off of fuel flowing into the vehicle. As discussed above, the length of the shank 14 can be varied so that the clip 10 can be used on a wide range of pump handles.
In an alternate embodiment, a magnet may be placed on either face of the shank 14 of the clip 10 . The magnet will allow the use to place and store the clip 10 on a metal surface, such as the inside of a gas cap. Alternate locations to store the clip on the car are possible, it being preferred that these alternate locations are close to the gas tank for ease of use.
The previously described embodiments of the present disclosure have many advantages. Other devices that automated the process of dispensing fuel were either too bulky to be easily carried on the person of the user, making their use inconvenient, or contained serrated teeth, sharp edges or other appendages that could cause the devices to become entangled with other articles when carried by the user or cause damage to the clothing or purse of the user when the clip is removed for use. The clip of the present disclosure overcomes these limitations. The clip of the present disclosure is capable of not only automating the process of dispensing fuel into the user's vehicle, but is also capable of being quickly and easily folded into a compact form when not in use. This compact form allows the user to store the clip on their person when not in use. The clip, in its folded form, has no teeth, sharp edges or other appendages to become entangled with other articles when carried by the user, or to damage the clothing or purse of the user when the clip is removed for use. These advantages are merely illustrative and are not intended to be a comprehensive listing of all the advantages inherent in the present invention.
Although the present invention has been described in considerable detail with reference to certain preferred and alternate embodiments thereof, other variations are possible which would be obvious to one of ordinary skill in the art. Therefore, the scope of the appended claims should not be limited to the description of the preferred and alternate embodiments contained herein.
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A clip that holds the dispensing lever of a fluid dispensing pump in an open position, thereby controlling the flow of liquid from the pump without the necessity of the user manually applying pressure to the dispensing lever. One use of the clip is on the gasoline pumps at self service gasoline pumps. The clip is of a generally U-shape and comprises a shank, two upwardly turning legs at each end of the shank and a first and second arm pivotally attached to the first and second legs, respectively. The clip is capable of alternating between a folded state and an extended state. The clip is constructed so that the first and second arms pivot inwardly towards the shanks reducing the clip to the compact form when not in use.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a ratchet-action open-end wrench.
[0003] 2. Description of the Prior Art
[0004] Conventional ratchet-action open-end wrench, as shown in U.S. Pat. No. 4,637,284, has a fixed jaw, a movable jaw which is able to slide linearly, and an elastic member. In an operation condition, user can pull the wrench back and forth. The movable jaw is able to reciprocate with respect to the fixed jaw. Thus, the movable jaw can clutch threaded member along only a predetermined direction, so that the threaded member is rotated along the predetermined direction. The threaded member would be released and would rotate with respect to the wrench when the wrench is pulled along the opposite direction. Threaded member can be detached or fastened easily.
[0005] However, the wrench mentioned above is not suitable for being used in a narrowed environment. Moving direction of the movable jaw is simply aimed away from the fixed jaw, even away from handle of the wrench. Considerable movement of the movable jaw is necessary for releasing the threaded member. Thus, the movable jaw would probably blocked by other objects, especially in narrowed environment, failing to move and to release the threaded member.
[0006] For the requirement of operation in narrowed space, wrenches are provided in several patents, such as U.S. Pat. No. 5,287,777, U.S. Pat. No. 5,582,082, and U.S. Pat. No. 7,827,887. These wrenches are suitable to be used in narrowed space, providing ratchet-action function. The wrench revealed in U.S. Pat. No. 5,287,777 is similar to the wrench revealed in U.S. Pat. No. 7,827,887. The movable jaws of the wrenches are slidable along a segmental pathway which is defined and limited by a pin, an arc-shaped hole, and several arc-shaped surfaces. Thus, the movable jaw is unable to rotate arbitrarily. The other wrench shown in U.S. Pat. No. 5,582,082 is provided with a pin and a linear extended hole, so that movable jaw of the wrench is able to slide. Further, both of movable jaw and fixed jaw of the wrench is formed with an arc-shaped surface. The arc-shaped surfaces are used for limiting sliding pathway of the movable jaw, so that the movable jaw can only slide with respect to the fixed jaw. The wrenches mentioned above are suitable for narrowed space, being welcomed in the market.
[0007] However, the wrenches are difficult to be produced. The components of the wrenches should be formed with several specific contours, especially arc-shaped surfaces, some of which are located in grooves. The arc-shaped surfaces are necessary for keeping the movable jaw in the predetermined pathway. The arc-shaped surfaces are very difficult to be machined or processed. For instance, the arc-shaped surface of the wrench described in U.S. Pat. No. 7,827,887 is located at an interior side of opening of the wrench. Machining tool, such as milling cutter, can hardly move into the opening. Thus, machining is obstructed.
[0008] For producing the wrenches, precision casting may be chosen as a main process. However, this would lead to a deterioration of quality of the wrench since precision casting is always accompanied with deficiencies about structure strength and surface precision. With lowered structure strength, the wrench would be unwelcomed in strict operation condition. With lowered surface precision, movement of movable jaw of the wrench would be obstructed by dust. On the other hand, precision casting would bring the manufacturing cost high. Market competitiveness of the wrenches would be probably destroyed by the disadvantages mentioned above.
[0009] The present invention is, therefore, arisen to obviate or at least mitigate the above mentioned disadvantages.
SUMMARY OF THE INVENTION
[0010] The main object of the present invention is to provide another ratchet-action open-end wrench which can be machined easily.
[0011] To achieve the above and other objects, a ratchet-action open-end wrench of the present invention includes a main body, a working portion, a slidable mechanism, and an elastic member.
[0012] Said main body has a handle, at least a head portion, and a fixed jaw. The head portion is connected to one end of the handle. The fixed jaw extends and protrudes out from the head portion.
[0013] Said working portion has at least a connection arm and a movable jaw. The connection arm abuts against the head portion. An opening is defined by the movable jaw and the fixed jaw.
[0014] Said slidable mechanism comprises a sliding groove and a sliding portion. The sliding groove is formed on one of the head portion and the connection arm. The sliding portion is firmly disposed on the other one of the head portion and the connection arm. The sliding portion is slidably disposed on the sliding groove, so that the working portion is able to slide along the sliding groove with respect to the main body. The working portion is slidable between a first position and a second position. A width of the opening is minified when the working portion slides toward the first position. The sliding groove is arc-shaped. An arc center of the sliding groove is located out of the head portion. The main body is located between the arc center and the movable jaw. The sliding portion has a non-circular cross section, so that the sliding portion is unable to rotate in the sliding groove arbitrarily.
[0015] Said elastic member abuts against the main body and the working portion, so that the working portion has a tendency to slide toward the first position.
[0016] The present invention will become more obvious from the following description when taken in connection with the accompanying drawings, which show, for purpose of illustrations only, the preferred embodiment(s) in accordance with the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a stereogram showing a first embodiment of the present invention;
[0018] FIG. 2 is a breakdown drawing showing a first embodiment of the present invention;
[0019] FIG. 3 is a side view showing a first embodiment of the present invention;
[0020] FIG. 4 is a front view showing a first embodiment of the present invention;
[0021] FIG. 5 is a schematic drawing showing using condition of a first embodiment of the present invention;
[0022] FIG. 6 is a breakdown drawing showing a second embodiment of the present invention;
[0023] FIG. 7 is a side view showing a second embodiment of the present invention;
[0024] FIG. 8 is a front view showing a second embodiment of the present invention;
[0025] FIG. 9 is a schematic drawing showing using condition of a second embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] Please refer to FIG. 1 to FIG. 4 for a first embodiment of the present invention. The ratchet-action open-end wrench of the present embodiment has an opening which is provided for clamping threaded member, such as screw, nut, or other similar component. User can pull the wrench back and forth. The wrench would drive the threaded member to rotate along a single direction so as to detach or fasten the threaded member. In the present embodiment, the wrench includes a main body 1 , a working portion 2 , a slidable mechanism 3 , and an elastic member 4 .
[0027] The main body 1 has a handle 11 , a head portion 12 , and a fixed jaw 13 . The head portion 12 is connected to one end of the handle 11 . The fixed jaw 13 extends and protrudes out from the head portion. Thus, the head portion 12 connects the handle 11 to the fixed jaw 13 . For purposes of handling or storing, handling bar or hanging hole may be disposed on one end of the handle 11 , where is away from the head portion 12 . The fixed jaw 13 may be further formed with a recess 131 . The head portion 12 is formed with a receiving groove 121 . Thickness of the fixed jaw 13 may be greater than thickness of the head portion 12 . Thus, the main body 1 can be formed with two step surfaces on two sides of the main body 1 , as shown in FIG. 2 and FIG. 3 . The step surfaces are located between the fixed jaw 13 and the head portion 12 . In some embodiments, it is also possible that the main body is formed with single step surface on one side of the main body.
[0028] The working portion 2 has two connection arms 21 and a movable jaw 22 , as shown in FIG. 2 and FIG. 3 . The connection arms 21 abut against the head portion 12 . The head portion 12 is located between the two connection arms 21 . The movable jaw 22 is connected to the connection arms 21 . The movable jaw 22 and the fixed jaw 13 are facing each other so as to define the opening therebetween. The movable jaw 22 may formed with the other recess 221 . The recess 221 of the movable jaw and the recess 131 of the fixed jaw are facing each other. Thus, the recesses 221 , 131 are able to clamp corners of a polygonal column of a threaded member 5 , as shown in FIG. 4 . Each of the connection arms 21 is formed with a fixation hole 211 .
[0029] In the present embodiment, the working portion 2 has two connection arms 21 so as to clip the head portion 12 therein. Dust or debris would be blocked out by the connection arms 21 so as to keep motion of the head portion 12 and the connection arms 21 smooth. In some embodiments, the working portion may have only one connection arm. The main body has two head portion correspondingly. Thus, connection arm can be positioned between the two head portion, obtaining similar dust-proof effect.
[0030] The slidable mechanism 3 includes a sliding groove 31 and a sliding portion. The sliding groove 31 is formed on the head portion 12 . The sliding portion is firmly disposed on the connection arms 21 . More particularly, the sliding portion includes a sliding member 321 and a fixation pin 322 . The sliding member 321 is slidably received in the sliding groove 31 . The sliding member 321 is formed with an aperture 323 . The fixation pin 322 penetrates through the aperture 323 and is received in fixation holes 211 of the connection arms 21 . It should be noted that the fixation pin 322 should be unable to rotate with respect to the sliding member 321 and the connection arms 21 . The fixation pin 322 , the aperture 323 , and the fixation holes 211 may be formed with non-circular cross section if necessary. Thus, the sliding portion is slidably disposed on the sliding groove 31 . The working portion 2 is able to slide along the sliding groove 31 with respect to the main body 1 . The sliding member 321 is formed in arc-shaped, so that the sliding portion has a non-circular cross section. The sliding portion is unable to rotate in the sliding groove 31 arbitrarily. The sliding groove 31 extends and is formed arc-shaped. Arc center 311 of the sliding groove 31 is located out of the head portion 12 , as shown in FIG. 4 . Further, the movable jaw 22 is located at right side of the main body 1 , and the arc center 311 is located at left side of the main body 1 . In other words, the movable jaw 22 and the arc center 311 are located at opposite sides divided by the main body 1 . Thus, width of the opening would be changed when the working portion 2 and the movable jaw 22 move along the sliding groove together with the sliding portion.
[0031] It should be noted that the sliding portion is still able to rotate in a universal aspect since the sliding groove 31 is arc-shaped. However, the rotation caused by sliding along the sliding groove 31 is ignored here. Rotation of the sliding portion discussed above is rotation of the sliding portion with respect to the sliding groove. Unable to rotate of the sliding portion with respect the sliding groove should not be regarded as that the sliding portion is unable to slide and rotate along curved sliding groove.
[0032] The elastic member 4 abuts against and locates between the main body 1 and the working portion 2 . More particularly, the elastic member 4 is received in the receiving groove 121 of the head portion, and abuts against the working portion 2 .
[0033] Accordingly, please refer to FIG. 4 and FIG. 5 , the sliding portion is able to slide along the sliding groove 31 . The sliding portion is firmly disposed on the connection arms 21 of the working portion. Thus, the working portion 2 can slide along the arc-shaped sliding groove 31 together with the sliding portion. The working portion 2 can slide between a first position and a second position.
[0034] Refer to FIG. 4 , the opening defines a width direction. When the working portion is located at the first position, the opening is used for clamping a threaded member 5 therein. Two opposite ends of the working portion 2 , the fixed jaw 13 , and the head portion 12 has an initial width Do therebetween.
[0035] Refer to FIG. 5 , the working portion 2 is able to slide along the sliding groove 31 toward the second position. The threaded member 5 can escape from the fixed jaw 13 and the movable jaw 22 so as to rotate in the opening arbitrarily. Two opposite ends of the working portion 2 , the fixed jaw 13 , and the head portion 12 has a maximum width Dm therebetween. Preferably, subtraction of the maximum width Dm and the initial width Do is smaller than tan percent of the initial width Do. Thus, in an operation condition, the threaded member 5 can escape from the opening without overly movement of the working portion 2 . When user pulls the wrench in an opposite direction, the opening can clamp the threaded member 5 immediately so as to fasten or detach the threaded member 5 easily. Further, the wrench is suitable for operating in narrowed space since motion of the working portion 2 is minified by employing the arc-shaped sliding groove.
[0036] Please refer to FIG. 4 . The elastic member 4 abuts against the working portion 2 , so that the working portion 2 has a tendency to slide toward the first position. The working portion 2 would slide to the first position when the working portion 2 is released from external force. The connection arms 21 would abut against the step surfaces. Width of two opposite ends of the working portion 2 , the fixed jaw 13 , and the head portion 12 is then return to the initial width Do.
[0037] In the present embodiment, the sliding groove 31 is formed on the head portion 12 . The sliding portion is firmly disposed on the connection arms 21 . In other possible embodiments of the present invention, position of the sliding groove 31 and position of the sliding portion may be interchanged. The sliding groove may be formed on the connection arms, and the sliding portion may be firmly disposed on the head portion. In addition, in the embodiment, the fixation holes of the connection arms should be removed, and the head portion should be formed with the corresponding fixation hole. Thus, the sliding portion can be assembled on or attached to the head portion by fabrication or other manners.
[0038] Please refer to FIG. 6 to FIG. 8 . In a second embodiment of the present invention, structure of the wrench is approximately similar to the wrench of the first embodiment. The sliding portion is replaced with two pins 324 . Each of the connection arms 21 is formed with two fixation holes 211 . Each of the pins 324 penetrates through the sliding groove 31 and is received in two corresponding fixation holes 211 which are located on the connection arms respectively. The pins 324 are able to slide along the sliding groove 31 . Thus, the working portion 2 is still able to slide along the arc-shaped sliding groove 31 between the first position and the second position, as shown in FIG. 8 and FIG. 9 . In the present embodiment, the pin 324 may has circular cross sections respectively; even so, the cross section of the sliding portion is still non-circular since each of the pins 324 is regarded as only a part of the sliding portion. The working portion 2 is still unable to slide in the sliding groove 31 arbitrarily. Thus, in the present embodiment, whether each of the pins 324 is able to rotate is not limited. As such, the structure of the wrench is further simplified in the second embodiment.
[0039] In view of foregoing, the wrenches of the present embodiments have simplified structures. It is noted that arc-shaped abutting surface is dismissed, and only arc-shaped groove which can be manufactured easily is retained. The components are suitable for machining and processing. Producing processes, such as machining, folding, casting, and pressing, can be chosen as the main producing process. As such, cost, precision, and structure strength can be managed well.
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A ratchet-action open-end wrench of the present invention has a simplified structure. Arc-shaped abutting surface and corresponding groove is dismissed from the present wrench. Thus, components of the wrench can be manufactured and fabricated easily, and specified producing process can be chosen for obtaining strengthened structure. In addition, cost of the wrench is abated, precision of the wrench is arisen, and lift-time of the wrench is prolonged.
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to European Patent Office application No. 12179634.6 EP filed Aug. 8, 2012, the entire content of which is hereby incorporated herein by reference.
FIELD OF INVENTION
The invention relates to a method of modifying the rate of temperature change and preferably of lowering the temperature of an epoxy resin composition in a resin container during a resin casting process, especially a resin infusion or a resin transfer moulding (RTM) process, a resin container arrangement for the use in such a resin transfer moulding process, a composite product comprising an epoxy resin composition, and a passivation agent in an epoxy resin casting process.
BACKGROUND OF INVENTION
WO 2009103736 describes a vacuum infusion or vacuum assisted resin transfer moulding process (VARTM) process used for moulding fibre composite mouldings. In such a process uniformly distributed fibres are layered in a first mould part, the fibres being rovings, i.e. bundles of fibre bands, bands of rovings or mats, which are either felt mats made of individual fibres or woven mats made of fibre rovings. A second mould part, which is often made of a resilient vacuum bag, is subsequently placed on top of the fibre material. By generating a vacuum in the mould cavity between the inner side of the first mould part and the vacuum bag, the liquid resin can is drawn in and fill the mould cavity with the fibre material contained in the mould. So-called distribution layers or distribution tubes are used between the vacuum bag and the fibre material in order to obtain as sound and efficient distribution of resin as possible. In most cases the resin applied is polyester, vinyl ester or epoxy, and the fibre reinforcement is most often based on glass fibres or carbon fibres, but may also be plastic fibres, plant fibres or metal fibres.
The liquid resin is provided in a resin container, also called mixing bucket, filled with a resin/curing agent composition prepared in a mixing unit, adapted for mixing the resin monomer components and the curing agent in the respective amounts. As the curing reaction has already been started in the mixing unit, the exothermic polymerisation continuously raises the temperature in the resin container.
During the process of filling the mould, a vacuum, i.e. an under-pressure or negative pressure, is generated in the mould cavity, whereby liquid resin is drawn from the resin container or mixing bucket into the mould cavity via the inlet channels in order to fill said mould cavity. From the inlet channels the resin disperses in all directions in the mould cavity due to the negative pressure as a flow front moves towards the vacuum openings for generating vacuum inside the mould.
In the resin container such as the mixing buckets or the overflow container in such casting processes, e.g. blade casting methods for wind rotor blades, no solution exists for preventing the ignition of fire during the curing process which is caused by the exothermic reaction between the epoxy resin monomers and the curing agent. Conventionally, the mixing bucket is moved outdoors if signs of fire ignition or smoke development are observed in the mixing bucket to avoid any damages of the casting apparatus or the casting facilities and to protect the working environment of the staff around the blade mould.
U.S. Pat. No. 5,721,323 describes a prepreg containing a resin composition consisting of a polyepoxide, a curing agent, a catalyst for the reaction of the polyepoxide with the curing agent and a Lewis acid cure inhibitor for inhibiting the catalyst by means of forming a catalyst Lewis acid inhibitor complex. Cured and partially cured epoxy resins are used in coatings or laminates, wherein the inhibitor is used for inhibiting the curing reaction of polyepoxide by forming a stable complex between the curing agent and the Lewis acid in the prepreg and releasing the catalyst if a predetermined temperature level has been reached during the curing process. This inhibiting method is used for storing the polyepoxide resin composition in prepregs which are then used in moulding processes of composite parts. However, these prepregs are not used in casting process such as rein transfer moulding processes.
SUMMARY OF INVENTION
It is an object of the present invention to improve the safety of casting processes, in particular to prevent the ignition of fire in a mixing bucket during a casting process like a resin infusion or resin transfer moulding process, and to provide composite products in a safe and economic manner.
The object of the invention is achieved by a method of modifying the rate of temperature change of an epoxy resin composition in a resin container during a resin casting process, a resin container arrangement for the use in such a resin transfer moulding process, a composite product comprising an epoxy resin composition, and the use of an organic acid in an epoxy resin casting process according to the claims.
The method of modifying or changing the rate of temperature change of an epoxy resin composition in a resin container, that means in the resin filled system, during a resin casting process according to a first aspect of the invention comprises the step of adding a passivation agent for the curing agent to the epoxy resin composition. The resin composition comprises at least one epoxy monomer component and a curing agent. A passivation agent as understood in the following description of the invention inhibits the polymerization reaction and is advantageously a curing agent reactive component, which causes a modification of the rate of temperature change and especially a lowering of the reaction temperature during the reaction with the curing agent. Especially, the passivation agent, as used according to the invention, does not cause a passivation of the surface of any reaction component, but changes the total reaction temperature or enthalpy of all reactions taking place in the resin mixture. More particularly, the passivation reaction is not an inhibition of the polymerization reaction by means of lowering the reaction rate, but reduces the amount of free curing agent by the passivation agent, while generating less heat in this reaction as will be generated by the polymerisation reaction. Hence, the reaction enthalpy can be reduced by adding a passivation agent into the curing reaction. In addition or alternatively, the time of generating reaction heat can be prolonged by the addition of the passivation agent.
The ignition of a fire in a mixing bucket in which the polymerisation reaction takes place can advantageously prevented by modifying the rate of temperature change or inhibiting the increase of the temperature of the reactions between the catalyst and the epoxy monomers and the catalyst and the passivation agent which are generally exothermic reactions.
Thus, the modification of the rate of temperature change of the exothermic polymerisation reaction by means of the addition of a passivation agent into the resin composition usually allows a safer processing. In particular, the step of potentially moving the mixing buckets out of the factory site in case first signs of fire ignition or smoke are observed in the mixing bucket can be omitted. Hence, a safer and more reliable casting process has been developed.
A resin container arrangement according to a second aspect of the invention is adapted for the use in a resin transfer moulding process. The arrangement can be an integrally provided system or a system with separated means which can be combined to the total arrangement or can be a part of a casting apparatus. The arrangement comprises at least a mixing bucket and a passivation agent container, which are preferably fluently connected with each other in order to can add the passivation agent into the mixing bucket. The resin container arrangement is used for mixing an epoxy resin composition comprising at least one epoxy resin monomer component and a curing agent with a passivation agent in the mixing bucket in order to achieve the effects described in the first aspect of the invention.
According to a third aspect of the invention, a composite product, preferably being prepared according to the method of the first aspect, comprises an epoxy resin composition or is based on an epoxy resin composition, generally containing 50 wt-% of epoxy resin or even more. The composite product comprises a passivation agent or a reaction product of a passivation agent and a curing agent. The product differs from conventional products in an amount of passivation agent or its reaction product obtained by the passivation reaction. The amounts can be 1 to 20 wt-%, preferably 1 to 10 wt-%, more preferably lower than 5 wt-%. Depending on the curing rate and the temperature within the mixing container, the free organic acid or any reaction product with the curing agent may be present in the finished product. Thus, it is easy to determine whether or not the product has been obtained by using an organic acid during the manufacturing method of the composite products. The products may have fewer defects due to high temperatures inside the mould during the casting process and, thus, are advantageous over the conventional products, especially are more reliable.
The epoxy resin composition used in such a method, resin container arrangement, or product comprises, according to another aspect of the invention, at least one epoxy resin monomer component, a curing agent and a passivation agent. This epoxy resin composition can advantageously used in a resin infusion or RTM process, for example for manufacturing blades for wind rotors. The epoxy resin composition preferably modifies the rate of temperature change or even lowers the temperature in a resin container used for mixing a resin monomer component with a curing agent. The passivation agent inhibits the increase of the temperature or reduces the total reaction temperature and, thus, prevents the resin mixture from ignition of a fire.
According to a further aspect of the invention, the application refers to the use of an organic acid in an epoxy resin casting process, preferably a resin infusion or resin transfer moulding process (RTM). The organic acid is added to a resin container, e.g. a resin filled system part such as the mixing bucket or resin overflow container, in order to keep the temperature level at a predefined maximum temperature by means of lowering the rate of the temperature increase by means of passivation an amount of the curing agent with the passivation agent. Thereby, the passivation reaction preferably elongates the time for raising the temperature in the resin container. Alternatively, the passivation reaction substantially keeps constant or lowers the temperature of the resin mixture contained therein. This can advantageously initiated by means of a reaction between the curing agent and the passivation agent as defined with regard to the first aspect of the invention. Keeping the temperature “substantially constant” means the temperature rising rate is very small or preferably nearly zero.
Particularly advantageous embodiments and features of the invention for improving, for example, the safety of such casting processes or making the processes more cost effective, are given by the dependent claims, as revealed in the following description. Further embodiments may be derived by combining the features of the various embodiments described in the following, and features of the various aspects and/or claim categories can be combined in any appropriate manner.
In a preferred embodiment of the method according to the invention, the curing agent comprises an amine-based curing agent because those curing agents are stable and cheap. Preferred examples are primary (R-NH 2 ) or secondary (R-NH-R′) amines. Amines generally have reactive sites for reacting with the epoxy groups of the epoxy resin monomers in a step (growth) polymerization reaction by generating epoxy-amine reaction products which can be combined to each other forming oligomers or polymers. Additionally, chain reactions or side reactions like forming side chains can take place. Exemplified amine-based curing agents can be aliphatic, cycloaliphatic or aromatic amines.
The passivation agent used in a preferred embodiment according to the invention may comprise an organic acid which can more preferably form a salt with the curing agent. More preferably, the organic acid is a hydrophilic organic acid comprising more than one hydrophilic group. Advantageously, divalent or trivalent organic acids, that means organic acids with at least two carboxyl groups such as citric acid or malic acid (e.g. two, three, or more carboxyl groups) can be used. The divalent or trivalent organic acids are preferred because breaking the hydrogen bonds or interactions between two carboxyl groups is an endothermic process which reduces the total reaction temperature (the free enthalpy) of the passivation agent modified curing process. After dissolution of the organic acid in resin mixture, the acid undergoes an exothermic reaction with the amine groups in the curing agent. The organic acid is chosen in such a manner that the enthalpy of the dissolution and the enthalpy of the amine reaction are of similar size. More preferably, the enthalpy of the dissolution exceeds that of the reaction between the amine and the organic acid. By reacting with the organic acid, the amine groups become unavailable for the exothermic reaction with the epoxy groups. Owing to the lower availability of amine groups, the temperature increase during the curing process of the epoxy is suppressed. Thereby, the rate of the rise of the temperature in the resin container can be slowed down. That means the rate of the temperature change, or the temperature generated in the resin container over the curing time can be lowered in the mixing container by passivation of a part of the curing agent.
The curing reaction, i.e. the polymerization reaction and especially the rate of the polymerization reaction, is not significantly affected. The amount of the curing agent is reduced and, thus, the addition of the passivation agent mainly reduces the curing extent which can for example be measured by determining the glass transition temperature of the cured resin mixture.
Alternatively, the passivation of the curing agent by the passivation agent may also be reversible. Then, the curing reaction is temporarily inhibited and the resin can be cured in its full extent after the temporary passivation has been removed This can for example be done if the formed salt is unstable at larger temperatures, i.e., the salt dissolves after the reaction heat of the polymerization reaction generated sufficient heat to liberate the amine groups. Furthermore, it is preferred that the acid evaporates after liberation from the salt during the curing reaction or is embedded in the cured epoxy. An incorporation or the acid into the cured epoxy can lower the strength of the cured epoxy resin.
A further preferred embodiment of the method according to the invention uses an organic acid comprising one or more hydrophilic substituents at its backbone. Preferred hydrophilic groups are additional carboxylic groups or hydroxyl groups. If more hydrophilic groups are present the enthalpy of dissolution of the passivation agent in the resin mixture is more positive and, thus, the increase in temperature of the total reaction is smaller or the temperature is even lowered to some extent in the resin container during the curing reaction.
The epoxy resin composition used in a further embodiment of the method according to the invention comprises the epoxy resin monomer component in an amount of 100 parts per weight and a curing agent in an amount of about 10 to 40 parts per weight, preferably more than 20 and less than 30 parts per weight, more preferably between 25 and 28 parts per weight. Advantageously, the passivation agent is contained in this composition in an amount sufficient for at least partly reacting with the curing agent and sufficient to lower the temperature of the resin composition, more preferably in a molar amount of about 2 to 30 parts per mole, more preferably about 5 to 20 parts per mole and in particular about 10 parts per mole of curing agent, for example of the molar amount of reactive amine groups.
According to a preferred embodiment of the method according to the invention, the passivation agent is added to the resin container in a step of curing a resin composition of a resin infusion or resin transfer moulding (RTM) process. Preferably the resin composition comprises excess resin not used for casting a product which is for example kept in the resin system such as the resin mixing bucket or the resin overflow container but also in the respective connections between the respective system parts such as lines. Preferred resin containers into which the passivation agent can be added, are the mixing bucket or overflow container in an RTM process, especially in a VARTM process.
It is preferred that the method according to a preferred embodiment comprises the step of adding the passivation agent in the form of a solution into the resin container. The solution can be prepared directly before the addition. Alternatively, the passivation agent can be stored in the form of a solution. Especially if the passivation agent is solid at room temperature, it is preferred to dissolve it into a suitable solvent, preferably a solvent which is already used in the resin composition or the reaction mixture. Of course, if the passivation agent is in solid or liquid (pure or dissolved in a solvent) form at room temperature, the direct addition in the respective form is likewise possible. After the addition of the solid passivation agents or the passivation agents in liquid or dissolved form, the resin mixture preferably is stirred by a stirrer in the resin container to dissolve the passivation agent in the resin mixture.
The method is preferably used for casting processes such as RTM processes in the field of manufacturing blades, for example wind rotor blades. However, it can be used in the field of automobile production or a similar field of engineering, in which high amounts, that means up to several kilograms, for example 1 to 10.000 kg, preferably, 10 to 5.000 kg, of mixed resin compositions are prepared in resin containers such as mixing buckets. Especially in these fields it is demanded to lower the temperature or at least the rate of temperature rise of the resin mixtures to be cured in the resin containers to improve the working environment of the workers in relation to safety and in order to reduce the risk of fire inside the production sites at the factories.
The use of an organic acid in an epoxy resin casting process as a passivation agent for modifying the rate of temperature change in a resin container containing an epoxy resin composition comprising at least one epoxy monomer component and a curing agent is therefore a relative economic solution and can easily be implemented in or added to conventional processes. More particularly, the reaction heat or the energy release during the polymerisation reaction is lowered, at least to some extent, or is generated over a larger reaction time. Therefore, the resin container according to the second aspect or the use of an organic acid according to the third aspect of the invention in a casting process such as a RTM process has the same advantages as described with regard to the method according to the invention. Thereby, the temperature of the resin contained in the resin container arrangement can be manually or automatically controlled to a temperature below the ignition point, preferably below about 250° C., and more preferably below about 190° C. In case of resin amounts below 2 kg, for example in amounts of between 0.2 kg to 1.5 kg, preferred upper temperature limits are about 160° C., more preferably about 150° C., 140° C., 130° C., 120° C., 110° C. or lower.
It is preferred that the resin container is a resin mixing bucket or a resin overflow container. According to a preferred embodiment, the organic acid can, thus, be used for preventing ignition of fire in a mixing bucket or resin overflow container of a resin infusion or a resin transfer moulding process. Such containers can contain about 1 to 50 l of mixed epoxy resin. The larger the epoxy resin amount contained therein the larger is the risk of ignition.
According to a preferred embodiment of the composite product according to the invention, the passivation agent or the reaction product is contained in the form of an organic acid, an ammonium carboxylate salt of an organic acid and an amine-based curing agent, an amide product between an organic acid and an amine-based curing agent or a mixture of them. Depending on the temperature during the casting process, the end product may contain either the free organic acid to some extent or a reaction product of the free acid and the curing agent, especially an amine-based curing agent. In this case, the first step of the passivation reaction can be the formation of an amine salt between the organic acid and the amine-based curing agent. At a temperature of 100° C. or higher, the ammonium carboxylate salt may be transformed into an amide consisting of the residues of the original acid and amine. Thus, depending on the temperature within the resin mixture, the free organic acid, the ammonium carboxylate salt or the amide may be contained alone or in a mixture of two or three of these components.
The composite product prepared by the method of the present invention or prepared by using an organic acid during the casting process can be a wing or blade, in particular for wind rotors, or a car part. As fewer defects are present within the composite product, those products are advantageous over the conventionally prepared products.
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawing. It is to be understood, however, that the drawing is designed solely for the purpose of illustration and not as a definition of the limits of the invention.
FIG. 1 shows a schematic cross-sectional view of an RTM apparatus comprising a passivation agent container,
FIG. 2 shows a temperature vs. time plot of the experimental results obtained in Examples 1 and 2,
FIG. 3 shows a temperature vs. time plot of the experimental results obtained in Examples 3 and 4.
DETAILED DESCRIPTION OF INVENTION
The FIG. 1 shows an RTM apparatus with a pure resin container A, a pure hardener or curing agent container B, a mixing unit C, a mixing bucket D, a blade mould E and an overflow container F for excess resin. Moreover, a passivation agent container G and a passivation agent inlet H are provided and connected with the mixing bucket D.
The RTM process is generally done by mixing the pure resin (an epoxy resin) and the pure hardener (an amine) in the mixing unit C and pouring the resin/hardener mixture into the mixing bucket D. The resin/hardener mixture is then used for casting the blade in the blade mould E by means of vacuum assisted resin transfer moulding. After the moulding of the blade in the blade mould, the excess resin is collected in the resin overflow container F and disposed after the resin mixture is hardened. Of course other casting processes can be used as well and also fall within the scope of the present invention.
In the mixing bucket D, the temperature raises because of the exothermic polymerization reaction of the epoxide monomers with the amine curing agent. In order to keep the temperature in the mixing bucket D within a predetermined temperature range, the temperature is controlled and, if necessary, an organic acid is added from the passivation agent container G via the passivation agent inlet H. The addition of the passivation agent can be controlled by means of a manual or automatic control means (not shown) which can receive temperature measuring signals from the temperature sensor inside the mixing bucket D. Thereby, the temperature can be controlled within a level in order to prevent fire ignition inside the mixing bucket D during or after the casting process, preferably to keep the temperature below 250° C.
FIG. 2 shows a temperature vs. time plot of the experimental results obtained with the organic acids ethanoic acid and octanoic acid in examples 1 and 2 compared to a reference sample. The monovalent acids both show a faster increase of the temperature than the reference sample. Moreover, the maximum temperature in the resin container is higher or similar to that of the reference sample.
FIG. 2 shows a temperature vs. time plot of the experimental results obtained with malic acid and citric acid in examples 3 and 4 compared to a reference sample. The samples containing organic acids having more than one carboxylic acid group, such as two in malic acid and three in citric acid, respectively, show a significantly reduced maximum temperature of about 90 to 110° C., and a slow temperature increase than the reference sample. Details will be explained in the following description of the examples.
EXAMPLES 1 to 4
General Experimental Procedure:
The experiments were carried out with the industrially available epoxy system from Momentive, RIM035/RIMH038. The RIM035 resin is based on at least 90 wt-% diglycidylether of bisphenol A (DGEBA) and less than 10 wt-% of C12 and C14 monooxiranes. The RIMH038 curing agent contains 50-70 wt-% polyoxypropylenediamine. The resin and the curing agent were prior to experiments preheated to 25° C. 587.3 g of RIM035 resin was mixed with 162.7 g RIMH038 curing agent (stoichiometric ratio). The curing agent and the resin were manually mixed with a wooden spatula for 4 minutes in a mixing bucket. After mixing the curing agent and the resin, the organic acid was added to the mixture in a molar ratio of 1/16 with respect to the curing agent content. The added organic acids had room temperature. After adding the acid, the mixture was stirred again. A J-type temperature sensor was placed in the centre of the mixing bucket containing the resin, curing agent and organic acid and the mixing bucket was placed in a Friocell heating chamber (MMM Medcenter Einrichtungen, Germany) operating at 25° C. The temperature in the mixture was measured every minute throughout the curing process.
The following organic acids have been used in the Examples 1 to 4 (all acids have been obtained from Sigma-Aldrich):
EXAMPLE 1
acetic acid (purity ≧99% LOT SHBB1567V), also called ethanoic acid
EXAMPLE 2
octanoic acid (purity ≧98% LOT STBC3482V)
EXAMPLE 3
DL-malic acid (purity ≧98% LOT SLBB6897V)
EXAMPLE 4
citric acid (99% purity, LOT 091M0211V)
The reference sample shown in the FIGS. 2 and 3 is the same resin mixture without the use of any passivation agent.
In FIG. 2 , the graphs represent the temperature measured in the mixing bucket every minute for the two organic acids ethanoic acid and octanoic acid and the reference sample. As the two organic acids are liquid at room temperature, they were added into the mixing bucket in liquid form. From FIG. 2 it can be gathered that the resin mixture containing ethanoic acid shows a strong increase of the temperature after about 50 minutes while the maximum temperature was about 180° C. (at about 70 to 130 minutes). The corresponding octanoic acid sample shows a significant temperature increase at about 100 minutes after the addition of the organic acid, while the maximum temperature was about 220° C.
FIG. 3 shows the respective graphs for the resin samples containing malic acid and citric acid, respectively, compared to the graph of the reference sample. The two organic acids are solid at room temperature and, thus, were added in the solid form. The resin mixture cured under heat generation by the exothermic polymerisation reaction. The maximum temperature was about 90° C. and about 110° C. for malic acid and citric acid, respectively. The maximum temperature in the mixing bucket was significantly lower in the samples with the organic acids compared to the temperature measured in the reference sample. The maximum temperature peak was measured after about 350 and 400 minutes, respectively. Therefore, the Examples 3 and 4 show that the hydrophilic organic acids having two or three carboxylic groups slow down the increase in temperature of the resin mixture during the polymerization reaction because of passivation of parts of the curing agent by the organic acid.
EXAMPLE 5
Temperature Increase
To clarify the different role of hydrophobic acids (ethanoic and octanoic acid) and hydrophilic acids (citric and malic acid), the temperature immediately after mixing was measured. The experimental setup was similar to the one described in the Examples 1 to 4 and the molar ratio of acid was 1/16 with respect to the curing agent. The temperature increase was determined as the difference between the highest obtained temperature within the first 5 minutes after the addition of the organic acid and the temperature prior to the addition of the organic acid.
These were the results:
Citric acid 0.3° C. DL-malic acid 0.4° C. Ethanoic acid 6.2° C. Octanoic acid 7.6° C.
In the light of the above results, it has been shown that organic acids capable of lowering the peak temperature during curing display a temperature increase below 1° C. in the first 5 minutes after the addition of the organic acid. That means, organic acids capable of limiting the temperature increase in the first minutes to a maximum change of about 1° C., such as the solid and/or hydrophilic organic acids having more than one carboxylic groups are preferred in the use as passivation agent. The reason may be the endothermic breakage of the hydrogen bonds in the hydrophilic organic acid, for example between the two or more carboxylic groups. Otherwise the dissolution enthalpy necessary for dissolving the solid organic acids in the resin mixture may be responsible for the advantageous results of the malic and citric acid.
Although the present invention has been disclosed in the form of preferred embodiments and variations thereon, it will be understood that numerous additional modifications and variations could be made thereto without departing from the scope of the invention. While the invention has been described with reference to RTM processes for manufacturing wind turbine blades, other resin composite materials such as wings or rotors for airplanes, helicopters, coolers, or car parts as well as parts in the automotive industry or similar devices may also be prepared with the method of the invention. An organic acid as passivation agents can generally be used in the field of casting processes or resin transfer moulding processes, e.g. in vacuum assisted resin transfer moulded processes etc. For example, the organic acid can be used for automatically controlling the temperature in resin containers used in casting processes. For the sake of clarity, it is to be understood that the use of “a” or “an” throughout this application does not exclude a plurality, and “comprising” does not exclude other steps or elements. A “container”, “unit”, “means” or “device” can comprise a number of separate containers, units, means or devices, unless otherwise stated.
|
A method for modifying a rate of temperature change of an epoxy resin composition in a resin container during a resin casting process is proposed. The resin composition has at least one epoxy monomer component and a curing agent. A passivation agent for the curing agent is added to the epoxy resin composition. A resin container arrangement for use in such a resin transfer moulding process, a composite product having an epoxy resin composition, and a use of an organic acid in an epoxy resin casting process as a passivation agent for modifying the rate of temperature change in a resin container containing an epoxy resin composition are proposed.
| 2 |
This is a continuation of application Ser. No. 07/956,500, filed as PCT/GB91/01182, July 17, 1991, which was abandoned upon the filing hereof.
BACKGROUND OF THE INVENTION
This invention relates to carotenoid pigments extractable from natural sources.
There is a need for a cost-effective natural source of astaxanthin, which is the carotenoid pigment that contributes the characteristic pink or red colour to the flesh of wild salmon. Salmonid fish are extensively farmed today, and there is a commercial need to produce such fish possessing a nature-identical flesh colour.
Astaxanthin occurs in various marine animals, such as crustacea, but its extraction from such sources is uneconomic. It is also possible to synthesise astaxanthin, but this is expensive, and moreover the use of such synthetic pigment does not convey the connotation of `natural` that many consumers regard as desirable.
Astaxanthin occurs in certain plants, especially certain species belonging to the genus Adonis. One such species is Adonis aestivalis, where it occurs predominantly in the petals of the bright red flowers. However, the reported wild strains of Adonis aestivalis possess only flower heads with very few petals, and the proportion of astaxanthin pigment relative to the total mass of the plant is too small for it to be cultivated and extracted on any sensible commercial scale.
SUMMARY OF THE INVENTION
By the invention we have discovered a novel true-breeding strain of Adonis aestivalis having substantially heavier flower heads, and in particular having a substantially greater number of petals. The proportion of astaxanthin pigment in the plant is sufficiently high to make cultivation of the plant for the purposes of extracting the pigment commercially attractive.
The invention provides plants of the genus Adonis having petals containing astaxanthin, the average number of petals per flower head being at least 10, more particularly at least 16.
The invention also provides plants of the genus Adonis having petals containing astaxanthin, wherein the amount of astaxanthin per flower head is at least 100 μg, more particularly at least 150 μg, and yet more particularly at least 200 μg.
The invention includes the cultivation of such plants for the purpose of obtaining astaxanthin, the extraction of astaxanthin from such plants, and the astaxanthin so obtained.
Extraction of the astaxanthin is preferably conducted using an organic solvent, and more preferably using a mixed solvent comprising a water-miscible organic solvent (such as ethanol) and a non-water-missible organic solvent (such as hexane).
Preferably, the harvested plant material is initially extracted with water or aqueous media to remove water soluble compounds such as glycosides.
The invention particularly provides a process for obtaining astaxanthin, wherein plants of the species Adonis aestivalis having an average flower head petal number of at least 16 are cultivated, harvested, and the astaxanthin is extracted from the harvested flower heads or petals thereof.
An important embodiment of the invention is a newly-discovered strain of Adonis aestivalis of which a seed sample has been deposited on 18 July 1990 with the National Collection of Industrial and Marine Bacteria Limited, Aberdeen, under Accession No. NCIMB 40309, in accordance with the provisions of the Budapest Treaty. The invention encompasses plants of the species Adonis aestivalis having the essential characteristics of this deposited strain. Plants of this deposited strain typically have an average of 18-22 petals per flower head, and the average amount of astaxanthin per flower head is 200-350 μg.
The invention also provides a process for obtaining astaxanthin, wherein the astaxanthin is extracted from the petals of plants having the essential characteristics of the deposited strain.
The invention particularly provides an oral composition for administration to fish, comprising such extracted astaxanthin, and a method of pigmenting the flesh of fish, especially salmonid fish, involving the oral administration to the fish of such a composition.
Preferably, the composition comprises the astaxanthin mixed with edible feed material. Alternatively, the astaxanthin can be in encapsulated form.
Alternatively, pigmentation of the flesh of fish can be achieved by feeding astaxanthin-containing portions of the plant to the fish. Preferably, the portion comprises the flower petals and more preferably, consists entirely of such material. If desired, the plant material can be extracted with water or aqueous media in order to remove water-soluble compounds such as glycosides which may be toxic to fish or other animals, without removing significant quantities of the required astaxanthin.
In the pigmentation of farmed fish, the astaxanthin obtained by the invention can be administered orally to the fish in any manner analogous to the techniques already used for astaxanthin derived from conventional sources. Normally the pigment is included in a composition, such as a pelleted compound feedstuff, that forms all or part of the diet on which the fish are reared. The pigment is soluble in oil, and can be incorporated in the diet in this form, either as free oil or as encapsulated oil. Alternatively, the petals or other plant material containing the astaxanthin can be mixed (e.g. in dried, ground form) with conventional fish feed ingredients. If desired, the plant material can be partially extracted with aqueous media (to remove water-soluble components such as glycosides) prior to being added to the feed. As a further alternative, the pigment can be added to the feed in the form of an organic solution, e.g. a solution obtained during extraction of the astaxanthin from the plant material, if the organic solvent used is not toxic to the fish in any amount that the fish are likely to ingest via the completed feedstuff.
When the astaxanthin is administered to fish via their feedstuff, the composition of the feedstuff need not be unconventional. The feedstuff formulation can contain any of the normal fish feed components, such as fish meal and/or other protein, oil such as fish oil, cereals, vitamins, minerals, preservatives and medicaments, in the various proportions that are normally used.
The extracted astaxanthin, or astaxanthin-containing portions of the plant, can also be used as a colouring agent in human foodstuffs, and also in poultry diets to enhance the colour of egg yolks.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Specific embodiments of the invention will now be described in detail, by way of example only.
Novel strain of Adonis aestivalis
The essential characteristics of the newly-discovered strain are:
Chromosome No. 2n=32
Erect, annual, leaves alternative, pinnately dissected into linear or filoform segments. Flowers bright red, actinomorphic, hypogynous, hermaphrodite, solitary and terminal on stem and branches.
Petals less than 15mm long, up to 2 times length of sepals. Sepals 5-8 in number. Petals 18-22 in number.
Values for these parameters, and for the astaxanthin level per flower head, can be taken from analysis of the first fully-open flower heads from 1000 plants.
Ripe achenes 3-5 mm, tooth on dorsal surface distant from the beak. Achenes having a transverse ridge passing around middle of achene. Achenes also having a dorsal hump a distance from the beak.
Cultivation
The plant can be grown under a wide range of temperature conditions. Germination requires a degree of alternating temperatures of 10-20° C. Mature flowering plants are obtained four months after sowing at field densities up to 150 plants/m 2 in a variety of soil conditions; flowering in the summer months (temperate climate). The plant prefers dry, well drained conditions. Seed can be harvested by combine, and flowers by hand.
Extraction of pigment
Pigment can be extracted by solvent extraction, e.g. into mixed solvents such as ethanol/hexane, and further purified by partitioning a mixed solvent with water followed by column chromatography. The final extract, thus purified, is rich with respect to carotenoids, and predominent is astaxanthin, present mainly as a racemic mixture in the form of mono- and diesters, generally of palmitic acid.
Typical starting material
Frozen block of flower heads, stored at -20° C. in the dark, or dried petals/flowerheads, finely ground, also stored at low temperature in the dark.
Primary Extraction
Mix with 10 vols hexane/ethanol (50:50 v/v), allow dispersion, and homogenise for 10 minutes in dark and cool conditions using shear blender; or mill with a shear blender in ethanol, then add hexane for safety reasons.
Leave overnight in dark and cool conditions.
Filter through filter (e.g. muslin) on vibrating sieve, and wash plug with 50:50 ethanol:hexane. Retain original filtered liquid and washings as primary extract. This primary extract contains water-soluble, ethanol-soluble and hexane-soluble material including pigments and glycoside.
Secondary Extraction
Add 1 part water to 2.5 parts primary extract, transfer to phase separator and remove bottom layer of ethanol. Wash upper hexane layer with 1:1 ethanol/water mixture allow to separate and discard lower layer.
Transfer to steam jacketed vacuum evaporator (with cyclone) and remove hexane at 45° C. for 15-30 minutes until a sludge is obtained. Wash with ethanol and evaporate, wash with hexane and evaporate (again at low temperatures, under vacuum or under nitrogen) to dryness. This yields a first concentrate of approximately 5% total pigment (80% astaxanthin) in dry matter. Take up in hexane and apply to silica column (1:1 or 2:1 extract to silica). Wash column with hexane in dark and cool conditions, and discard washings. Elute with 2.5% ethanol in hexane until a red-orange band appears. Collect the red-orange washings until the colour changes to orange-green. Dry eluent as before, take up in hexane or oil (fish oil, vegetable oil). This yields a second concentrate of approximately 20% total pigment containing approximately 80% astaxanthin.
______________________________________Typical Salmon Grower Diet % inclusion by weight______________________________________Fishmeal 75.0Vegetable protein 5.0Cereal 7.8Fish oil 11.0Minerals/Vitamins 1.0Antioxidants/preservatives 0.2______________________________________
Pigment incorporation
Astaxanthin pigment from an Adonis strain of the invention can be added at levels ranging for example from 1-100 ppm to the above type of diet in a variety of ways:
a) as extracted astaxanthin carried in a fish oil base, optionally containing antioxidants.
b) as extracted astaxanthin carried as a free-flowing powder in wheatflour or any finely ground foodstuff for salmon.
c) as for (b) but encapsulated in alginate, gelatin or xanthan gum, eg. by pan granulation or spray cooling.
d) as extracted astaxanthin carried in an encapsulated lipid, eg. casein-protected lipid.
Pigmentation
The above typical salmon grower formulation containing 50-100 ppm of astaxanthin extracted from the deposited Adonis strain of the invention and carried in one of the product forms described above, is fed as pellets to fish of 300 g liveweight plus for a minimum period of 3 months. Typical values for pigmentation efficiency, compared with commercially-available synthetic astaxanthin, are at least about 80% of synthetic.
The skilled reader will readily appreciate that the foregoing extraction procedures, diet formulations, feeding regimes and other details may be subject to considerable variation without departing from the scope of the invention as claimed herein.
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A novel strain of Adonis aestivalis having an average of 18-22 petals per flower head and containing an average of 200-350 μg of astaxanthin pigment per flower head is cultivated, harvested and extracted to provide a source of natural astaxanthin. The extracted astaxanthin, or the harvested astaxanthin-containing plant material, can be used for example in salmonid fish diets to promote correct flesh pigmentation of the fish.
| 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This non-provisional application claims priority under 35 U.S.C. §119(a) on Patent Application No(s). 201010171074.3 filed in China on May 13, 2010, the entire contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The present invention relates to a method for inhibiting pancreatic islet β-cell dysfunction and a method for preventing or treating a pancreatic islet β-cell dysfunction related disorder by use of a rhein compound or a pharmaceutically acceptable salt thereof.
[0004] 2. Background Art
[0005] In humans, the function of pancreatic islet β-cell undergoes a series of changes during the development from obesity to insulin resistance, and finally to type 2 diabetes. In the initial stages, β-cells can secret sufficient insulin as a compensation so as to maintain the blood sugar at a normal level. However, long-term over-secretion of insulin would result in function decompensation and failure of islet cells, and ultimately lead to the occurrence and development of type 2 diabetes. The results from United Kingdom Prospective Diabetes Study (UKPDS) show that the β-cell function of the newly-diagnosed patients suffering from type 2 diabetes only is about 50% that of the normal persons, and declines at a rate of 4.5% per year. At present, clinically there still lacks effective treatments for protecting and repairing pancreatic islet β-cell function.
[0006] Rhein compounds or salts thereof are compounds with established structure as follows,
[0000]
[0000] wherein M is H, alkali metal, alkaline-earth metal or organic base residue, and R 1 and R 2 are independently of each other H or acetyl group.
[0007] Presently, the representative examples of rhein compounds or salts thereof are rhein (each of M, R 1 and R 2 is H), sodium rhein (M is Na, and both R 1 and R 2 are H), potassium rhein (M is K, and both R 1 and R 2 are H), 1,8-diacetyl rhein (M is H, and both R 1 and R 2 are acetyl group), 1,8-diacetyl rhein sodium (M is Na, and R 1 and R 2 are acetyl group) and 1,8-diacetyl rhein potassium (M is K, and R 1 and R 2 =acetyl group). In intestines, the acetyl group of 1,8-diacetyl rhein may be completely hydrolyzed, and the active form is rhein.
SUMMARY OF THE INVENTION
[0008] The present invention provides a method for inhibiting pancreatic islet β-cell dysfunction, comprising administering to a subject in need thereof an inhibitory effective amount of a rhein compound having the general formula (I) or a pharmaceutically acceptable salt thereof,
[0000]
[0009] wherein M is H, alkali metal, alkaline-earth metal or organic base residue, and R 1 and R 2 are independently selected from H and acetyl.
[0010] In one preferred embodiment according to the method of the present invention, in the general formula above, both R 1 and R 2 are H, or both R 1 and R 2 are acetyl.
[0011] In one preferred embodiment according to the method of the present invention, in the general formula above, M is H or alkali metal.
[0012] In this invention, a rhein compound having the general formula (I) or a pharmaceutically acceptable salt thereof can be administered for inhibiting pancreatic islet β-cell dysfunction at an inhibitory effective amount of 35˜140 mg/kg, preferably at an inhibitory effective amount of 120 mg/kg.
[0013] The present invention provides a method for preventing or treating a pancreatic islet β-cell dysfunction related disorder, comprising administering to a subject in need thereof a therapeutic effective amount of a rhein compound or a pharmaceutically acceptable salt thereof above mentioned.
[0014] In this invention, a subject can be any mammal including a human. In particular embodiments, the subject is a human.
[0015] In this invention, a rhein compound having the general formula (I) or a pharmaceutically acceptable salt thereof can be administered for preventing or treating a pancreatic islet β-cell dysfunction related disorder at a therapeutic effective amount of 35˜140 mg/kg, preferably at a therapeutic effective amount of 120 mg/kg.
[0016] In this invention, a pancreatic islet β-cell dysfunction related disorder includes metabolic syndromes, such as obesity and diabetes mellitus, and the diabetes mellitus are particularly type 2 diabetes.
[0017] The inventor found that the rhein compound or the pharmaceutically acceptable salt thereof in this invention could protect and repair the functions of pancreatic islet β-cells, and could inhibit pancreatic islet β-cells dysfunction for patients suffering from metabolic syndromes, such as obesity and diabetes mellitus. Thus, the rhein compound or a pharmaceutically acceptable salt thereof can be used for preventing and treating a pancreatic islet β-cells dysfunction related disorder such as a diabete, particular a type 2 diabete.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 shows IPGTT results of rhein-treated group and control group.
[0019] FIG. 2 shows pancreatic islet perfusion with rhein Ex vivo significantly improves the first phase insulin secretion in type 2 diabetic db/db mice.
[0020] FIG. 3 shows rhein intervention increases the mass of pancreatic islet β-cells of db/db mice, *p<0.05, as compared with db/db mice.
[0021] FIG. 4 shows insulin staining of rhein-treated group and control group.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The characteristics and advantages of this invention can be understood well by the illustration of the examples below. However, this invention is not limited to these examples.
[0023] The studies of the present invention show that oral administration of rhein can very significantly improve the glucose tolerance of obese insulin-resistant rat and type 2 diabetic db/db mice, reduce the loss of pancreatic islet β-cells, and protect the function of pancreatic islet β-cell. The present inventors find and confirm that rhein has the protective effect on pancreatic islet β-cell, and can be applied into the treatment of metabolic syndromes, such as obesity and diabetes mellitus.
[0024] According to the experiments of the present invention, it is shown that rhein improves the function of pancreatic islet β-cells in the obese rats, and increased the content of pancreatic islet β-cells. The hyperglycemic clamp experiment shows that the glucose infusion rate (GIR) at steady-state in the rhein-treated group [(26.1±2.9) mg.kg −1 min −1 ] is significantly higher than that in the untreated obese group [(35.9±4.1) mg.kg −1 .min −1 , P<0.05] after treatment with rhein for 4 weeks (Table 1). In the normal control group, the insulin is strongly strained and uniformly distributed in the pancreatic islets. The insulin expression level in the obese control group is merely 70% that in the normal control group. Compared with the rats in the obese control group, rhein treatment significantly improves the insulin expression level in the islets.
[0000]
TABLE 1
Hyperglycemic clamp characteristic parameters in obese rats after
treatment with rhein for 4 weeks
Normal control
Obese
rhein-treated obese
Parameters
group
group
group
FBG (mmol/L)
6.2 ± 0.5
6.9 ± 0.6
5.3 ± 0.5
SSBG(mmol/L)
14.9 ± 0.8
15.2 ± 0.7
14.9 ± 0.8
GIR(mg.kg -1 .min -1 )
35.7 ± 3.3
23.1 ± 3.2*
32.2 ± 2.9#
*P < 0.05 vs normal control,
#P < 0.05 vs Obese group;
FBG: Fasting blood glucose;
SSBG: Steady state blood glucose;
GIR: Glucose infusion rate
[0025] According to the experiments of the present invention, it is also shown that rhein can improve glucose tolerance. The intraperitoneal glucose tolerance test (IPGTT) is performed after treatment with rhein for 8 weeks, and the results show that the blood glucose levels in rhein-treated type 2 diabetic db/db mice are significantly lower than those of the untreated control mice at 0, 60 and 120 min after glucose loading (p<0.05) (Table 2, FIG. 1A ). Furthermore, the plasma insulin levels in rhein-treated type 2 diabetic db/db mice are significantly increased at 30 and 60 min ( FIG. 1B ). In the rhein-treated group, the area under the curve (AUC) of blood glucose is significantly reduced as compared with that of the mice in the untreated group, the AUC of insulin is significantly increased, and specifically the AUC of insulin is most significantly increased within 0-30 min after glucose loading (Table 3). The above results suggest that the improvement of glucose tolerance by rhein is resulted from the improvement of pancreatic islet β-cell functions.
[0000]
TABLE 2
The results of intraperitoneal glucose tolerance test (IPGTT) on
db/db mice after treatment with rhein for 8 weeks
Parameters
Groups
0 min
30 min
60 min
120 min
Blood
db/m
3.5 ± 0.2*
6.3 ± 0.5*
5.9 ± 0.7*
3.9 ± 0.4*
glucose
db/db
21.9 ± 1.1
24.8 ± 2.8
28.8 ± 1.6
21.8 ± 4.6
(mmol/L)
rhein-
7.6 ± 0.7*
19.5 ± 1.5
18.3 ± 2.0*
10.4 ± 1.1*
treated
db/db
plasma
db/m
0.4 ± 0.1*
0.5 ± 0.0*
0.4 ± 0.1*
0.5 ± 0.1*
insulin
db/db
4.9 ± 1.0
3.3 ± 0.7
2.6 ± 0.8
3.8 ± 1.3
(ug/L)
rhein-
5.3 ± 0.7
9.5 ± 1.9*
6.0 ± 0.7*
5.9 ± 0.6
treated
db/db
Compared with db/db mice, *p < 0.05
[0000]
TABLE 3
AUC of glucose and insulin in intraperitoneal glucose tolerance test
(IPGTT)
Parameters
db/m
db/db
rhein-treated db/db
AUC-glucose
627 ± 56*
3023 ± 251
1834 ± 151*
AUC-insulin
57 ± 7*
401 ± 85
812 ± 80*
AUC INSO-30
15 ± 3*
-24 ± 10
63 ± 32*
AUC INSO-30 : AUC of insulin within 0-30 min, compared with db/db mice, *p < 0.05
[0026] It is shown by the experiments of the present invention that rhein increases the first phase insulin secretion in type 2 diabetic db/db mice. Pancreatic islet perfusion is a golden standard for evaluating the first phase insulin secretion. The insulin-secreting function of pancreatic islet β-cells is fully evaluated in the respect of secretion phases and secretion amounts. With stimulation of high glucose of 16.7 mmol/L, the insulin level of untreated db/db mice is increased slightly, and the peak insulin level is merely 3 times as high as basal level. In contrast, the insulin level of rhein-treated mice is significantly increased after high glucose stimulation for 1 min, and is 7 times as high as basal level ( FIG. 2 ). There is a significant difference between two groups.
[0027] It is shown by the experiments of the present invention that rhein increases the amount of pancreatic islet β-cells. After administration for 8 weeks, the pancreatic islet β-cell amount in the untreated db/db group is considerable low, while rhein treatment significantly reduces the loss of pancreatic islet β-cells ( FIG. 3 ). In the normal control group of db/m mice, the insulin is strongly strained and uniformly distributed in the pancreatic islets. In contrast, in the diabetic control group of db/db mice, the pancreatic islets exhibit week and sparse insulin expression, and the staining intensity is merely 50% that of the db/m control group. Compared with db/db control group, rhein treatment significantly enhances insulin expression level in the pancreatic islets.
[0028] According to the oral absorption kinetics and pharmacokinetics of rhein in rats, it is shown that after ig (intragastric gavage) administration with 35 mg/kg, 70 mg/kg or 140 mg/kg rhein, the calculated half lives are 3.22±1.21 h, 3.68±1.42 h and 4.30±1.55 h, respectively; the actually-measured peak times are 0.42±0.26, 0.50±0.27 h and 0.38±0.14 h, respectively; the peak concentrations are 37.96±12.87 μg/ml, 54.64±11.60 μg/ml and 67.17±14.62 μg/ml, respectively; and the AUCs are 69.52±9.13 μg.h/ml, 164.29±44.77 μg.h/ml and 237.75±42.81 μg.h/ml, respectively. The relationship between AUC and dosage as well as the relationship between peak concentration and dosage shows that there is a linear relationship between AUC and dosage. The three dosages exhibit the similar half lives. The above results show that in the tested dosage range, the pharmacokinetics of rhein in rats is approximately linear.
[0000]
TABLE 4
Plasma rhein concentration (μg/ml) in rats after gavage administration with 35 mg/kg rhein
Time (h)
1
2
3
4
5
6
X
s
0.033
15.34
19.11
10.10
10.54
24.21
9.45
14.79
5.94
0.083
22.07
44.52
22.33
16.18
40.94
19.99
27.67
11.92
0.25
27.43
45.05
26.00
26.86
59.77
24.59
34.95
14.33
0.50
22.01
22.71
28.87
26.88
55.32
22.99
29.80
12.79
0.75
18.92
18.72
35.43
35.51
45.07
15.62
28.21
12.04
1.0
19.13
19.96
21.75
27.32
37.07
15.78
23.50
7.66
2.0
8.25
4.26
7.88
7.44
7.45
15.41
8.45
3.70
3.0
4.03
4.23
4.39
4.04
2.99
4.38
4.01
0.52
4.0
3.98
4.16
1.70
3.75
1.31
4.91
3.30
1.45
6.0
3.08
2.69
3.08
2.89
0.57
0.86
2.19
1.16
8.0
4.99
0.75
1.94
2.05
1.07
0.34
1.86
1.68
12.0
0.58
0.18
1.13
1.35
ND
0.36
0.60
0.54
14.0
0.51
ND
0.50
0.56
ND
ND
0.35
0.27
ND: Lower than the minimal detectable concentration 0.13 μg/ml.
[0000]
TABLE 5
Plasma rhein concentration (μg/ml) in rats after gavage administration with 70 mg/kg rhein
Time (h)
1
2
3
4
5
6
x
s
0.033
34.64
37.28
24.38
23.12
14.12
14.57
24.68
9.74
0.083
30.38
48.63
34.14
42.68
26.18
22.27
34.05
10.01
0.25
38.86
65.89
62.98
49.02
24.12
31.05
45.32
16.99
0.50
50.53
43.37
44.14
56.14
33.63
52.37
46.70
8.05
0.75
30.33
40.26
34.20
46.37
24.94
49.16
37.54
9.41
1.0
30.42
40.86
29.41
35.89
20.75
58.65
36.00
12.99
2.0
13.29
34.33
26.24
26.80
15.09
12.71
21.41
8.95
3.0
13.61
21.97
27.09
11.54
16.35
9.87
16.74
6.62
4.0
7.23
12.76
19.78
13.32
14.65
10.51
13.04
4.20
6.0
4.81
6.74
18.98
7.55
3.85
5.39
7.89
5.59
8.0
6.32
7.32
11.38
6.09
2.52
6.32
6.66
2.84
12.0
2.52
5.62
6.21
4.94
1.14
2.79
3.87
2.00
14.0
0.44
0.40
0.93
3.56
1.75
1.91
1.50
1.19
[0000]
TABLE 6
Plasma rhein concentration (μg/ml) in rats after gavage administration with 140 mg/kg rhein
Time (h)
1
2
3
4
5
6
x
s
0.033
13.55
21.88
9.42
14.25
22.00
13.23
15.72
5.10
0.083
30.55
35.10
46.58
22.35
50.52
24.47
34.93
11.54
0.25
61.22
59.53
69.37
27.07
54.64
64.74
56.09
15.06
0.50
51.20
87.95
82.06
52.43
31.95
45.63
58.54
21.83
0.75
33.65
64.91
48.63
44.00
31.47
39.56
43.70
12.18
1.0
30.46
49.08
43.04
18.64
24.25
35.51
33.50
11.43
2.0
22.45
35.15
37.37
14.29
28.00
37.98
29.21
9.47
3.0
20.79
25.58
28.39
16.91
17.23
24.19
22.18
4.66
4.0
15.52
24.69
20.82
16.50
26.59
18.69
20.47
4.44
6.0
10.85
19.98
20.49
17.58
17.34
19.34
17.59
3.54
8.0
6.47
15.42
14.46
10.29
13.74
11.21
11.93
3.31
12.0
4.11
2.48
4.35
6.63
11.63
6.14
5.89
3.19
14.0
3.40
3.15
4.05
4.81
6.83
4.27
4.42
1.33
Example 1
Improvement Effects of Rhein on Glycuse Tolerance
[0029] Agents: Rhein dissolved in 0.1% cellulose sodium.
[0030] Administration to the experimental animals: Thirty diabetic db/db mice of 4 week old are randomly assigned to treatment group and control group. Additional fifteen normal db/m mice of 4 week old are used as normal control group. The treatment group of diabetic db/db mice is treated with rhein (120 mg/Kg, dissolved in 0.1% cellulose sodium) by gavage for continuous 8 weeks. The diabetic control group of db/db mice and the normal control group of db/m mice are administrated 0.1% cellulose sodium by gavage.
[0031] Experimental methods: The intraperitoneal glucose tolerance test (IPGTT) is carried out on the mice after administration for 8 weeks. The mice are fasted overnight, and then are administrated by i.p. injection of glucose at 0.5 g/kg body weight. Blood is collected at 0, 30, 60 and 120 min for detecting whole blood glucose level and insulin level and calculating the area under the curve (AUC) of insulin. The area under the curve of insulin during 0˜30 min (AUC INS0.30 ) is calculated as: (insulin level at 30 min−insulin level at 0 min)×15, for evaluating the ability of early phase insulin secretion.
[0032] Experimental results: Rhein can improve glucose tolerance. The results of intraperitoneal glucose tolerance test (IPGTT) show that after treatment with rhein for 8 weeks, the blood glucose levels in rhein-treated type 2 diabetic db/db mice are significantly lower than those of the untreated control mice at 0, 60 and 120 min after glucose loading (p<0.05) (Table 2, FIG. 1A ). Furthermore, the plasma insulin levels in rhein-treated type 2 diabetic db/db mice are significantly increased at 30 and 60 min ( FIG. 1B ). In the rhein-treated group, the area under the curve (AUC) of blood glucose is significantly reduced as compared with that of the mice in the untreated group, the AUC of insulin is significantly increased, and in particular the AUC of insulin is most significantly increased during 0-30 min after glucose loading (Table 3). The above results suggest that the improvement of glucose tolerance by rhein is resulted from the improvement of pancreatic islet β-cell functions.
Example 2
Effects of Rhein on the First Phase Insulin Secretion in Type 2 Diabetic db/db Mice
[0033] The agents and animals used in this example are the same as those used in example 1.
[0034] Experimental methods: After 8 weeks of administration, 5 mice are randomly selected from each group for pancreatic islet isolation and perfusion as follows. After anesthesia, the opening of common bile duct at duodenal papilla for each animal is clamped in vivo. 2 ml IV type collagenase is injected at the concentration of 1 mg/ml after performing common bile duct puncture under a stereoscopic microscope. After entering the pancreatic duct reversely to expand the pancreas, the pancreas is rapidly removed. The pancreas is placed in Hank's buffer containing 1 mg/ml collagenase and digested for 40 min to remove the collagens, and then washed under vibration for several times. Pancreatic islets are successfully isolated under microscopy. The pancreatic islets are incubated in a CO 2 incubator for 2 hour with 50 islets per group, and then the islets are placed into a specially manufactured constant-temperature perfusion equipment. The mice are perfused with 2.8 mM glucose using a Harvard micro-pump at 0.5 ml/min for glucose starvation perfusion, and after 30 min, perfusion of high glucose (16.7 Mm) is performed at 1 ml/min. The effluent liquid is collected every 20 s for first 5 mM, and then collected every 1 min. The collected effluent liquids are stored for insulin level detection via ELISA. The first phase insulin secretion and dynamic secretion level of insulin are reflected from the curve of insulin levels measured.
[0035] Experimental results: This experiment shows that rhein increases the first phase insulin secretion in type 2 diabetic db/db mice. Pancreatic islet perfusion is a golden standard for evaluating the first phase insulin secretion. The insulin-secreting function of pancreatic islet β-cells is fully evaluated in the respect of secretion phases and secretion amounts. With the stimulation of high glucose of 16.7 mmol/L, the insulin level of untreated db/db mice is increased slightly, and the peak insulin level is merely 3 times as high as basal level. In contrast, the insulin level of rhein-treated mice is significantly increased after high glucose stimulation for 1 min, and is 7 times as high as basal level ( FIG. 2 ). There is a significant difference between two groups.
Example 3
Effects of Rhein on the Amount of Pancreatic Islet β-Cells
[0036] The agents and animals used in this example are the same as those used in example 1.
[0037] Experimental methods: Immunohistochemical assay. The mice are anaesthetized with phenobarbital sodium, perfused with physiological saline via heart, and fixed with 4% polyoxymethylene. The pancreas are removed, and then placed in 4% polyoxymethylene for 4-6 hours, embedded in paraffin, and sliced into a thickness of 5 um. The slices are dewaxed with xylene, rehydrated with ethanol at different gradient concentrations, and then treated with 0.3% hydrogen peroxide at room temperature for 20 min, so as to block the activity of endogenous peroxidase. The samples are treated with steams at 121° C. under high pressure for 10 min for repairing the antigen. 10% goat serum is added for blocking non-specific antigens. Rabbit-anti-mouse insulin antibody is added, and reacted at 4° C. overnight for 14 hours. Biotin-labeled goat-anti-rabbit secondary antibody is added and reacted at room temperature for 30 min. Diaminobenzidine is added for developing color. The samples are stained with hematoxylin, dehydrated and embedded.
[0038] Metrology analysis of pancreatic islets: All of the slices are observed with optical microscope E800 (Nikon, Japan), and photographed with a digital camera (Sony, Japan) connected with the microscope. The digital photographs are obtained via Axiovision 4.3 software, and analyzed with Image-Pro Plus 5.0.1. Fifteen pancreatic islet photographs are randomly selected for each mouse, and at least 50 pancreatic islet photographs are analyzed for each group. The pancreatic islet β-cell amounts are determined by analyzing the insulin-stained photographs, and calculated according the following formula: pancreatic islet β-cell amount (mg)=(the area of the pancreatic islet (β-cells/the area of the pancreas)×the mass of the pancreas (15 pancreas photographs/group). The staining intensity of insulin is determined with Scion Image B4. 0. 3 for windows (U.S.) (30 pancreatic islets/group).
[0039] Experimental results: This experiment shows that rhein increases the amount of pancreatic islet β-cells. After administration for 8 weeks, the pancreatic islet β-cell amount in the untreated db/db group is considerable low, while rhein treatment significantly reduces the loss of pancreatic islet β-cells ( FIG. 3 ). In the normal control group of db/m mice, the insulin is strongly strained and uniformly distributed in the pancreatic islets. In contrast, in the diabetic control group of db/db mice, the pancreatic islets exhibit week and sparse insulin expression, the staining intensity is merely 50% that of the db/m control group. Compared with db/db control group, rhein treatment significantly enhances insulin expression level in the pancreatic islets ( FIG. 4 ).
Example 4
Protective Effects of Rhein on Pancreatic Islet β-Cells of Obese Rats
[0040] The agents used in this example are the same as those used in example 1.
[0041] Experimental animals: Insulin-resistant obese rats are 4-week in-bred female Wistar rats induced by feeding with high-sugar high-fat feedstuff (20% sugar, 10% lard, 2.5% cholesterol, 1% cholic acid and 66.5% normal feedstuff) for 3 weeks.
[0042] Administration to the experimental animals: Thirty insulin-resistant obese rats are randomly assigned to treatment group and control group. Additional fifteen normal Wistar rats of 7 week old are used as normal control group. The treatment group of insulin-resistant obese rats is treated with rhein (100 mg/Kg, dissolved in 0.1% cellulose sodium) by gavage for continuous 4 weeks. The insulin-resistant obese control group and the normal control group are administrated with 0.1% cellulose sodium by gavage.
[0043] Experimental results: The hyperglycemic clamp experiment shows that the glucose infusion rate (GIR) at steady-state in the rhein-treated group [(26.1±2.9) mg.kg −1 min −1 ] is significantly higher than that in the untreated obese group [(35.9±4.1) mg.kg −1 .min −1 , P<0.05] after treatment with rhein for 4 weeks (Table 1). In the normal control group, the insulin is strongly strained and uniformly distributed in the pancreatic islets. The insulin expression level in the obese control group is merely 70% that in the normal control group. Compared with the rats in the obese control group, rhein treatment significantly improves the insulin expression level in the islets.
Example 5
Oral Absorption Kinetics and Pharmacokinetic Parameters of Rhein in Rats
[0044] The agents used in this example are the same as those used in example 1.
[0045] Grouping of the animals and experimental procedure: Eighteen Wistar rats (male: female=1:1; body weight=180˜210 g) are randomly divided into 3 groups, 6 animal each group (male 3, female 3). The animals are fastened but supplied with free water for 10 h, and then are administrated ig with 35 mg/kg, 70 mg/kg or 140 mg/kg rhein. Blood samples are collected from carotid artery cannula at 0.033 h, 0.083 h, 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 14 h after administration, and centrifuged. 50 μl plasma is used for HPLC-fluorescence (FLD) analysis. The obtained plasma rhein concentration-time data are used for calculating pharmacokinetic parameters via corresponding pharmacokinetic programmes.
[0046] Experimental results: after ig administration with 35 mg/kg, 70 mg/kg or 140 mg/kg rhein, the calculated half lives are 3.22±1.21 h, 3.68±1.42 h and 4.30±1.55 h, respectively; the actually-measured peak times are 0.42±0.26, 0.50±0.27 h and 0.38±0.14 h, respectively; the peak concentrations are 37.96±12.87 μg/ml, 54.64±11.60 μg/ml and 67.17±14.62 μg/ml, respectively; and the AUCs are 69.52±9.13 μg.h/ml, 164.29±44.77 μg.h/ml and 237.75±42.81 μg.h/ml, respectively. The relationship between AUC and dosage as well as the relationship between peak concentration and dosage shows that there is a linear relationship between AUC and dosage. The three dosages exhibit the similar half lives. The above results show that in the tested dosage range, the pharmacokinetics of rhein in rats is approximately linear.
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This invention provides a method for inhibiting pancreatic islet β-cell dysfunction, comprising administering to a subject in need thereof an inhibitory effective amount of a rhein compound having the general formula (I) or a pharmaceutically acceptable salt thereof,
| 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a compact multiple purpose golf tool with a lengthwise body element serving as a handle and having a receptacle area for functional pieces which can be pulled out to a functional position from the handle.
2. Discussion of the Related Art
Such compact or pocket tools are known, for example pocket knives, with two opposing handle half-shells between which one or more functional pieces, such as knife blades, cork screws, screw drivers, can openers, nail files, and the like, are arranged so that they can be swung out and which are held in the collapsed or extended position basically by spring force. These are known in the most varied design forms. Thus, for example, different sizes of flat head or Phillips head screw drivers or different sizes of Allen keys or machinist's wrenches have been arranged on a pocket knife. These functional pieces are located between parallel plates, which are connected to one another by clinch bolts, with the outer plates being, covered each by one of the shells. The shells provide the visual appearance of a pocket knife, on the one hand, and are also responsible for its ergonomic properties and grip, on the other, hand. It is also known to provide the shells with push-in channels which can hold for, example, tooth picks, pincers, or cleaning needles for the spray jets of windshield washer systems on vehicles.
The equipment of pocket knives with functional pieces suitable for the most varied purposes is reflected also in the fact that known pocket knives have also been combined with a typing system. Such pocket knives are subject to high assembly expenses and therefore cause a very expensive manufacturing process.
Previously known pocket tools, especially pocket knives, usually have swingable functional elements which stick out somewhat on the side from the contour of the housing element and which are grippable with the finger tips in a way that is well-known. They are positioned in a way that they can be swung out against a spring force, so that a holding force is active both in the collapsed carrying position and in the extended functional position. This is provided by the elastic elements and cannot be controlled. Thus it may occur that the functional elements inadvertently collapse during use. Moreover, the springs become fatigued with time, which has further unfavorable effects. Another disadvantage of swingable functional elements is that they are usually swingable around one axle and thus absorb torsion forces only to a limited degree. Functional elements in previously known pocket tools cannot be opened and closed with one hand. With many special knives, the knife blade can be opened with one hand by releasing a pre-set spring, but usually they cannot be closed with one hand. Other functional elements are plugged into and can be taken out of slots in the shells or the body element.
Starting from the previously known state of technology, the present invention is based on the task, of preparing a pocket tool of the usual kind, which has different functional elements that can be used for various purposes in the sport of golf, and which is economically manufacturable and easy to use.
In particular, a tool is to be prepared in which functional elements useful for the exercise of golf are operable with one hand and can absorb leverages and torsion forces at least to the usual extent.
Beyond that, an improved control of the holding forces should be made possible, both in the carrying position and in the functional position.
For the technical solution of this task, a normal pocket tool is further developed in that a divot repair tool is arranged in the body element which can be moved by single-hand operation between a carrying position and a functional position and which can be locked in both positions.
The multiple purpose golf tool according to the invention has a divot repair tool which can be moved by single-hand operation between a carrying position and a functional position. This divot repair tool is completely housed in the body element in the carrying position and can be moved out to a functional position. Divot repair tools are used in golf primarily to repair pitch marks on the green, that is, ball divots. For this purpose, the tool is moved in the grass surface of the green using lifting and twisting movements.
According to a preferred embodiment for the invention, the divot repair tool is arranged within a tool guide in the body element. The body element has two external side shells, between which essentially parallel plates are arranged. In the manner according to the invention, the divot repair tool is arranged in a lengthwise sliding manner in a plate which is designed as a tool guide plate and arranged essentially parallel to a side shell. Thus the repair tool can be pushed out on a narrow side surface of the pocket tool. In an advantageous manner, an operating pin is mounted on the divot repair tool, arranged essentially perpendicular to the guide plate and projecting through one of the side shells. This operating pin can thus be gripped from one of the side shells and slid lengthwise, whereby the repair tool is also slid lengthwise. Preferably the repair tool can be automatically locked in the body element both in the carrying position drawn into the body element and in the functional position extending out of the body element. For this purpose it is proposed according to the invention to arrange a locking plate parallel to the guide plate which has locking grooves into which the spring-elastic element of the divot repair tool can lock. This spring-elastic element can be the operating pin designed in a spring-elastic manner on the divot repair tool, with the spring elasticity acting perpendicular to the guide plate. The operating pin call be pressed in from the side shell in a spring-elastic manner by pressure and thus press a locking element, which is connected elastically with the divot repair tool, out of a locking groove. In the side shell, according to an advantageous proposal for the invention, a lengthwise groove is designed, in which the operating pin is guided. The lengthwise groove can be carried out at the base of a depression designed in the side shell, so that an operating button set on top of the operating pin is led in this depression. By use of the spring-elastic element on the divot repair tool, therefore, no separate spring is needed for locking the divot repair tool in different positions. The fork guidance can be a guide plate with recesses for the divot repair tool. The guide plate can also be formed by individual elements, however. Thus two or more individual guide elements can be combined to form a guide plate. Two identical elements can be aligned in reflection to the lengthwise median and form a guide area for the divot repair tool. The divot repair tool is designed as a plate-shaped element. This element can preferably be formed from stainless steel. In this way, the divot repair tool can be kept very thin, for example≦1 mm, so that a light and above all delicate insertion into the precious lawns of the golf course can be guaranteed. Moreover, the plate-shaped element can be moved through an opening slot which has very narrow tolerances with respect to the divot repair tool. In this way, the opening slot functions as a stripper for sand, dirt, and the like which is on the divot repair tool.
According to another advantageous proposal for the invention, the multiple purpose golf tool has a ball marker. Ball markers are usually plate or coin-shaped plates which are inserted into the green to mark the position of a ball. According to an advantageous proposal for the invention, the ball marker is removably inset into a side shell. For this purpose, the side shell can have a plate-shaped recess in which the ball marker is positioned. In order to arrange the ball marker on the pocket tool in a way that it cannot be lost, it is proposed that the side shell and at least a part of the plates have a groove open from one side edge, into which the holding pin arranged on the ball marker can be inserted. According to an advantageous proposal for the invention, one of the plates can be designed in a spring-elastic manner in the area of the receptacle groove for the holding pin of the ball marker, so that the ball marker can be locked in the position of insertion in the pocket tool. Preferably the spring-elastic area for the holding pin of the ball marker is designed in the guide plate for the divot repair tool. Thus for the ball marker as well, no additional spring is required. The ball marker can be pushed out of the body element with one hand and placed in the desired position at the same time. In order to improve the pushing out of the ball marker, it can be provided that an operating depression is designed in the side plate of the body element. Alternatively, it is also possible not to arrange the ball marker on the tool by pinching of the holding pin, but rather for example to design the ball marker only as a plate-shaped element which can be elastically inset in a recess or depression of the side shell. The elastic force can act for example on the perimeter of the ball marker. A design of this type is economically less expensive.
Both the ball marker and the operating button for the divot repair tool are preferably arranged in the same side shell and can both be operated with one hand. Due to the lengthwise guidance of the divot repair tool, it is also designed to absorb leverage and torsion forces to a limited degree. For this purpose, the end which remains in the body element in the functional position is precisely led and held fast between two plates and the two hardened side guides for the divot repair tool.
Because in hard or frozen soils, the tees cannot easily be placed, a new kind of tool in the form of a tee hole puncher is arranged on the pocket tool in another advantageous proposal for the invention. It is preferably positioned as a swingable functional element against the force of a spring, swingable between a carrying position collapsed into the body element and a functional position extended out of the body element. The spring serves to provide a holding force against inadvertent extension in the Carrying position on the one hand, and a spring force against inadvertent collapse in the functional position. In a manner which is known per se, the functional element is moved with its talon across from a leaf spring. In the invention, in order to improve the holding force, it is proposed that the movement edge between the talon of the functional element and the leaf spring is designed as a locking cam/cam depression pair. While at least one locking cam is positioned on one of the two elements, the other element can have a cam depression, positioned so that in the desired end position the cam is locked in the cam depression. This provides an increased holding force. In an advantageous manner, a cam is designed on the talon of the tee hole puncher, which locks into a cam depression on the leaf spring in the extended position. Meanwhile the cam depression can preferably be designed on the spring at one of the ends of the guiding lane. In an advantageous manner, one cam each is designed on the talon of the tee hole puncher both for the carrying position and for the functional position, which work together with respective cam depressions on the spring. In this way the respective holding forces can be controlled and pre-set by the dimensioning of the cams and the cam depressions, so that even when the spring becomes fatigued, a still adequate holding force for the functional element is provided. The tee hole puncher, which is used to bore holes in the ground surface, is thus protected against unintended collapse during use.
The tee hole puncher can in an advantageous manner be complemented by additional functional elements, for example a cap opener or the like. One lengthwise edge of the tee hole puncher is ground sharp, while the other lengthwise edge is U-bent in a rounded manner to stiffen the punch. The lengthwise flute created in this way is designed as a very practical nail file. The tip of the tee hole puncher is shaped in such a way that it can be used to clean the golf club flutes. Furthermore, additional functional elements such as a knife blade, scissors, and the like can be arranged as swingable functional elements in the pocket tool according to the invention. In these as well a locking cam/locking depression arrangement can be designed in an advantageous manner between the talon and the spring. The multiple purpose golf tool according to the invention can also have removable functional elements like pincers, tooth picks, ball-point pens and the like, for which the side shell, in which the operating button for the pitch fork is not led, is preferably suitable.
The body element is preferably ergonomically shaped. In order to be well usable, it is important that the ball marker and the divot repair tool are operable with one hand. For this purpose, the multiple purpose golf tool must lie well in the hand in general, while the operation of the elements is preferably done with the thumb. In order to insert the divot repair tool and, as the case may be, the tee hole puncher as well, into the ground and to move it there, the tool preferably also has back-grippable areas, so that in the lengthwise direction as well a force can be applied well with application of the necessary feeling. This demand is initially opposed to the desire of being able to design the multiple purpose golf tool overall to be as small as possible. In the collapsed position, usually many functional pieces sit on the side of the multiple purpose golf tool so that they are grippable and extendible with the finger tips. According to the invention it is proposed to be able to insert these functional elements into the body element elastically in order to generate the external ergonomic shape of the body element. After release, the functional elements move back into their normal position, in which they are grippable and extendible.
With the invention, a pocket tool with functional elements for the sport of golf is provided which is economically manufacturable and simple to use, in particular one that is usable with one hand. The divot repair tool arrangement in particular allows the application of slight leverage and torsion forces, which is functionally necessary. The design of locking cams and locking depressions between the tee hole puncher and the corresponding spring increases the operation safety and improves the functionality, since in particular an unintended collapsing of the tee hole puncher during use is largely avoided. To improve the economic viability, the invention proposes one more improvement of the springs. While conventionally the springs have to be counterpositioned across from counterpositioning elements on the plates, the springs now have cams at suitable places which can be counterpositioned against the cams on adjacent springs. In this way, specific counterpositioning points in the intermediate plates can be largely given up.
Further advantages and features of the invention are found in the following detailed description of the invention taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an exploded view of an embodiment of a pocket tool with functional elements suitable for the sport of golf, and
FIG. 2 shows an embodiment of a locking cam/cam depression arrangement between the blade talon and the spring.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows in an exploded view, the individual elements of a pocket tool ( 1 ). The upper and lower surface of the pocket tool are formed by side shells ( 2 , 3 ), preferably made of plastic. Between these, parallel to the internal surfaces of the side shells, intermediate plates ( 4 ) are arranged, and between the latter functional plates ( 5 , 6 ) with functional elements. In a manner which is known per se, the plates and side shells are connected by means of clinch pins ( 7 ) and clinch rings ( 8 ). In lower side shell ( 3 ), lengthwise running grooves ( 9 ) are designed in the inner surface into which a pincer ( 10 ) and a tooth pick ( 11 ) can be inserted in a removable manner. The grooves are closed by intermediate plate ( 4 ) which is placed on top. In functional plate ( 6 ), a divot repair tool ( 12 ) is led. The functional plate ( 6 ) is formed by guide tracks on the side, in which divot repair tool ( 12 ) can be slid lengthwise. The guide tracks are formed by two identical elements aligned in reflection to the lengthwise median of the body element. These are preferably stampings. The guide tracks have recesses along the guide lane in order to keep the frictional forces as low as possible. The two guide tracks, as well as intermediate plates ( 4 ) arranged above and below the divot repair tool, form a front guide slot, through which divot repair tool ( 12 ) is pushed out of the body element and drawn back into it. Guide plates ( 4 ) and guide tracks ( 6 ) are arranged as closely as possible to plate-shaped divot repair tool ( 12 ) —which is preferably formed of stainless steel —so that they can serve as strippers for the dirt, soil and the like found on the divot repair tool when the divot repair tool is drawn in. In the embodiment shown, the divot repair tool ( 12 ) has an operating pin ( 13 ) generated by bending and stamping. The essentially T-shaped punch-out is bent up on the free end to create the operating pin. The operating pin can be slotted and provided with a locking head so that an operating button ( 14 ) can be stuck on it. The operating button has a surface like a golf ball according to the proposal. Operating button ( 14 ) is led in a depression ( 16 ) in upper shell ( 2 ). It sits on operating pin ( 13 ), which projects through a lengthwise groove ( 15 ) in upper shell ( 2 ). As can be seen in the depicted embodiment, the free end of operating pin ( 13 ) is bent up toward upper shell ( 2 ). To it is attached a cross bridge, to which in turn is attached a spring arm, which is bent slightly upward. Locking grooves ( 17 ) and ( 18 ) are designed in intermediate plate ( 4 ) lying above this. In the assembled state, the divot repair tool ( 12 ) can be simply slid back and forth, with operating pin ( 13 ) being pressed to the level of the divot repair tool ( 12 ) against the spring elasticity by light pressure on operating button ( 14 ), so that the divot repair tool ( 12 ) can be slid forward until operating pin ( 13 ) hits against locking groove ( 17 ). If operating button ( 14 ) is now let go, the cross bridge on operating pin ( 13 ) is led by spring elasticity into locking groove ( 17 ), so that the divot repair tool ( 12 ) is locked into its functional position. By the large-surface design of the part of divot repair tool ( 12 ) located inside pocket tool ( 1 ), the divot repair tool ( 12 ) withstands leverage and torsion forces well. By pressure on operating button ( 14 ), which continues through operating pin ( 13 ), the cross bridge is pressed out of locking groove ( 17 ) into the plane of the divot repair tool and the latter can then be moved back to the rear position, where the cross bridge locks behind locking groove ( 18 ) in the carrying position of the divot repair tool.
A plate-shaped ball marker, depicted in perspective and in side view, with an only partially visible holding pin, can be laid into a recess ( 20 ), in upper side shell ( 2 ). Recess ( 20 ) can be extended further in a depression form toward depression ( 16 ), in order to make it easier to push out ball marker ( 19 ) with one hand. It is especially important in this that the overall contour of side shell ( 2 ) be completed by it and that the pocket tool is given an especially nicely-shaped exterior. In depression ( 20 ) of side shell ( 2 ) a groove ( 21 ) is designed, which continues in grooves ( 22 ) of intermediate plates ( 4 ) and also in groove ( 23 ) of functional plate ( 6 ).
Groove ( 23 ) in functional plate ( 6 ), formed by two spring arms, serves to clamp in the pin sticking out from ball marker ( 19 ). The ball marker can thus be pushed out of the groove with one hand, for example by thumb pressure, and positioned on the desired place. To do this, the force of spring groove ( 23 ) must be overcome, when the pin arranged on the ball marker is just being pushed out of groove ( 21 , 22 , 23 ) away from pocket tool ( 1 ).
Alternatively, it is also possible not to arrange the ball marker on the tool by clamping in the holding pin, but for example to design the ball marker only as a plate-shaped element, which can be elastically inset into a recess of a depression in the side shell. The elastic force can act, for example, on the perimeter of the ball marker. Such a design is economically less expensive.
The additionally depicted functional plate ( 5 ) is formed in a manner known per se by functional elements such as a knife blade ( 25 ) or a scissors ( 26 ) with a corresponding cover. The cover protects the inside of the tool from dirt. The knife blade includes a blade which can be swung out on the side against the force of a spring, and scissors ( 26 ) can also be swung out on the side against the force of a spring. Number ( 24 ) designates a tee hole puncher, in which a blade element ( 27 ) is positioned in a manner to be swung out on the side against spring ( 28 ), and in which in the depicted embodiment the blade element is arranged in parallel to knife blade ( 25 ). Blade ( 27 ) has a stabbing element provided for forming an essentially vertical hole in the ground, so that a hole for a tee can be made. In the rear area, an additional functional element can be designed, for example a bottle opener or the like, In the rear area of blade ( 27 ), the latter is arranged in a swingable manner around axle
The rear area is designated as a talon.
The described pocket tool ( 1 ) with divot repair tool ( 12 ), ball marker ( 19 ), and tee hole puncher ( 24 ) represents a very attractive-looking tool due to its integrated surface, which can be operated with one hand at least with respect to the divot repair tool and ball marker, and which is extremely functional, providing good service in the sport of golf. The manufacture is economical and the corresponding force absorption is appropriate to the purpose.
In functional plate ( 5 ) it can be seen that the two springs ( 28 ) are positioned against one another with cams designed about half length. Due to this counterpositioning, corresponding counterpositions on the intermediate plates are unnecessary. In this way it becomes possible in an economical manner to use identical intermediate plates ( 4 ) in the depicted embodiment.
FIG. 1 also shows that the middle area of the body element is constricted, so that at least in the head area, from which the divot repair tool can be slid out, a T-shaped widening is designed. In the functional position, these enlargements can be back-gripped. For this purpose, functional elements ( 24 , 25 , and 26 ) are designed so that they can be pressed elastically into the body element, but moved back into their depicted normal position after release. In this way, the especially ergonomic shape of the pocket tool can be supported by the spring-movability of the functional elements.
A special feature for controlling and improving the holding forces of swingable functional elements is shown in FIG. 2 . FIG. 2 shows talon ( 30 ) of blade ( 27 ) which is swingable around axle ( 29 ), as well as the corresponding end area of spring ( 28 ). In the position of functional element ( 24 ) depicted in FIG. 1, blade ( 27 ) rests with its rest stopping area ( 31 ) on rest stopping area ( 32 ) of spring ( 28 ). In the depicted embodiment, a cam ( 33 ) on blade talon ( 30 ) is locked in in a cam depression ( 34 ) on the spring. Thus depending on the size of cam ( 33 ) and the spring force, there results a corresponding holding force in the carrying position, that is, the collapsed position of the blade. Angle ( 35 ), for example between 22° and 37°, determines the force which must be applied in order to leverage cam ( 33 ) out of depression ( 34 ). Correspondingly, angle ( 36 ) must be adjusted to cam depression ( 34 ), for example in a range between 20° and 35°. If then the blade is gripped and the holding force is overcome by the expenditure of force, so that cam ( 33 ) is lifted out of cam depression ( 34 ), movement lane ( 37 ) at the extreme end of the blade talon runs through rest stop ( 32 ). This crank guide effects a clean swing movement of blade ( 27 ) with respect to spring ( 28 ). Finally the cam on the talon, designated in the embodiment with number ( 38 ), arrives in cam depression ( 39 ) on the further spring edge. The height of stop ( 42 ) defines the extended blade position. In this cam/depression pair as well, angle ( 40 ) at cam ( 38 ) on blade talon ( 30 ) and angle ( 41 ) at cam depression ( 39 ) on spring ( 28 ) are adjusted to one another, for example both at about 60°. This results in a corresponding holding force of blade ( 27 ) in the extended position, so that for example an inadvertent collapse of the blade during use is largely ruled out.
The described embodiments serve only for explanation and are not limiting. In particular, there can also be only one holding cam designed on the end of the blade talon, in order to increase the force in one of the end positions. Also cams can be designed on the spring and cam depressions on the blade talon. Also corresponding crank guides of a similarly functioning type are conceivable.
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The invention relates to an especially handy and user-friendly multiple purpose tool for the sport of golf, which is light yet solidly built. Operation of the pitch fork is done with one hand, as well as the removal and insertion of the ball marker. The blade of a new kind of tee hole puncher for hard or frozen ground also serves for cleaning the flutes of the golf club. It is also combined with additional functional elements like nail files, cap openers, and the like. The economically manufacturable tool can also include, for general use, a knife blade, a scissors, a pincer, a tooth pick, a ball point pen, and other tools as the case may be.
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SUMMARY OF THE INVENTION
[0001] The present invention is a sandal having two independent support straps that are joined over the metatarsal region of the foot and tensioned posterior to the strap junction. The two independent straps allow the user to easily modify the lace/webbing geometry and tension across the metatarsal region, around the ankle, and around the heel, for optimal support and comfort. The user can adjust the positon of the junction of the independent support straps to improve comfort over the metatarsal region of the foot and to change the alignment of the strap portion that extends between the user's toes. Tension adjustment is at the rear of the foot, rather than on top of the metatarsals, creating a more aesthetically pleasing strap configuration, knots or hardware are behind the foot to avoid being bumped or pressed into the users skin; and in several embodiments the knots or hardware can be moved to different positions around the user's heel or Achilles to improve comfort.
[0002] A first embodiment of the present invention includes a pre-formed sandal sole having an integrated heel cup, elevated side lace attachment tabs and a thong strap attachment hole through the sole, proximate the location of the gap between the users first and second toes. A first strap extending through the thong strap attachment hole and secured at the bottom of the sole, the free end inserted through a hole formed in the side lace attachment tab on the lateral side of the sandal sole, the strap inserted from the top surface and then immediately routed from the bottom surface, back around the edge portion of the sole and inside of the portion of first strap that extends into the tab and then extended to the rear heel cup area of the sandal sole. A second strap is attached to the first strap just above the attached end of the first strap and proximate the metatarsal region of the Users foot. The second strap inserted through the side lace attachment tab on the medial side of the sandal sole, and likewise the free end is wrapped back to the top surface of the sole, around the running portion of the strap and extended toward the heel cup of the sole. The free ends of the first and second straps are adjustably joined or coupled proximate the heel cup of the sole to comfortably engage the Achilles region of the users' foot. In one embodiment the first strap is secured under the bottom surface of the sole by tying an overhand or surgeons knot and then partially melting the knot to fuse the overlaying strap portions together. The knot and partially melted strap portion is pressed against hard surface to flatten the knot which increases user comfort and improves the wear rate on the knot. In another embodiment an injection molded button is used to secure the first strap to the sole. In one embodiment the second strap is attached to the first strap at the metatarsal region using a knot. In another embodiment, the second strap is doubled over forming a loop, which is wrapped around the first strap, and the free ends of the second strap are extended through the loop forming a clinch around the first strap. In another embodiment, the second strap includes a loop end through which the first strap is inserted. In another embodiment, the second strap is sewn to the first strap proximate the metatarsal region of the users foot. In yet another embodiment , the second strap is secured to the first strap using a hardware piece, such as a, ring, buckle, ladder-lock as known in the art, or modified hardware as developed for a perpendicular attachment application. Some hardware arrangements create a fixed attachment point of the second strap to the first strap, other hardware arrangement create a moveable attachment point between the first strap and the second strap. A moveable attachment point between the first strap and second strap allows the user to move the attachment point and corresponding knot or hardware to a more comfortable position on the foot or to create tension allowing angular adjustment of the toe strap or toe post. In one embodiment the routing of the first and second straps is reversed, the first strap extending from the toe attachment hole to the medial side attachment tab and the second strap extending from the connection with the first strap to the lateral side attachment tab. In another embodiment the first strap connects to the sole proximate the gap between the users' first and second toes but does not extend through the sole to the bottom and is anchored in an intermediate layer of the sole.
[0003] The adjustable junction or coupling of the free ends of the first and second straps can be accomplished in a first embodiment using an overhand or fisherman's knot. This is accomplished by extending the free end of the first strap over the running portion of the second strap and forming an overhand knot of the second strap. Conversely, the second strap is extended over the running portion of the first strap and an overhand knot is formed in the free end of the second strap over the running portion of the first strap. Once the knots are tied the excess is trimmed away and the knots can be moved along the running portion of the opposing strap allowing the user to tension the strap system. In another embodiment the adjustable junction is formed using a ladder lock hardware secured on the running portion of each strap and having the free ends of the opposing strap adjustably inserted through the ladder lock. In another embodiment a cushion cover sleeve or tube is placed over the overlapping portion of the first and second straps and between the ladder lock hardware. In another embodiment the first and second straps are secured using a spring loaded barrel lock or similar mechanism. In another embodiment, an independent heel strap or pad, designed to comfortably engage the rear of the user's foot, is used at the adjustable junction between the first and second straps. The heel strap including hardware pieces which allow the free ends of the first strap and second straps to adjustably attach. In yet another embodiment the adjustable connection is accomplished using a hook and loop fastener such as Velcro R.
[0004] In another embodiment of the present invention the sandal sole has a recess formed to receive a pre-formed toe-post. A toe-post is formed using durable elastomeric material that resists wear when in contact with the ground, but is also supple enough to provide a reasonable level of comfort for the user. The toe-post is designed having a base lug portion that securely engages the recess formed in the bottom of the sole, the post that extends through the sole forms an arcuate structure that is positioned between the users first and second toes. The terminal end of the toe-post includes an aperture or opening where first strap is attached.
[0005] In another embodiment the toe-post is formed using an independent strap section having a sole connection button or lug and a loop or aperture formed in the free for connecting the first strap.
[0006] In one embodiment the first strap and second straps are single straps, laces. In another embodiment the first strap is formed using single strap or lace and the second strap is formed using a single strap or lace double back over itself, essentially forming two parallel straps or laces that extend to the heel portion of the sole. In another embodiment both the first strap and second strap including doubled over or parallel straps that extend toward the heel portion of the sole.
[0007] It contemplated that the straps can be such material as cordage formed from material such as natural fiber, hemp, jute, cotton or leather, or the cordage may be a material such as nylon or polypropylene. It is also contemplated that the straps can be flat material such as leather straps or formed using webbing material.
[0008] These and other features and advantages of the disclosure will be set forth and will become more fully apparent in the detailed description that follows and in the appended claims. The features and advantages may be realized and obtained by the instruments and combinations particularly pointed out in the appended claims. Furthermore, the features and advantages of the disclosure may be learned by the practice of the methods or will be obvious from the description, as set forth hereinafter.
BRIEF DESCRIPTION OF DRAWINGS
[0009] The following description of the embodiments can be understood in light of the Figures, which illustrate specific aspects of the embodiments and are part of the specification. Together with the following description, the Figures demonstrate and explain the principles of the embodiments. In the Figures the physical dimensions of the embodiment may be exaggerated for clarity. The same reference numerals in different drawings represent the same element, and thus their descriptions may be omitted.
[0010] FIG. 1 illustrates a top view of a sandal of the present invention,
[0011] FIG. 2 illustrates a top view of a sandal of the present invention having an independent heel strap,
[0012] FIG. 3 illustrates a top view of a sandal of the present invention having an independent heel strap,
[0013] FIGS. 4 illustrates a top view of a sandal of the present invention having a tubular heel pad,
[0014] FIG. 5 illustrates a top view of a sandal of the present invention having a single rear tensioning point,
[0015] FIG. 6 illustrates a top view of a sandal of the present invention having a single barrel lock for rear tensioning,
[0016] FIG. 7 illustrates a top view of a sandal of the present invention having a hardware attachment and formed using webbing,
[0017] FIG. 8 illustrates a top view of a sandal of the present invention formed using webbing and having a sewn strap attachment point, and,
[0018] FIG. 9 illustrates the sandal fit on the user's foot.
DETAILED DESCRIPTION OF THE INVENTION
[0019] For the purposes of promoting an understanding of the principles in accordance with the disclosure, reference will be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Any alterations and further modifications of the inventive features illustrated herein, and any additional applications of the principles of the disclosure as illustrated herein, which would normally occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the disclosure.
[0020] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In describing and claiming the present disclosure, the following terminology will be used in accordance with definitions set out below. The term sole refers to the base portion of the sandal. The term strap refers to cord, cordage or webbing used for fastening the sandal to the user's foot. The cordage may be, but not limited to, a natural material such as cotton, hemp, jute or leather or a synthetic material such as nylon or polypropylene.
[0021] As used herein, the terms “comprising,” “including,” “containing,” “characterized by,” and the grammatical equivalents thereof are inclusive or open-ended terms that do not exclude additional, unrecited elements or method processes.
[0022] Illustrated in FIGS. 1 through 9 are first embodiment of the present invention or sandal strap arrangement and tensioning system. The sandal platform including a sole portion 100 having a toe strap hole 101 , lateral side lace attachment tab 102 , medial side lace attachment tab 103 and integrated heel cup 104 . The first embodiment of the strap arrangement 200 of the present invention includes a first strap portion 201 inserted through the toe strap hole 101 and secured on the bottom surface of the sandal sole 100 . The free end of first strap 201 extends from the toe strap hole 101 to the lateral side lace attachment tab 102 and is inserted into hole 1021 , the free end is immediately reversed around the edge of sole 100 and wrapped behind the running potion just prior to the entry point of hole 1021 and extended toward the heel cup 104 at the rear of sole 100 . The second strap 202 is attached to first strap 201 above toe hole 101 and proximate the metatarsal region of the user's foot forming attachment point 203 . In one embodiment attachment point 203 is movable or sliding, in another embodiment attachment point 203 is fixed using knots, sewing or hardware. The free end of the second strap portion 202 is extended toward the medial side attachment tab 103 and inserted through hole 1031 . The free end is reversed around the edge of sole 100 and around the running portion of the second strap 202 and extended to the rear of sole 100 proximate the heel cup 104 . The free ends of the first strap 201 and the second strap 202 are secured together in an adjustable attachment 204 configuration proximate the Achilles region of the user's foot. As shown in FIG. 1 the adjustable attachment configuration 204 is formed using an overlapping fisherman's knot formed using the free ends of the first strap 201 and the second strap 202 .
[0023] Shown in FIGS. 2 and 3 includes an independent toe post 110 attached through a recess formed proximate the toe strap attachment hole 101 . A lacing aperture is formed in the end of toe post 110 wherein providing an attachment point for the first strap portion 201 . An independent heel strap portion 220 is shown detached in FIG. 1 and attached in FIG. 2 . Heel strap portion includes tensioning hardware 221 and 222 where the free ends of the first strap 201 and second straps 202 are laced. In this embodiment the user can adjust the position of the adjustable attachment 204 by tensioning or loosening the straps 201 and 200 extended through hardware 221 and 222 . This allows the user's having different bone structure or size to move hardware 221 and 222 or adjustable attachment 204 into a more comfortable location on the heel or away from any boney protuberances. FIG. 3 including a pull tab 224 attached to the free ends of the first strap 201 and the second strap 202 .
[0024] In one embodiment, shown in FIG. 4 the overlap formed between the first strap 201 and the second strap 202 in covered using a silicon tube or pad 230 to protect the user's Achilles area. Ladder lock hardware 240 may be used for strap tension adjustment.
[0025] FIGS. 5 and 6 show embodiments including a single point adjustable attachment 204 including a ladder lock hardware 240 and barrel lock assembly 250 as shown in FIG. 6 .
[0026] FIGS. 7 and 8 show an embodiment using substantially flat webbing to form straps 201 and 202 . FIG. 7 includes hardware 2031 to form sliding attachment point 203 and FIG. 8 shows the attachment point 203 formed by sewing second strap 202 to the first strap portion 201 . Tension may be adjusted using hook and loop fastener 260 .
[0027] FIG. 9 is one embodiment of the present invention ( FIGS. 2 and 3 ) demonstrating fit on a user's foot 500 . Sole 100 including a toe strap attachment hole 101 , a medial side attachment tab 102 and a heel cup 104 . The first strap 201 is attached to sole 100 at point 101 and extends between the first toe 507 and the second toe (not shown) toward metatarsal portion 506 of the user's foot 500 . The first strap 201 is attached to the sole at the lateral side attachment tab 103 and extended toward the heel cup 104 . The second strap 202 is attached to the first strap 201 at attachment point 203 and then extended to, and laced through, medial side attachment tab 102 . The free end of the second strap 202 is attached to independent heel strap piece 220 using hardware 221 . The free end of the first strap is attached to independent heel strap 220 using hardware 222 . Once in place the fit and location of heel strap 220 , and hardware 221 and 222 , can be adjusted in relationship to the user's Achilles 504 and ankle bone 503 for improved comfort.
[0028] It is to be understood that the above mentioned arrangements are only illustrative of the application of the principles of the present disclosure. Numerous modifications or alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present disclosure and the appended claims are intended to cover such modifications and arrangements. Thus, while the present disclosure has been shown in the drawings and described above with particularity and detail, it will be apparent to those of ordinary skill in the art that numerous modifications, including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.
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A sandal having two independent support straps that are joined over the metatarsal region of the foot and tensioned, over the top of the foot and around the ankle of the user, posterior to the connection point.
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This is a continuation of application Ser. No. 435,842, filed Jan. 23, 1974, now abandoned.
BACKGROUND OF INVENTION
1. Field of Invention
GAMMA-Piperidino-butyrophenones; central depressant, neuroleptic compounds.
2. Prior Art
A number of ketones of the general formula ##STR1## wherein R 3 and R 4 are widely different groups, have been made and tested.
Janssen (Cavallito; "Structure-Activity Relationships I", page 37) has stated that one of the groups R 3 and R 4 must be aromatic and that only one may be hydrogen if the ketone is to be an antipsychotic.
For comparison with the compounds of the present invention, we have used two clinically-established piperidino ketones, namely: Haloperidol, wherein ##STR2## AND Methylperon, wherein R 3 ═ H and R 4 ═ CH 3 .
Several compounds having the above-mentioned general formula have also been described in the literature as having, for instance, tranquilizing, central blocking, analgetic, antipyretic, and antiphlogistic properties.
In that context, for instance, compounds are described wherein:
R 3 ═ oh or acyloxy and R 4 ═ lower alkyl. (See Brit. pat. 1,131,534; Jap. pat. appl. 4,718,877.)
However, the established clinically-useful compounds of the prior art have pronounced shortcomings and side-effects, and there is a clear demand for more specific and advantageous compounds in this activity and utility area, especially as neuroleptics (anti-psychotics). The fulfillment of this demand is one of the objects of the present invention, as further elucidated hereinafter.
SUMMARY OF THE INVENTION
This invention relates to novel basic ketones, a process for their preparation, pharmaceutical compositions thereof, and method of treating therewith.
The compounds provided by the present invention are selected from the group consisting of (a) basic ketones having the general formula ##STR3## wherein R 1 and R 2 each represents a straight or branched alkyl group having one to five carbon atoms, inclusive, and
B. ACID ADDITION SALTS THEREOF
These novel gamma-piperidino-butyrophenones have valuable pharmacological properties, especially central depressant effects, which makes them useful as neuroleptics (i.e., antipsychotically active substances).
OBJECTS
It is an object of the present invention to provide novel gamma-(4-lower-alkyl-4-lower-alkoxypiperidino)-p-fluorobutyrophenones and acid addition salts thereof, which are useful as central depressants, e.g., neuroleptics (antipsychotics), a process for producing the same, pharmaceutical compositions thereof, and a method of treating psychotic states therewith. Additional objects will become apparent hereinafter, and still others will be obvious to one skilled in the art.
PREPARATION:
According to the present invention, the novel ketones of general Formula I are prepared: a. by reacting a 4-alkyl-4-alkoxypiperidine of the general formula ##STR4## with a butyrophenone of the formula ##STR5## wherein X is halogen (Cl, Br, I) or a sulfonic acid radical ##STR6## Other processes may also be employed, e.g., inter alia: b. 1. a ketoamide of the formula ##STR7## is reduced to the alcohol ##STR8## which is oxidized to I. b. 2. a ketoamide according to b 1. with the keto group protected ##STR9## wherein R 3 is a methylene chain, possibly substituted with one or more methyl groups, e.g., ##STR10## is reduced to ##STR11## whereupon this compound is hydrolyzed to I. b. 3. p-Fluorobenzaldehyde is reacted with a metalorganic compound of the general formula ##STR12## wherein Y is --Mg hal (Cl, Br, I) or Li, whereupon the obtained alcohol II is oxidized to I. c. 1. a metalorganic compound of the formula ##STR13## wherein Y is Mg hal (Cl, Br, I) or Li is reacted with a piperidinoderivative of the formula ##STR14## wherein Z is a carboxylic group or a derivative thereof (nitrile, acid halide, or ester), whereupon the obtained product is hydrolyzed to I. c. 2. the compound ##STR15## is reacted with a metalorganic compound of the formula ##STR16## wherein Y and Z have the meanings hereinbefore defined, whereupon the obtained compound is hydrolyzed to I.
d. a compound of the formula ##STR17## in which Z is as hereinbefore defined, is hydrolyzed and decarboxylated to I. e. in a compound of the general formula ##STR18## the amino group is converted to F by standard procedure for such replacement.
In the foregoing reactions a - e, R 1 and R 2 have the meanings hereinbefore defined (in Formula I). Of the described synthetic methods, method a) is the method of choice because the starting products are inexpensive and readily manufactured and because the synthesis can be performed with good yields to give pure end products.
The starting 4-methyl-4-methoxypiperidine is synthesized according to Manus et al., J. Med. Chem. 8, 766 (1965). The other 4-lower-alkyl-4-loweralkoxypiperidine starting materials are prepared in exactly the same manner from the appropriate starting materials, which are known.
The selected substituted piperidine is reacted with the selected p-fluoro-gamma-halogen-butyrophenone, preferably in a suitable non-polar solvent, e.g., benzene, toluene, or xylene. If a polar solvent is employed, dimethylformamide is preferred. The reaction is preferably performed using an excess of the piperidine or in the presence of an acid binding agent, e.g., triethylamine or potassium carbonate. The reaction can additionally be carried out in the presence of potassium iodide, whereby undesired side reactions are avoided. After the reaction is complete, the product is generally treated with water or aqueous alkali and the thusformed basic ketone is extracted with ether. From the dried ether-solution, the hydrochlorides are precipitated with hydrochloric acid. The hydrochlorides are readily recrystallized from, e.g., ethanol-ether, acetone-ether, methylethylketone, ethylacetate, and like solvents or solvent mixtures.
After completion of other reactions which may also be employed for their production, isolation of the basic ketone is carried out in the same manner.
The novel compounds of the invention are thus usually obtained as an acid addition salt thereof, e.g., their hydrochloride. Other pharmaceutically acceptable addition salts can be prepared from the hydrochloride via the base, or directly from the base.
The compounds of the invention are most conveniently employed as pharmaceuticals in the form of water-soluble, non-toxic acid-addition salts. Although the non-toxic salts are preferred, any salt may be prepared for use as a chemical intermediate, as in the preparation of another but non-toxic acid-addition salt. The free basic compounds of Formula I may be conveniently converted to their acid addition salts by reaction of the free base with the selected acid, preferably in the presence of an organic solvent inert to the reactants and reaction products under the conditions of the reaction. The acids which can be used to prepare the preferred non-toxic acid addition salts are those which produce, when combined with the free bases, salts the anions of which are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions. Appropriate acid-addition salts are those derived from mineral acids such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, methanesulfonic, isothionic, sulfamic, phosphoric, and organic acids such as acetic, citric, lactic, fumaric, propionic, maleic, oxalic, benzoic, and tartaric. The preferred acid addition salt is the hydrochloride.
The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and the selected acid in an organic solvent, in which case the salt ordinarily separates directly or can be conventionally recovered by concentration of the solution or the like. Conversely the free base may be obtained conventionally by neutralizing the acid-addition salt with an appropriate base such as ammonia, ammonium hydroxide, sodium carbonate or the like, extracting the liberated base with a suitable solvent, illustratively ethyl acetate or benzene, drying the extract, and evaporating to dryness of fractionally distilling, or in other conventional manner.
DETAILED DESCRIPTION OF THE INVENTION
The following preparations and examples are given by way of illustration only, and are not to be construed as limiting: Preparation of 4-alkyl-4-alkoxy-piperidines of the formula ##STR19##
Preparation A
wherein R 1 and R 2 are alkyl with 1-5 carbon atoms.
The piperidines used in ex. 1-16 are prepared according to Manus et al. J. Med. Chem. 8, 766 (1965).
1-Benzyl-4-piperidone is treated with alkylmagnesiumbromide (R 1 MgBr) or alkylithium (R 1 Li) and the 1-Benzyl-4-alkyl(R 1 )-4-hydroxy piperidine formed is alkylated in known manner, whereupon the benzylgroup is removed by catalytic reduction.
Preparation B
wherein R 1 is alkyl with 1-5 carbon atoms and R 2 alkyl with 3-5 carbon atoms. The following modification of the methods is preferred.
Preparation of 4-methyl-4-butoxy-piperidine (No. 4 in the table)
a. 10-Benzyl-1.6-dioxa-11-aza-spirododecane
1-Benzyl-4-piperidino and butane-1.4-diol are reacted in chloroform, saturated with HCl to produce compound a). B.p. 110°-115° C/0.01 mm Hg. M.p. 51°-53° C.
b. 4-[(-Benzyl-4-methyl-4-piperidyl)oxy]butanol
Compound a) is added to methylmagnesiumiodide to produce compound b). B.p. 120°-127° C/0.01 mm Hg.
c. 4-[(1-Benzyl-4-methyl-4-piperidyl)oxi]butylchloride
Compound b) is chlorinated by thionylchloride to produce compound c). B.p. 118°-120° C/0.01-2 mm Hg. The melting point of the hydrochloride is 173°-175° C.
d. 1-Benzyl-4-methyl-4-butoxypiperidine
Compound c) is reduced with lithium aluminum hydride in tetrahydrofuran to compound produce d). B.p. 88°-90° C/0.01 mm Hg.
e. 4-Methyl-4-butoxypiperidine
The benzylgroup in 1-Benzyl-4-methyl-4-butoxy-piperidine is removed in known manner as described in the literature.
______________________________________Summary of starting 4-alkyl-4-alkoxypiperidines ##STR20## M.p. ° C (B.p. ° C)NO. R.sub.1 R.sub.2 hydrochloride mm Hg______________________________________1 CH.sub.3 CH.sub.3 180-1812 SAME AS IN EXAMPLES 118 62-63/10 2-14, Following.3 " 63-65/114 " 78-81/10-115 " 146-1476 " 117 77-78/107 " 81-84/108 " 128-1309 " 131-13210 " 194-19611 " 93-95/11-1212 " 123-12513 " 126-129/14-1514 " 99-103/12-14______________________________________
Example 1
gamma-(4-methyl-4-methoxy-piperidino)-p-fluorobutyrophenone
A solution of 20.1 g (0.1 m) of gamma-chloro-p-fluorobutyrophenone, 30 g (0.2 m) of 4-methyl-4-methoxy-piperidine and 0.1 g. of potassium iodide in 150 ml of toluene is heated in a glass autoclave for 15 hours at 100°-110° C. The KI and the 4-methyl-4-methoxy-piperidine hydrochloride formed in the reaction are separated by filtration and the solvent removed from the filtrate by evaporation under a vacuum on a steam bath. The obtained base is dissolved in ether and the hydrochloride is precipitated with alcoholic HCl. The reaction product is purified by recrystallization from ethanol-ether. Yield 22 g. Melting point 182° C.
EXAMPLES 2-14
Proceeding generally as described in Example 1, further compounds according to the invention enumerated in the following table are prepared.
__________________________________________________________________________ ##STR21## B.p. of theNO. R.sub.1 R.sub.2 M.p. ° C base ° C/mm Hg__________________________________________________________________________2 CH.sub.3 CH.sub.2 l CH.sub.3 163-1643 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 158-1594 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 167-168 124-130/0.015 CH.sub.2 CH.sub.3 CH.sub.3 2006 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 176-177 130-135/0.017 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.3 167-1698 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.3 174-1759 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 149-15210 ##STR22## CH.sub.3 190-19111 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.3 175-17612 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 168-17113 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 136-13814 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 -- 128-132/ 0.005-0.01__________________________________________________________________________
EXAMPLE 15
Preparation of gamma-(4-ethyl-4-ethoxypiperidino)-p-fluoro-4-butyrophenone hydrochloride
To a Grignard solution prepared from 70.0 g (0.4 m) of p-fluorobromo-benzene and 9.8 g (0.4 m) of magnesium in 500 mls. of ether, 22.4 g (0.1 m) of gamma-(4-ethyl-4-ethoxy-piperidino) butyronitrile dissolved in 200 mls. of ether was added dropwise. After the addition was complete, the reaction mixture was refluxed for seven hours, whereupon water and finally a saturated ammonium chloride solution was added for decomposition of the reaction mixture. The ether phase was separated and evaporated in vacuo. To the residue 500 mls. of 5 N hydrochloric acid was added, and the mixture then refluxed for twenty hours. After cooling, an excess of concentrated ammonia was added and the reaction mixture was extracted with ether. The ether solution was evaporated in vacuo and the residue was distilled. 26 g of the compound was obtained at 130°-135° C/0.01 mms. of Hg.
The hydrochloride was prepared in the manner of Example 1. Melting point 176°-177° C. The hydrobromide is prepared in the same manner, using hydrogen bromide in place of hydrogen chloride. The citrate is prepared using citric acid.
EXAMPLE 16
Preparation of gamma-(4-isopropyl-4-methoxy-piperidino)-p-fluorobutyrophenone hydrochloride
To a mixture of 21.5 g (0.1 m) of gamma-(p-fluorophenyl)-gamma-oxo-butyric acid chloride and 15.7 (0.1 m) of 4-isopropyl-4-methoxy-piperidine in 200 ml of benzene, 15.5 ml (0.11 m) of triethylamine is added. The triethylamine hydrochloride formed is filtered off and the solvent removed by evaporation under vacuum on a steambath. The residue is dissolved in dry ether and added dropwise to a suspension of 15 g of lithium aluminum hydride in ether. The reaction mixture is refluxed for two hours and the obtained mixture decomposed with water. The precipitate is filtered off and the ether solution evaporated. The residue, which consists of the alcohol corresponding to the butyrophenone, is oxidized according to Oppenauer with 60 g of aluminum-isopropylate in 500 ml of dry acetone. The reaction mixture is refluxed for 12 hours, cooled, and decomposed with water. After centrifugation, the solution is evaporated to dryness, whereafter the residue dissolved in ether and the hydrochloride precipitated with alcoholic hydrochloric acid. After recrystallization, the hydrochloride melts at 190°-192° C. Yield 19 g. The tartrate is prepared using tartaric acid.
EXAMPLE 17
Preparation of gamma-(4-methyl-4-butoxypiperidino)-p-fluorobutyrophenone hydrochloride
3.1 g (0.127 m) of sodium is granulated in 200 ml of boiling toluene. After cooling, 26.5 g (0.126 m) of ethyl beta-(p-fluorophenyl)-beta-oxopropionate is added drop by drop and then the solution is stirred for one-half hour at 50° C. The yellow solution which forms is cooled and 30 g (0.30 m) of beta-(4-methyl-4-butoxy-piperidino)-ethyl-chloride is added rapidly thereto. The reaction mixture is stirred for four hours at 60° C and for five hours at 85° C. After evaporation on a steam bath and addition of 500 ml of 2.5-N sulphonic acid, the solution is refluxed for sixteen hours, cooled, alkalized with an excess of potassium carbonate, and extracted with ether. The solution is evaporated and the residue distilled at 124-130/0.01 mm Hg. Yield 19.5 g. The hydrochloride has the m.p. 167°-169° C.
PHARMACOLOGY, COMPOSITIONS, AND USE
Even if it should be possible to predict some kind of activity in butyrophenones having the foregoing formula "A", it has been and still is accepted in the art that it is necessary to use a series of established pharmacological tests in order to establish the "pharmacological profile" of a neuroleptically active compound. For that reason we have carried out a series of tests, which are especially suited for the evaluation of new piperidinobutyrophenones, but which are also useful for comparison of new compounds with other compounds having the same field of application.
In the following series of tests, we have compared the new ketones of the present invention with the following:
Haloperidol -- formula hereinbefore mentioned (R 3 ═ OH; R 4 ═ p-chlorophenyl)
Methylperon -- formula hereinbefore mentioned (R 3 ═ H; R 4 ═ CH 3 ) chlorpromazine ##STR23## in each of the following established standard tests: 1. Inhibition of aggressive behaviour in male mice.
2. Inhibition of climbing in mice (inhibition of exploratory behaviour).
3. Amphetamine antagonism in rats (antipsychotic effect).
4. Cataleptogenic effect in rats (measure of the extrapyramidal side effects).
5. Inhibition of conditioned behaviour in rats. These tests were in accord with published test procedures and protocols, for instance:
1. Valzelli, L. in Aggressive Behaviour, Eds. Garattini and Sigg, p. 70 (1969)
2. Sandberg, S. in Arzneimittelforschung, 9, 203 (1958)
3. Randrup, A. et al. in Acta Pharmacol. (Kph), 20, 145 (1963)
4. Stille, G. in Schweiz. Med. Wochenschrift, 99, 1645 (1969)
5. Jacobsen and Sonne in Acta Pharmacol. & Toxicol., 11, pp. 135-147 (1955)
On comparison of these test results from the Table, it is possible to separate the compounds into three groups, all of which show a pattern of neuroleptic activity, but which are in fact characterized by importantly different "pharmacological profiles". See the Table and FIG. 1.
__________________________________________________________________________ 1. 2. 3. 4. 5. Inhibition of Inhibition of Amphetamine Cataleptogenic Inhibition ofTEST agression, exploratory antagonism, effect, conditionedCompound mice behaviour, mice rats rats avoidance responseof Example ED50 mg/kg s.c. ED50 mg/kg s.c. ED50 mg/kg s.c. ED50 mg/kg s.c. rats ED50 mg/kg__________________________________________________________________________ s.c.1 0.20 0.65 0.35 10.0 0.62 0.70 1.00 0.10 6.0 1.33 0.35 1.00 0.20 7.0 0.54 0.35 2.00 0.75 20.0 2.55 0.70 0.70 0.10 10.0 1.56 0.08 1.40 0.10 5.0 1.57 0.70 1.20 0.35 6.08 0.50 3.10 1.00 6.2 5.510 0.15 1.10 0.10 5.0 1.212 0.35 1.60 0.07 3.0 5.013 0.50 1.30 0.35 6.8Haloperidol 0.80 1.30 0.03 0.27 0.15Methylperon 2.20 2.00 3.50 12.00 6.80Chlorpromazine 0.40 0.75 1.20 4.50 4.50__________________________________________________________________________
Group I Example: Haloperidol
The profile is characteristic of low-dosed specific neuroleptics. Their great disadvantage is their extrapyramidal side effects [demonstrated by a pronounced cataleptogenic effect in rats (Table-Test No. 4)].
Group II Example: Chloropromazine, Methylperon
Their profiles are characteristic of high-dosed unspecifically sedative neuroleptics. Methylperon is not very active in Tests 1 and 3. Chlorpromazine is not very active in Test 3.
Group III Example: New ketones with Formula I
These compounds have considerably lower extrapyramidal effect than compounds from Group I. The new compounds are specifically antiaggressive (Table-Test No. 1) anti-psychotic, and have an anxiolytic effect (Table-Test No. 3). The cardiovascular effects are insignificant.
Up to the present time, such favorable neuroleptic profiles have not been described for any compound in this area.
The antipsychotic effect as shown in Test No. 3 is further confirmed by the blocking of apomorphine emesis in dogs. Ref: Janssen, P. A. J. et al. Arzneimittelforschung, 1, 1196 (1965) Furthermore, the compounds have a pronounced serotonine inhibiting effect, Ref: Alps, J. et al. Br. J. Pharmac. 44, 52 (1972) and a strong anti-inflammatory effect (measured with carrageenin-induced edema in rats). Ref: Takashima, T. et al. Arzneimittelforschung 22, 711 (1972) Their toxicity is rather low, 200 - 300 mg/kg. In comparison, the toxicity for haloperidol is 70 mg/kg and for methylperon is 280 mg/kg (all toxicities being performed subcutaneously on mice).
In view of their unusual properties, the novel compounds of the present invention are also suited for treatment of mental disturbances in humans, for instance schizophrenic, manic, anxious and agony states. Their general properties as tranquilizers also make the new compounds suitable for veterinary applications. the present invention has been evidenced by tests in lower animals and representative of these are reported herein.
In their most advantageous form, the compositions of the present invention will contain a non-toxic pharmaceutical carrier in addition to the active ingredient. Exemplary carriers are: solids-lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium phosphate, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia, or the like; liquids -- peanut oil, sesame oil, olive oil, water, or the like. The active agents of the invention can be most conveniently administered in such compositions containing about 0.01 to 67 percent, preferably 0.04 to 12.15 percent, by weight of the active ingredient. Such formulations are illustrated in U.S. Pat. No. 3,402,244.
A wide variety of pharmaceutical forms suitable for many modes of administration and dosages may be employed. For oral administration the active ingredient and pharmaceutical carrier may, for example, take the form of a granule, pill, tablet, lozenge, or liquid suspension; for parenteral administration, the composition may be a sterile solution; and for rectal administration, a suppository.
The method of using the compounds of the present invention comprises internally administering a compound of Formula I, usually in the form of a non-toxic, pharmacologically acceptable acid-addition salt, and preferably admixed with a pharmaceutical carrier, for example, in the form of any of the above-mentioned compositions, or filled into a capsule, to alleviate psychotic conditions and symptoms thereof in a living animal body. The compounds and their non-toxic salts, especially the hydrochlorides, may be advantageously employed in amounts approximating those employed for any of the three clinically-useful compounds used for comparative testing as reported herein. Illustratively, they may be used in an amount of from about 0.1 to 200 milligrams per unit dose, preferably from about 2.5 to 50 milligrams for an oral dose, while parenteral dosages are usually less and ordinarily about one-half the oral dose so that the preferred parenteral unit dosage will be about one to 25 milligrams. The unit dose is preferably given a suitable number of times daily so that the daily dose may vary from 0.3 to 600 milligrams. Preferred daily dosages will vary from about 7.5 to 150 milligrams (oral) to about three to 75 milligrams (parenteral). However, these compounds are subject to wide variations in optimum daily and unit dosages, and the invention should therefore not be limited by the exact ranges stated. The exact dosage, both unit and daily, will of course have to be determined according to established medical principles. In addition, the active ingredients of the present invention or compositions containing the same may either be administered together with or include other physiologically active materials and/or medicaments, e.g., buffering agents, antacids, sedatives, stimulants, anticholinergics, analgesics, or the like.
The following formulations are representative for all of the pharmacologically active compounds of the invention, but have been particularly designed to embody as active ingredient gamma-(4-methyl or ethyl-4-methoxy or ethoxypiperidino)-p-fluoro-butyrophenone, and especially a pharmacologically acceptable salt thereof, for example its tartrate, hydrochloride, hydrobromide, fumarate, or like pharmacologically acceptable salt.
For oral use the compounds are usually administered as tablets, although other forms may be employed. Tablets may be made by compounding one of the compounds of the invention, preferably as an acid-addition salt, with customary carriers and adjuvants, e.g., talc, magnesium stearate, starch, lactose, gelatine, gums, or the like.
The following is a suitable tablet formulation:
0.1 - 1g of gamma-(4-ethyl-4-ethoxypiperidino)-p-fluorobutyrophenone hydrochloride
9 g of potato starch
1 g of colloidal silica
2 g of talc
0.2 g of magnesium stearate
2.5 g of 5% aqueous solution of gelatine.
This mixture is made up into 100 tablets, containing 1-10 mg of the active component.
The hydrochlorides or other acid addition salts are readily soluble in water, which makes them particularly useful, since it enables the new compounds to be administered parenterally by injection.
For injection, the following solution is suitable:
5 - 500 mg of gamma-(4-methyl-4-methoxypiperidino)-p-fluoro-butyrophenone hydrochloride dissolved in 100 ml of water containing 0.6 g of NaCl. The resulting solution is filled into ampoules; each contain 2 ml of solution and thus 0.1-10 mg of the active compound. They are sterilized in the usual manner.
The pharmacologically active compounds provided by the present invention may also be administered successfully by embodying an effective quantity thereof in an injectable emulsion or suspension for injection into an animal body, in oral powders, suspension or syrups, and in other acceptable dosage forms.
Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above and preferably twenty-five, fifty or one-hundred milligrams or even higher, depending of course upon the emergency of the situation and the particular result desired. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to established medical principles and under the supervision of the physician or veterinarian involved.
Various modifications in the compounds, compositions, and methods of the invention will be apparent to one skilled in the art and may be made without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.
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Novel gamma-(4-lower-alkyl-4-lower-alkoxypiperidino)-p-fluorobutyrophenones and acid addition salts thereof, useful as central depressants, e.g., neuroleptics (antipsychotics). Pharmaceutical compositions thereof and method of treating therewith.
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FIELD OF THE INVENTION
[0001] The invention relates to a method of identifying biologically active compounds, libraries of compounds.
BACKGROUND
[0002] Small molecules involved in molecular interactions with a therapeutic target, be it enzyme or receptor, are often described in terms of binding elements or pharmacophoric groups which directly interact with the target, and non-binding components which form the framework of the bioactive molecule. In the case of peptide ligands or substrates for instance, usually a number of amino add side chains form direct interactions with their receptor or enzyme, whereas specific folds of the peptide backbone (and other amino acid residues) provide the structure or scaffold that controls the relative positioning of these side chains. In other words, the three dimensional structure of the peptide serves to present specific side chains in the required fashion suitable for binding to a therapeutic target. The problem is that such models do not allow for rapid identification of drug candidates owing to the necessity to synthesize an enormous amount of compounds to identify potential active compounds.
[0003] A pharmacophoric group in the context of these libraries is an appended group or substituent, or part thereof, which imparts pharmacological activity to the molecule.
[0004] Molecular diversity could be considered as consisting of diversity in pharmacophoric group combinations (diversity in substituents) and diversity in the way these pharmacophoric groups are presented (diversity in shape). Libraries of compounds in which either diversity of substituents, or diversity of shape, or both of these parameters are varied systematically are said to scan molecular diversity.
[0005] Carbohydrate scaffolds provide a unique opportunity to create libraries of structurally diverse molecules, by varying the pharmacophoric groups, the scaffold and the positions of attachment of the pharmacophoric groups in a systematic manner. Such diversity libraries allow the rapid identification of minimal components or fragments containing at least two pharmacophoric groups required for an interaction with a biological target. These fragments can be further optimized to provide potent molecules for drug design. Therefore these types of carbohydrate libraries provide an excellent basis for scanning molecular diversity.
[0006] In previous applications (WO2004014929 and WO2003082846) we demonstrated that arrays of novel compounds could be synthesized in a combinatorial manner. The libraries of molecules described in these inventions were synthesized in a manner such that the position, orientation and chemical characteristics of pharmacophoric groups around a range of chemical scaffolds, could be modified and/or controlled. These applications demonstrate the synthesis and biological activity of a number of new chemical entities.
[0007] Many drug discovery strategies fall owing to lack of knowledge of the bioactive conformation of, or the inability to successfully mimic the bioactive conformation of the natural ligand for a receptor. Libraries of compounds of the present invention allow for the systematic “scanning” of conformational space to identify the bioactive conformation of the target.
[0008] Typically in the prior art, libraries based on molecular diversity are generated in a random rather than a systematic manner. This type of random approach requires large number of compounds to be included in the library to scan for molecular diversity. Further, this approach may also result in gaps in the model because of not effectively accessing all available molecular space.
[0009] Therefore, one of the problems in the prior art is the necessity to synthesize an enormous amount of compounds to identify potential active compounds. Attempts have been made to develop peptidomimetics using sugar scaffolds by Sofia et al. ( Bioorganic & Medicinal Chemistry Letters (2003) 13, 2185-2189). Sofia describes the synthesis of monosaccharide scaffolds, specifically containing a carboxylic acid group, a masked amino group (N 3 ) and a hydroxyl group as substitution points on the scaffold, with the two remaining hydroxyl groups being converted to their methyl ethers. Sofia teaches a specific subset of scaffolds not encompassed by the present invention and does not contemplate methods to simplify the optimization of pharmacophoric groups.
[0010] Therefore there remains a need to provide a method of effectively scanning libraries designed from compounds with a wider range of different pharmacophoric groups.
[0011] The present invention is directed to a method of drug design utilizing iterative scanning libraries, resulting in surprisingly efficient identification of drug candidates, starting from a selected number of pharmacophores (e.g., two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library.
[0012] The invention can provide a new method for the rapid identification of active molecules.
[0013] In an embodiment, and to demonstrate the versatility of our invention, one of the G-protein coupled receptors (GPCR's) was chosen as a target the somatostatin receptor (SST receptor). The tetradecapeptide somatostatin is widely distributed in the endocrine and exocrine system, where it has an essential role in regulating hormone secretion [1-3]. Five different subtypes have been identified to date (SST1-5), which are expressed in varying ratios throughout different tissues in the body. Somatostatin receptors are also expressed in tumours and peptide analogues of somatostatin affecting mainly SST5, such as octreotide, lanreotide, vapreotide and seglitide [4-7] have antiproliferative effects. They are used clinically for the treatment of hormone-producing pituitary, pancreatic, and intestinal tumours. SST5 is also implicated in angiogenesis, opening up the possibility of developing anti-angiogenic drugs that act on the SST5 receptor, for example for the use in oncology. The “core sequence” in somatostatin responsible for its biological activity is Phe-Trp-Lys (FWK), representing a motif of two aromatic groups and a positive charge, which is found in almost all SST receptor active compounds.
[0014] It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.
SUMMARY OF THE INVENTION
[0015] In one form, the invention provides a method of identifying biologically active compounds comprising:
(a) designing a first library of compounds of formula 1 to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; b) assaying the first library of compounds in one or more biological assay(s); and (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library;
such that the/each component of the first and second library is a compound of formula 1:
[0000]
[0000] wherein the ring may be of any configuration;
Z is sulphur, oxygen, CH 2 , C(O), C(O)NR A , NH, NR A or hydrogen, in the case where Z is hydrogen then R 1 is not present, R A is selected from the set defined for R 1 to R 5 , or wherein Z and R1 together form a heterocycle,
X is oxygen or nitrogen providing that at least one X of Formula I is nitrogen, X may also combine independently with one of R 1 to R 5 to form an azide.
R 1 to R 5 are independently selected from the following nor groups H, methyl and acetyl, and pharmacophoric groups, R 1 to R 5 are independently selected from the group which includes but is not limited to C 2 to C 20 alkyl or acyl excluding acetyl; C 2 to C 20 alkenyl, all heteroalkyl; C 2 to C 20 aryl, heteroaryl, arylalkyl or heteroarylalkyl, which is optionally substituted, and can be branched or linear,
or wherein X and the corresponding R moiety, R 2 to R 5 respectively, combine to for a heterocycle.
[0019] In another form, the invention comprises biologically active compounds when identified by the method described above.
[0020] In a preferred embodiment, the invention relates to said method wherein in the first library, three of the substituents R 1 -R 5 are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl.
[0021] In a preferred embodiment, the invention relates to said first method wherein in the first library, two of the substituents R 1 -R 5 are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl.
[0022] In a preferred embodiment, the invention relates to said first method wherein Z is sulphur or oxygen;
[0023] In a preferred embodiment, the invention relates to said first method wherein at least one of the pharmacophoric groups is selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl or acyl
[0024] In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula 1 wherein in the first library, three of the non-pharmacophoric groups R 1 -R 5 are hydrogen or methyl or acetyl when used according to said first method.
[0025] In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula 1 wherein in the second library, two of the non-pharmacophoric groups R 1 -R 5 are hydrogen or methyl or acetyl when used according to said first method.
[0026] In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4
[0000]
[0027] In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco- or galacto- or allo-configuration.
[0028] In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 wherein the/each compound is of the galacto-configuration.
[0029] In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco-configuration.
[0030] In a preferred embodiment, the invention relates to said first method wherein each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the allo-configuration.
[0031] In a preferred embodiment, the invention relates to said first method wherein designing the library comprises molecular modeling to assess molecular diversity.
[0032] In a preferred embodiment, the invention rebates to said first method wherein R 1 to R 5 optional substituents include OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.
[0033] The term “halogen” denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
[0034] The term “alkyl” used either alone or in compound words such as “optionally substituted alkyl”, “optionally substituted cycloalkyl”, “arylalkyl” or “heteroarylalkyl”, denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2trimethylpropyl, 1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3 or 4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2 pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
[0035] The term “alkylene” used either alone or in compound words such as “optionally substituted alkylenyl” denotes the same groups as “alkyl” defined above except that an additional hydrogen has been removed to form a divalent radical. It will be understood that the optional substituent may be attached to or form part of the alkylene chain.
[0036] The term “alkenyl” used either alone or in compound words such as “optionally substituted alkenyl” denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as defined above, preferably C2-6 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1 decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3 cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
[0037] The term “alkynyl” used either alone or in compound words, such as “optionally substituted alkynyl” denotes groups formed from straight chain, branched, or mono- or poly- or cyclic alkynes, preferably C 2-6 alkynyl.
[0038] Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-l-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11tridecynyl, 3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like.
[0039] The term “alkoxy” used either alone, or in compound words such as “optionally substituted alkoxy” denotes straight chain or branched alkoxy, preferably C1-7 alkoxy. Examples of alkoxy include methoxy, ethoxy, npropyloxy, isopropyloxy and the different butoxy isomers.
[0040] The term “aryloxy” used either alone or in compound words such as “optionally substituted aryloxy” denotes aromatic, heteroaromatic, arylalkoxy or heteroaryl alkoxy, preferably C6-13 aryloxy. Examples of aryloxy include phenoxy, benzyloxy, 1-napthyloxy, and 2-napthyloxy.
[0041] The term “acyl” used either alone or in compound words such as “optionally substituted acyl” or “heteroarylacyl” denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl. Examples of acyl include carbamoyl; straight chain of branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cycle cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthlpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoy) (e.g. naphthylpropenoyl, napthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl and thienyglyoxyloyl.
[0042] The term “aryl” used either alone or in compound words such as “optionally substituted are”, “arylalkyl” or“heteroaryl” denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetra anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocyclic ring system contains 1 to 4 heteroatoms independently selected from N, O and S and containing up to 9 carbon atoms in the ring.
[0043] The term “heterocycle” used either alone or in compound words as “optionally substituted heterocycle” denotes monocyclic or polycyclic heterocycyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated to 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidin or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, benzimidazoyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.
[0044] In a preferred embodiment, the invention relates to said first method wherein the compounds are synthesized.
[0045] In a preferred embodiment, the invention relates to said first method wherein the biological assays are selected from peptide ligand class of GPCRs.
[0046] In another aspect the invention provides a compound according to formula 1 in which at least one X is nitrogen, and said X is combined with the corresponding R 2 -R 5 to form a heterocycle. The synthesis of the heterocyclic components of the present invention is disclosed in WO 2004/022572.
[0047] In a preferred embodiment, the invention provides a compound according to formula 1 wherein X and R 2 combine to form a heterocycle.
[0048] In a preferred embodiment, the invention provides a compound according to formula 1 wherein the heterocycle is heteroaryl, including triazoles, benzimidazoles, benzimidazolone, benzimidazolothione, imidazole, hydantoine, thiohydantoine and purine.
DETAILED DESCRIPTION OF THE INVENTION
[0049] The embodiments of the invention will be described with reference to the following examples. Where appropriate, the following abbreviations are used.
Ac Acetyl
[0050] DTPM 5-Acyl-1,3-dimethylbarbiturate
Ph Phenyl
[0051] TBDMS t-Butyldimethylsilyl
TBDPS t-Butyldiphenylsilyl
Bn benzyl
Bz benzoyl
Me methyl
DCE 1,2-dichloroethane
DCM dichloromethane, methylene chloride
Tf trifluoromethanesulfonyl
Ts 4-methylphenylsulfonyl, p-toluenesulfonyl
DMF N,N-dimethylformamide
DMAP N,N-dimethylaminopyridine
[0052] α,α-DMT α,α-dimethoxytoluene, benzaldehyde dimethyl acetal
DMSO dimethylsulfoxide
DTT dithiothreitol
DMTST Dimethyl(methylthio)sulphoniumtrifluoro-methanesulphonate
[0053] TBAF tetra-n-butylammonium fluoride
Part A
Preparation of Building Blocks
[0054] In order to fully enable the invention, there is described below methods for the preparation of certain building blocks used in the preparation of the compounds of the invention. The building blocks described are suitable for both solution and solid phase synthesis of the compounds of the invention.
Example A
Synthesis of a 2,4 Dinitrogen Containing Galactopyranoside Building Block
[0055]
Example B
Synthesis of a 3-nitrogen Containing Gulopyranoside Building Block
[0056]
Example C
Synthesis of a 2,6-dinitrogen Substituted Glucopyranoside Building Block
[0057]
Example D
Synthesis of a 2-nitrogen Containing Tallopyranoside Building Block
[0058]
Example E
Synthesis to 3-nitrogen Containing Altropyranoside Building Block
[0059]
Example F
Synthesis 2-nitrogen Containing Glucopyranoside Building Block
[0060]
[0000]
Example G
Synthesis of a 2-nitrogen Containing Allopyranoside Building Block
[0061]
[0062] The Solid Phase Library Synthesis of Sugars is illustrated in Scheme 1.
[0063] The reaction conditions are as follows:
(A) 2P Compound Synthesis: R 1 =R 2 =OMe;
[0064] i) 2-naphthalene methanol, DMTST, DCM; TCA-Wang resin, BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv a. KOtBu, DMF; b. Mel, DMF; v) HF ‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. Mel, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (¼); x) TFA, Et 3 SiH, DCM
(B) 3P Compound Synthesis: R 1 =methyl-2-naphthyl, R 2 =OMe;
i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b, 2-bromomethyl-naphthalene, DMF; v) HF ‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. Mel, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (¼), x) TFA, Et 3 SiH, DCM
(C) 4P Compound Synthesis: R 1 =methyl-2-naphthyl, R 2 =4-chlorobenzyl
i) 2-napthalene methanol, DMTST, DCM; ii) TCA-Wang BF 3 .Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. 2-bromomethyl-naphthalene, DMF; v) HE ‘proton sponge’, AcOH, DMF, 65° C.; vi) a. KOtBu, DMF; b. 4-chlorobenzylbromide, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-β-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (¼); x) TFA, Et 3 SiH, DCM
[0000]
[0000]
[0065] The synthesis of the Allose 2,6N building block is illustrated in Scheme 2. The reaction conditions are as follows:
[0000] i) p-methoxybenzaldehyde dimethylacetal, camphorsulfonic acid, N,N-dimethylformamide (DMF); ii) Tf 2 O, pyridine, dichloromethane (DCM); iii) tetrabutylammonium benzoate, DMF, 55° C.; iv) BH 3 .THF, Bu 2 BOTf, DCM; v) methanesulfonylchloride, pyridine, DCM; vi) sodium azide, DMF, 85° C.; vii) sodium methanolate (NaOMe), methanol; viii) n-butanol, ethylene diamine, reflux; ix) DTPM reagent, methanol; x) benzoic anhydride, pyridine xi) trifluoroacetic acid, triethylsilane, DCM
Designing Libraries
[0066] The design of the libraries is based on the presentation of a positive charge and a crying number of aromatic substituents in different spatial arrangements on a monosaccharide scaffold. Starting with a positive charge and one aromatic displayed on the core scaffold, actives from this first library were elaborated on by further variation and addition of more aromatic substituents to quickly identify highly active molecules.
[0067] The first library of compounds comprises two pharmacophoric groups, known as a 2P library, in particular, one containing an aromatic and a positive charge. The library was designed such that each molecule presents two pharmacophoric groups in different relative orientation or presentation (e.g., distance, relative angle, i.e. relative position in, space is different).
[0068] Actives from this library were identified and SAR information from this library was used to design subsequent library of compounds wherein each compound may include three pharmacophoric groups, known as a 3P library. Subsequent libraries with four pharmacophoric groups are called 4P library, etc.
[0069] Members of significantly improved activity were identified out of the second library and were selected for further drug development.
[0070] The method of the invention includes real and virtual libraries.
[0071] Thus, the molecules according to formula 1 are well suited for generating iterative scanning libraries, starting from a selected number of pharmacophores (eg, two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library, thereby assisting in delineating pharmacophores.
[0072] The 2P and 3P library of compounds were synthesized according to the budding blocks as described in Examples A-G.
[0073] The 2P library (Table 1) was designed to scan molecular diversity for 3P molecules, comprising an aromatic and a positive charge.
[0074] The 2P library was screened for biological activity and the results are given in Table 1.
[0075] Similarly, the 3P library was designed to scan molecular diversity for 3P molecules. Design of 3P library resulted from SAR obtained from 2P library in Table 1.
[0076] The 3P library was screened for biological activity and the results are given in Table 2.
[0077] A visual analysis of the results according to Table 1 (2P library) and Table 2 (3P Library) indicates that:
[0000] 1. 1, 2 allose substitution according to formula 0.3 (and Scaffold C/D) presents the most active arrangement of molecules in the library wherein Z is oxygen, R 1 is naphthyl and R 2 is propylamine or ethylamine.
[0078] These compounds represent most actives at low mM range, and are suitable candidates for further drug development.
[0000] 2. R 1 as naphthyl is more active than the corresponding o-chlorobenzyl substituent.
3. 1, 2 allose according to formula 3 (Scaffold C/D) is more active than the corresponding 1, 2 glucose conformation (Scaffold A/B).
4. 1. 2 substitution according to formula 3 (Scaffold C/D) is more active then the corresponding 2, 6 substitution according the formula 4 (Scaffold G)
5. R 2 as propylamine and ethylamine are more active than methylamine wherein Z, R 1 and R 2 are as described above.
6. 2, 3 allose substitution according to formula 3 (Scaffold C/D) presents the more actives wherein R 2 is ethylamine, and R 3 is p-chlorobenzyl compared to corresponding R 2 as propylamine and ethylamine wherein R3 is p-chlorobenzyl substituent, and also wherein R 2 is methylamine, ethylamine or propylamine and R3 is naphthyl.
7. 2, 3 glucose substitution according to formula 3 (scaffold A/B) presents the more actives wherein R 2 propylamine and R 3 is naphthyl compared to corresponding R 2 as methylamine or ethylamine, and also wherein R 2 is methylamine, ethylamine or propylamine and R 3 is p-chlorobenzyl.
8. 2, 4 and 3, 4 substitutions according to formula 3 (Scaffold G) present the least actives.
Part B
Biological Assays
Example H
In Vitro Screening of Compounds Against Somatostatin Subtypes SSTR-1 to SSTR-5
General Method
[0079] Receptor membrane preparations containing the desired cloned receptor (for example cloned human somatostatin receptor subtype 5, SSTR5) and radio-labeled ligand were diluted at the concentration required for testing and according to the specific parameters associated with the selected receptor-ligand combination, including receptor B max , ligand K d and any other parameters necessary to optimize the experimental conditions. When tested for competition activity to the reference ligand, “compound” was mixed with membrane suspension and the radiolabeled reference ligand (with or without an excess of unlabeled ligand to the receptor for determination of non-specific binding) and incubated at the temperature required by internal standard operating procedures. Following incubation, the binding reaction was stopped by the addition of ice-cold washing buffer and filtered on appropriate filters, which are then counted. Data analysis and curve-fitting was performed with XLfit (IDBS).
Preparation of Compounds
[0080] 10 mM solutions of test compounds in 100% DMSO were prepared, ˜160 μl was used for each dilution (20 μl/well in triplicate).
[0081] A 1.25 mM assay stock was prepared by making a 1:8 dilution of the 10 mM solution. To 30 μL of the 10 mM solution was added 210 μL milli-Q H 2 O. A 1:5 dilution series in milli-Q H 2 O was then prepared.
[0000]
Final concentration
Final concentration
in SST4 assay
in SST5 assay
A.
240 μL of 1.25 mM
0.25 mM
0.125 mM
B.
48 μL A + 192 μL mQ
0.05 mM
0.025 mM
C.
24 μL B + 192 μL mQ
0.01 mM
0.005 mM
etc
[0082] Assays were performed in triplicate at each concentration within the 1:5 dilution series: 250 μM, 50 μM, 10 μM, 2 mM, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, etc. (for SST4 assay and 125 μM, 10 μM, 2 μM, 1 μM, 0.5 μM, etc (for SST5 assay).
Fitter Plate Assay for SST5 Receptor
[0083] Human SST5 somatostatin receptor was transfected into HEK-293 EBNA cells. Membranes were suspended in assay buffer (50 mM Tris-HCl, 1 mM EGTA, 5 mM MgCl 2 , 10% sucrose, pH 7.5). The receptor concentration (B max ) was 0.57 pmol/mg protein K d for [ 125 I]SST-14 Binding 0.31 nM, volume 0.4 ml per vial (400 microassays/vial), and protein concentration 1.03 mg/ml.
[0084] After thawing the frozen receptor preparation rapidly, receptors were diluted with binding buffer, homogenized, and kept on ice.
1. Use Multiscreen glass fiber filter plates (Millipore, Cat No MAFCNOB10) precoated with 0.5% PEI for ˜2 hr at 4° C. Before use add 200 μl/well assay buffer and filter using Multiscreen Separation System. 2. Incubate 5.5 μg of membranes (40 μl of a 1:40 dilution), buffer and [ 125 I]SST-14 (4 nM, ˜80 000 cpm, 2000 Ci/mmol) in a total volume of 200 μl for 60 min at 25° C. Calculate IC50 for SST-14 (a truncated version of the natural ligand SST-28) (Auspep, Cat No 2076) and SST-28 (Auspep, Cat No 1638). Prepare serial dilutions (1:5) of compounds, as described above and instead of adding SST-14 in well, add 20 μl of compounds (Table 3). 3. Filter using Multiscreen Separation System with 5×0.2 ml ice-cold Assay buffer. 4. Remove the plastic underdrain and dry plate in oven for 1 hr at 40° C. 5. Seal tape to the bottom of the plate. 6. Add 50 μl/well scintillant (Supermix, Wallac, Cat No 1200-439). 7. Seal and count in the BJET, program 2.
[0000]
TABLE 3
Compounds
Volume (ul)
TB
NSB
testing
Membranes (5.5 μg/well)
40
40
40
Radio-labeled label (~80 000
40
40
40
cpm, ~4 nM)
Unlabeled ligand
—
20
—
mQH 2 O
20
—
—
Compounds
20
Assay buffer
100
100
100
Total volume (μI)
200
200
200
TB: total binding
NSB: non-specific binding
Part C
General Experimental Methods
Example I
HPLC Method for compounds in Tables 1 and 2
[0092] The HPLC separation of compounds in Tables 1 and 2 was conducted under Method A or Method B as shown below.
Method A
[0093] Column: Agent SB Zorbax C18 4.6×50 mm (5 μm, 80 À)
LC mobile phase:
5% aqueous MeCN/1 min
100% MeCN/7-12 min
Method B
[0094] Column: Agilent SB Zorbax C18 4.6×50 mm (5 μm, 80 À)
LC mobile phase:
5% aq MeCN/1 min
30% aq MeCN/3 min
40% aq MeCN/12 min
100% MeCN/13-15 min
Key to Building Blocks for Tables 1 and 2
[0095] Table 1: *% SST5 radio-ligand binding displaced at conc (μM) for 2P library of compounds
Table 2: *% SST5 radio-ligand binding displaced at conc (μM) for 3P library of compounds; R 4 =X30; compounds 60-63, 119 and 156-159 are comparative compounds from 2P library
“++”: % SST5 radio-ligand binding displaced at conc (μM) >60%
“+”: % SST5 radio-ligand binding displaced at conc (μM) 60>+>40%
“−”: % SST5 radio-ligand binding displaced at conc (μM) −<40%
Blank: not determined
RT: retention time/minutes
M+H: mass ion+1
[0000]
TABLE 1
Biological activity of example 2P library
conc
conc
conc
Object ID
Scaffold
R1
R2
R3
R4
R5
500
250
50*
RT
M + H
1
E
—
X15
X2
X30
X24
3.24
449.58
2
A
X7
X20
X24
X30
X24
3.4
383.46
3
A
X7
X15
X24
X30
X24
3.42
397.48
4
E
—
X20
X2
X30
X24
3.49
435.55
5
A
X2
X20
X24
X30
X24
++
+
−
3.88
419.21
6
A
X2
X15
X24
X30
X24
++
+
−
3.83
433.23
7
E
—
X19
X24
X30
X3
−
−
−
3.42
405.12
8
E
—
X19
X24
X30
X2
++
+
−
3.81
421.17
9
E
—
X19
X3
X30
X24
−
−
−
3.62
405.12
10
E
—
X19
X2
X30
X24
−
−
−
4.03
421.17
11
A
X3
X19
X24
X30
X24
−
−
−
3.39
389.14
12
A
X2
X19
X24
X30
X24
−
−
−
4.08
405.19
13
B
X3
X19
X24
X30
X24
−
−
−
3.4
389.14
14
B
X2
X19
X24
X30
X24
−
−
−
3.88
405.19
15
E
—
X20
X24
X30
X3
−
−
−
3.25
419.13
16
E
—
X20
X24
X30
X2
+
−
−
3.59
435.19
17
E
—
X20
X3
X30
X24
−
−
−
3.68
419.13
18
E
—
X20
X2
X30
X24
−
−
−
4.06
435.19
19
A
X3
X20
X24
X30
X24
++
−
−
3.56
403.16
20
B
X3
X20
X24
X30
X24
+
−
−
3.37
403.16
21
B
X2
X20
X24
X30
X24
++
+
−
3.7
419.21
22
E
—
X15
X24
X30
X3
−
−
−
3.22
433.15
23
E
—
X15
X24
X30
X2
+
−
−
3.59
449.2
24
E
—
X15
X3
X30
X24
−
−
−
3.7
433.15
25
E
—
X15
X2
X30
X24
+
−
−
4.06
449.2
26
E
X3
X15
X24
X30
X24
++
−
−
3.57
417.17
27
B
X3
X15
X24
X30
X24
−
−
−
3.4
417.17
28
B
X2
X15
X24
X30
X24
++
−
−
3.68
433.23
29
F
—
X19
X24
X30
X3
−
−
−
3.55
405.12
30
F
—
X19
X24
X30
X2
+
−
−
3.84
421.17
31
F
—
X19
X3
X30
X24
+
−
−
3.75
405.12
32
F
—
X19
X2
X30
X24
−
−
−
4.05
421.17
33
C
X3
X19
X24
X30
X24
−
−
−
3.38
389.14
34
C
X2
X19
X24
X30
X24
−
−
−
3.72
405.19
35
D
X3
X19
X24
X30
X24
−
−
−
3.41
389.14
36
D
X2
X19
X24
X30
X24
+
−
−
3.77
405.19
37
F
—
X20
X3
X30
X24
−
−
−
3.76
419.13
38
C
X3
X20
X24
X30
X24
++
+
−
3.33
403.16
39
D
X3
X20
X24
X30
X24
++
−
−
3.44
403.16
40
D
X2
X20
X24
X30
X24
++
++
−
3.8
419.21
41
F
—
X15
X24
X30
X3
−
−
−
3.51
433.15
42
F
—
X15
X24
X30
X2
+
−
−
3.81
449.2
43
F
—
X15
X3
X30
X24
−
−
−
3.66
433.15
44
D
X3
X15
X24
X30
X24
++
−
−
3.51
417.17
45
D
X2
X15
X24
X30
X24
++
+
−
3.86
433.23
46
G
—
X24
X3
X19
X30
−
−
−
3.31
386.14
47
G
—
X19
X2
X24
X30
−
−
−
3.27
402.2
48
G
—
X19
X24
X8
X30
−
−
−
2.48
352.18
49
G
—
X2
X24
X19
X30
−
−
−
3.64
388.18
50
G
—
X8
X24
X19
X30
−
−
−
2.61
352.18
51
G
—
X24
X3
X20
X30
−
−
−
3.08
400.16
52
G
—
X2
X24
X20
X30
−
−
−
3.46
402.2
53
G
—
X8
X24
X20
X30
−
−
−
2.73
366.2
54
G
—
X24
X3
X15
X30
−
−
−
3.27
414.17
55
G
—
X2
X24
X15
X30
−
−
−
3.79
416.21
56
G
—
X8
X24
X15
X30
−
−
−
2.78
380.21
57
F
—
X20
X2
X30
X24
−
−
−
4.01
435.19
58
F
—
X15
X2
X30
X24
−
−
−
4.08
449.2
59
C
X2
X20
X24
X30
X24
++
++
+
3.74
419.21
[0000]
TABLE 2
Biological activity of example 3P library
Object
conc
conc
conc
conc
conc
conc
conc
conc
conc
ID
Scaffold
R1
R2
R3
R5
500
250
50
10
1.0
0.5
0.25
0.10
0.001*
RT
M + H
60
A
X2
X20
X24
X24
++
+
−
3.88
419.21
61
B
X2
X20
X24
X24
++
+
−
3.7
419.21
62
D
X2
X20
X24
X24
++
++
−
3.8
419.21
63
C
X2
X20
X24
X24
++
++
+
3.72
419.21
64
C and D
X2
X20
X8
X24
++
++
++
+
−
4.98
65
C and D
X2
X20
X8
X24
++
4.98
66
C and D
X2
X20
X3
X24
++
++
++
−
−
5.25
67
C and D
X2
X20
X3
X24
++
5.25
68
C and D
X2
X20
X1
X24
++
++
++
−
−
−
5.49
69
C and D
X2
X20
X2
X24
++
++
++
++
+
5.23
70
C and D
X2
X20
X3
X2
+
−
5.85
71
C and D
X2
X20
X3
X8
++
−
5.61
72
C and D
X2
X20
X3
X3
++
−
5.51
73
C and D
X2
X20
X2
X2
+
−
5.95
74
C and D
X2
X20
X2
X8
++
−
5.45
75
C and D
X2
X20
X2
X3
++
−
6.46
76
C and D
X2
X20
X8
X2
++
−
5.7
77
C and D
X2
X20
X8
X8
++
−
5.01
78
C and D
X2
X20
X8
X3
++
+
5.37
79
B
X2
X20
X2
X2
++
−
10.31
80
A
X2
X20
X2
X2
++
−
10.88
81
B
X2
X20
X2
X8
++
−
8.02
82
A
X2
X20
X2
X8
++
+
8.68
83
B
X2
X20
X2
X3
++
−
9.39
84
A
X2
X20
X2
X3
++
−
10.24
85
D
X2
X20
X2
X24
++
++
50.92
86
C
X2
X20
X2
X24
++
++
54.37
87
A or B
X2
X20
X8
X24
−
−
3.78
495.59
88
A or B
X2
X20
X8
X24
−
−
3.86
495.59
89
A or B
X2
X20
X3
X24
−
−
3.95
530.03
90
A or B
X2
X20
X3
X24
++
+
3.97
530.03
91
A or B
X2
X20
X1
X24
−
−
4.5
571.69
92
A or B
X2
X20
X2
X24
+
−
4.33
545.65
93
A and B
X2
X20
X24
X8
+
−
4.13
495.59
94
A or B
X2
X20
X24
X3
−
−
4.33
530.03
95
A or B
X2
X20
X24
X3
−
−
4.33
530.03
96
A or B
X2
X20
X24
X1
−
−
4.77
571.69
97
A and B
X2
X20
X24
X2
+
−
4.52
545.65
98
A
X2
X20
X2
X24
++
+
5.45
545.65
99
A
X2
X31
X2
X24
+
−
5.07
559.67
100
A
X2
X32
X2
X24
++
+
5.05
559.67
101
A
X2
X33
X2
X24
+
−
4.79
557.66
102
A
X2
X34
X2
X24
−
−
6.24
613.77
103
A
X2
X35
X2
X24
++
+
5.85
585.71
104
A
X2
X36
X2
X24
−
−
6.33
599.74
105
A
X2
X37
X2
X24
−
−
6.72
599.74
106
A
X2
X45
X2
X24
−
−
4.96
573.7
107
A
X2
X20
X46
X24
++
++
4.22
530.03
108
A
X2
X20
X47
X24
++
+
4.87
564.48
109
A
X2
X20
X48
X24
++
−
4.98
530.03
110
A
X2
X20
X49
X24
++
++
4.43
546.64
111
A
X2
X20
X50
X24
−
−
5.44
552.66
112
A
X2
X20
X51
X24
++
+
3.78
546.64
113
A
X2
X20
X52
X24
++
++
5.71
564.48
114
A
X2
X20
X9
X24
++
++
5.89
545.65
115
A
X2
X20
X53
X24
++
+
5.8
564.48
116
A
X2
X20
X54
X24
++
+
4.43
546.64
117
A
X2
X20
X55
X24
++
++
5.71
564.48
118
A
X2
X20
X56
X24
++
++
6.9
587.68
119
A
X2
X15
X24
X24
++
+
−
120
A and B
X2
X15
X8
X24
++
+
4.29/4.57
121
A and B
X2
X15
X24
X1
+
+
5.4
122
A and B
X2
X15
X24
X2
++
++
5.18
123
A and B
X2
X15
X24
X8
−
−
4.78
124
A and B
X2
X15
X24
X3
+
−
5.07
125
A and B
X2
X15
X24
X4
+
−
4.28
126
C and D
X2
X15
X8
X24
++
+
+
−
−
4.97
127
C and D
X2
X15
X3
X24
++
++
++
−
−
5.17
128
C and D
X2
X15
X1
X24
++
+
++
−
−
−
5.45
585.71
129
C and D
X2
X15
X2
X24
++
++
−
+
−
5.18
559.67
130
A and B
X2
X15
X4
X24
++
131
A and B
X2
X15
X1
X24
++
132
A and B
X2
X15
X2
X24
++
133
A and B
X2
X15
X3
X24
++
134
A
X2
X15
X3
X24
++
++
++
++
+
4.78
135
A
X2
X15
X3
X2
++
−
9.87
136
A
X2
X15
X3
X8
++
−
7.82
137
A
X2
X15
X3
X3
++
−
9.32
138
A
X2
X38
X2
X24
−
−
3.67
574.69
139
A
X2
X39
X2
X24
+
−
5.07
573.7
140
A
X2
X40
X2
X24
++
++
4.96
573.7
141
A
X2
X41
X2
X24
−
−
5.16
587.73
142
A
X2
X53
X2
X24
++
+
5.69/7.43
599.74
143
A
X2
X42
X2
X24
−
−
5.98
613.77
144
A
X2
X15
X46
X24
++
+
4.34
544.06
145
A
X2
X15
X47
X24
++
+
5.07
578.5
146
A
X2
X15
X48
X24
++
−
5.05
544.06
147
A
X2
X15
X49
X24
++
+
4.5
560.66
148
A
X2
X15
X50
X24
−
−
5.34
566.69
149
A
X2
X15
X51
X24
+
−
3.95
560.86
150
A
X2
X15
X52
X24
++
++
5.78
578.5
151
A
X2
X15
X9
X24
++
+
5.78
559.67
152
A
X2
X15
X53
X24
++
+
5.97
578.5
153
A
X2
X15
X54
X24
++
++
4.32
580.66
154
A
X2
X15
X55
X24
++
++
5.88
578.5
155
A
X2
X15
X56
X24
++
++
7.25
601.71
156
A
X3
X19
X24
X24
−
−
−
3.39
389.14
157
B
X3
X19
X24
X24
−
−
−
158
C
X3
X19
X24
X24
−
−
−
3.38
389.14
159
D
X3
X19
X24
X24
−
−
−
160
C and D
X3
X19
X8
X24
−
−
−
−
−
4.8
161
C and D
X3
X19
X3
X24
++
−
−
−
−
5.14
162
C and D
X3
X19
X1
X24
+
−
−
−
−
−
5.45
542.04
163
C and D
X3
X19
X2
X24
++
−
−
−
−
5.2
164
C and D
X3
X43
X24
X2
+
−
3.45
165
C and D
X3
X44
X24
X2
++
−
4
166
A and B
X3
X43
X24
X2
++
−
3.59
167
A and B
X3
X44
X24
X2
++
++
3.97
168
A or B
X3
X19
X8
X24
−
−
169
A or B
X3
X19
X8
X24
−
−
170
A or B
X3
X19
X3
X24
−
−
171
A or B
X3
X19
X3
X24
−
−
172
A or B
X3
X19
X1
X24
−
−
173
A or B
X3
X19
X1
X24
−
−
174
A or B
X3
X19
X2
X24
−
−
175
A or B
X3
X19
X2
X24
−
−
176
A and B
X3
X19
X24
X8
−
−
4.88/5.61
465.95
177
A and B
X3
X19
X24
X3
−
−
6.06/6.52
500.39
178
A and B
X3
X19
X24
X1
−
−
9.09
542.04
179
A and B
X3
X19
X24
X2
−
−
7.43
516.01
FIG. 1: Sidearms for Tables 1 and 2
[0096]
[0097] Throughout the specification and the claims (if present), unless the context requires otherwise, the term “comprise”, or variations such as “comprises” or “comprising”, will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers.
[0098] Throughout the specification and claims (if present), unless the context requires otherwise, the term “substantially” or “about” will be understood to not be limited to the value for the range qualified by the terms.
[0099] It should be appreciated that various other changes and modifications can be made to any embodiment described without departing from the spirit and scope of the invention.
REFERENCES
[0000]
[1] Patel, Y. C. (1999) Somatostatin and its receptor family. Front. Neuroendocr. 20, 157-198
[2] Csaba, Z. and Dournaud, P. (2001) Cellular biology of somatostatin receptors. Neuropeptides 35, 1-23
[3] T. Reisine, T. (1995) Somatostatin receptors: Am. J. Pysiol . ( Gastrointest. Liver Physiol. 32) 269, G813-G820
[4] Bauer, W. et al. (1982) SMS201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 31, 1133-1140
[5] Lamberts, S. W. J. et al. (1996) Drug therapy: Octreotide. N. Eng. J. Med. 334, 246-254
[6] Robinson, C. and Castaner, J. (1994) Lanreotide acetate. Drugs Future 19, 992-999
[7] Reisine, T. and Bell. G. I. (1995) Molecular biology of somatostatin receptors. Endocr. Rev. 16, 427-442
|
The invention provides a method of identifying biologically active compounds comprising: (a) designing a first library of compounds of formula (1) to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; (b) assaying the first library of compounds in one or more biological assay(s); and (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library; such that the/each component of the first and second library is a compound of formula (1).
| 2 |
This application is a divisional of application Ser. No. 07/742,983, filed on Aug. 9, 1991, now abandoned.
BACKGROUND OF THE INVENTION
Chitin, poly-β-(1→4)-N-acetyl-D-glucosamine, is a cellulose-like biopolymer which is the primary constituent of the cell wall in most fungi, molds, and yeasts and the exoskeleton of crustaceans and insects. The amount of chitin relative to total dry weight of these organisms is highest in crustaceans, where it is commonly found as the tough polymer matrix of crab and shrimp shells. Crustacean shells are currently the primary source of commercial chitin.
Chitosan, poly-β-(1→4)-2-deoxy-D-glucosamine, the deacetylated derivative of chitin, has great potential value because of its free amines, for new chemical and medical applications. Chemically, chitosan's free amines possess the ability to chelate with many metals (see Muzzarelli et al., Journal of Membrane Science 16: 295-308 (1983)) and other ions. It thus has the potential for use in a wide variety of applications such as metal recovery from industrial wastes and fibers with improved dyeability, among others.
Biologically, chitin and chitosan provide sources of glucosamine, a potentiator for antibiotics (see Austin et al., Science 212: 749-753 (1981)) and consequently a substance with wound-healing properties. Chitosan is a hemostatic, and it also promotes collagen formation, thus preventing scar formation. The chemistry of chitosan also confers upon it excellent film forming properties (see Muzzarelli et al.), and it would be expected to have great utility in the formation of membranes. Its toughness can be utilized in producing high strength fibers and bioseparation films and it therefore may have other medical applications such as sutures.
Chitosan can itself be chemically modified to provide materials with other additional useful properties. Muzzarelli et al. discloses N-alkylation of chitosan as a method of varying the plasticity and other properties of membranes, fibers and other chitosan-derived materials. This method for production of various N-alkyl chitosans, however, requires the expensive chitosan as the starting material.
Chitin's ready availability and abundance, as waste material from canning food industries, allow broad research on its capabilities and make it very attractive as starting material for the synthesis of chitosan. One drawback of the natural starting product, however, is that its properties can vary considerably depending on the source and method of preparation (see Austin et al.); this could pose great difficulty in controlling and attributing the properties of the end product.
Problems have also been encountered during the production of chitosan from chitin, normally attempted by alkaline hydrolysis of the chitin. Reports have contended that solvents doped with chlorides such as LiCl are useful in adjusting the solubility of chitin during alkaline hydrolysis. Chitin, however, lacks a good direct solvent; in fact, chitin is insoluble in conventional solvent systems. Chitin is also easily degraded in the presence of acid. Therefore acid catalyzed hydrolysis is very difficult and one has to balance the rate of hydrolysis with the rate of degradation. One alternative, then, for the production of chitosan from naturally-occurring chitin would be a process involving less harsh conditions and one affording greater solubility of the starting material.
Due to the variability of chitin sources and the difficulty of working with chitin it may be advantageous to develop synthetic molecules similar to chitin and chitosan by aminating or amidating cellulosic materials. Haskins, U.S. Pat. No. 2,136,299 and Meigs, U.S. Pat. No. 1,801,053 disclose processes for the amination of carbohydrate and cellulosic materials. However these do not involve direct amination; rather they rely upon an initial step of harsh and degradative acid treatment. Dreyfus, U.S. Pat. Nos. 2,007,950; 2,186,101; and 2,233,475 disclose processes for the production of cellulosic materials containing nonacidic nitrogen, including amino groups, but the processes are not directed to any specific derivatizations or sites of derivatization. Furthermore, the amination processes do not afford direct (i.e., one-step) amination of the cellulosic materials.
Accordingly, new methods have been sought for the synthesis of chitin and chitosan under milder reaction conditions and for synthesis from more economical, tractable and homogeneous starting materials. Additionally, methods have been sought which have the regioselectivity to ensure that the important functional groups are placed as in the naturally occurring counterparts. Finally, new methods have been sought for the synthesis of N-alkylated chitosans from starting materials considerably cheaper than the parent chitosan itself.
SUMMARY OF THE INVENTION
The invention provides more efficient, and economical methods for the production of chitosan polymers. One embodiment of the invention provides a process for the methanolysis of plentiful, naturally occurring chitin to form chitosan. This process allows for economy and for easier handling of the starting material as well as increased maintenance of the integrity thereof.
The invention further provides a process for the amidation of water soluble cellulose acetate to produce chitosan. This process allows for the production of the expensive chitosan from an inexpensive, tractable and relatively homogeneous starting material.
The invention also provides a process for the amination of water soluble cellulose acetate to produce a variety of N-alkyl chitosans. This process affords the direct amination of cellulosic materials. Furthermore, it does not require the expensive chitosan as a starting material.
DETAILED DESCRIPTION OF THE INVENTION
Methanolysis of Chitin
The current process for alkaline hydrolysis of chitin, using NaOH as a solvent, is particularly uneconomical and generates large amounts of waste. The process requires stoichiometric amounts of alkali and demands harsh reaction conditions. Acid catalyzed methanolysis of chitin is a more economical and safer procedure. Methanolysis of chitin in NMP (1-methyl-2-pyrrolidinone) and 5% LiCl as solvent system proceeds as follows: ##STR1##
Hydrolysis of chitin was attempted in various solvents and with different acids. The preferred system shown above with methanol as the solvent and methanesulfonic acid as the catalyst as described in Example 1 was found to be the best medium to carry out this reaction. The resulting product from this reaction displayed an identical infrared spectrum to that of pure chitosan. Various other-attempted reactions with many different acids such as concentrated sulfuric acid, hydrochloric acid and a range of solvents such as water, methanol, and ethanol were unsuccessful and did not result in any appreciable amounts of hydrolyis.
As illustrated in Example 1, in a preferred embodiment of the invention, hydrolysis of the acetyl group is achieved by using methanol as the solvent, methanesulfonic acid as the catalyst, and NMP with 5% LiCl to dissolve the chitin.
EXAMPLE 1
5.0 g LiCl was dissolved in 100 ml NMP, with gentle stirring, in a 250 ml round-bottom flask. 1.0 g chitin was added and dissolved by reflux in the solvent system for 6 hours. 5 ml CH 3 SO 3 H and 12 ml CH 3 OH were then added to the flask of viscous dark liquid, followed by refluxing for about 8 hours. At the end of this time, the product was precipitated out by slowly dropping the reaction mixture into 500 ml acetone by way of a separatory funnel. After all of the reaction mixture was dropped into acetone, the pH was raised to 8.5-9.0 with 25% by weight Na 2 CO 3 /H 2 O solution. 300 ml water were added to the stirring solution to remove any salt formed. The product was then vacuum filtered and oven dried at 100° C. until a constant weight was obtained.
Infrared spectroscopy was performed on the product after drying and it was determined that hydrolysis did indeed occur. The product was further purified as follows: 25 ml concentrated HCl was added to 100 ml water in a 150 ml Erlenmeyer flask. The product was added and heated to boiling for no more than 5 minutes. It was then filtered hot and the filtrate was allowed to cool. The filtrate was neutralized with 20% by weight Na 2 CO 3 /H 2 O to a pH of about 9.0-10.0. A greenish brown precipitate was formed. The resulting hydrolyzed chitin--chitosan--was filtered and oven dried at 100° C. until a constant weight was obtained as before.
Amidation of Water Soluble Cellulose Acetate
The direct amidation of alcohols by nitrilic solvents in the presence of strong acids is known as the Ritter reaction (Ritter and Minieri, Journal of the American Chemical Society 70: 4045-4048 (1948)). The reaction proceeds as follows: ##STR2## The reaction is more facile with alcohols which result in stable carbocations; tertiary or benzylic alcohols react more readily than secondary alcohols, and primary alcohols do not give the reaction. The present invention uses a Ritter type reaction to amidate water soluble cellulose acetate (WSCA), preferably at the secondary position. However, the reaction conditions must be selected to promote regioselectivity, that is to amidate preferentially at the second position of the glucose ring in the cellulose as follows: ##STR3##
Although the site of amidation of WSCA is shown at the preferred position 2, equal probability of amidation at position 3 of the glucose ring cannot be ruled out. The resulting product with amidation primarily at position 2 should be structurally identical to naturally occurring chitin with an acetyl group esterified at position 6. Hydrolysis of this product should produce chitosan.
The amidation of WSCA was carried out in various solvents, in different acids and under different temperatures to determine the best reaction conditions for amidation of WSCA. Two different grades, low and medium viscosity, of WSCA were used. The conditions giving the highest degree of substitution, as determined by the percent nitrogen in the product by elemental analyses, were found to be when low viscosity grade WSCA dissolved in DMSO, and concentrated sulfuric acid in acetonitrile were heated at 75° C. as in Example 2. The results are summarized in Table 1. Other solvents such as NMP and other protonating agents such as methanesulfonic acid may also be used.
There was no appreciable reaction at room temperature either using methanesulfonic acid (MSA) or sulfuric acid as the acid and using NMP or dimethyl sulfoxide (DMSO) as solvent. The WSCA used in these runs was completely recovered by precipitating the product in acetone. There was no degradation of WSCA under these conditions. When the reaction mixtures were heated to higher temperatures, the product isolation was more difficult, and probably some degradation of WSCA may have occurred between 50° and 75° C. Significant degradation of WSCA took place at 100° C.
TABLE 1__________________________________________________________________________Summary of Results of Amidation of Water Soluble Cellulose Acetate Reaction conditions Elemental AnalysisReactants Acid Temp. Time % C % H % N Remarks__________________________________________________________________________10 g Low viscosity 50 g MSA r.t. overnight 38.70 6.05 <0.1 mostly hydrolyzed celluloseWSCA in NMP 38.73 5.92 <0.1 still water soluble70 ml Acetonitrile10 g Med. viscosity 50 g MSA r.t. overnight 30.21 6.39 <0.05WSCA in DMSO 30.02 6.59 <0.0570 ml Acetonitrile10 g Low viscosity 50 g MSA r.t. overnight 36.65 5.99 <0.05WSCA in DMSO 36.43 5.99 <0.0570 ml Acetonitrile10 g Low viscosity 50 g 50° C. overnight 25.95 4.10 <0.05WSCA in DMSO Sulfuric 26.03 3.91 <0.0570 ml Acetonitrile Acid10 g Low viscosity 50 g 75° C. 2 h 28.06 7.32 0.97WSCA in DMSO Sulfuric 28.21 7.51 0.9670 ml Acetonitrile Acid__________________________________________________________________________
EXAMPLE 2
10 g of water soluble cellulose acetate was dissolved in 70 ml DMSO. To 70 ml acetonitrile in a 250 ml round bottom flask, cooled in an ice bath, 50 g of sulfuric acid was slowly added dropwise via an addition funnel, making sure no heating occurred. The water soluble cellulose acetate solution was then slowly added to the sulfuric acid solution, which was still in the ice bath. After most of the materials were dissolved, the reaction solution was placed and stirred in an oil bath which was heated to 75° C. under argon atmosphere. After two hours, the reaction solution was taken out of the oil bath and was hydrolyzed by the addition of 50 ml of distilled water. The resulting solution was then dropped into 750 ml of acetone to precipitate the product. The product was then filtered, dried in a vacuum oven at 50° C. until constant weight was obtained.
Amination of Water Soluble Cellulose Acetate
The amination of alcohols in the presence of nickel is a well known process. Primary and secondary alcohols have been aminated with secondary amines using aluminum t-butoxide and Raney nickel (see Botta et al., Synthesis, 722-723 (1977)) as depicted in the following equation: ##STR4## Amination of water-soluble cellulose acetate proceeds as follows: ##STR5##
The present invention provides a method of selectively aminating cellulose acetate with amines. The invention may be practiced by using the methods as set forth in Example 3 wherein ethylamine, Raney Ni and aluminum t-butoxide were used to aminate the low-viscosity, water-soluble cellulose acetate in NMP as solvent. Other polar solvents such as dimethyl acetamide and other metal catalysts, and aluminum alkoxides may also be used. It was determined that the best amination results were obtained at 75° C. reaction temperature as set forth in Example 3. The site of amination was not conclusively determined but the 2nd and 3rd positions on the cellulose ring have an equal probability of attack. The 6th position can undergo amination, but as a primary hydroxyl group, it is not very favorable for attack under these reaction conditions. The results are summarized in Table 2.
TABLE 2______________________________________Summary of Results of Amination ofWater Soluble Cellulose Acetate Reaction Elemental conditions Analysis.sup.aReactants Catalyst Temp. Time % C % H % N______________________________________10 g Low 3.5 g Raney r.t. overnight 37.51 6.55 0.81viscosity Ni, 12 g Al 37.54 6.45 0.76WSCA in t-butoxideNMP10 g ethyl-amine10 g Low 3.5 Raney 50° C. overnight 33.93 6.18 0.68viscosity Ni, 12 g Al 33.98 5.95 0.57WSCA in t-butoxideNMP10 g ethyl-amine10 g Low 3.5 g Raney 75° C. 6 h 31.39 5.81 1.11viscosity.sup.b Ni, 12 g Al 31.17 6.09 1.09WSCA in t-butoxideNMP10 g ethyl-amine10 g Low 3.5 g Raney 75° C. overnight 34.39 5.78 1.13viscosity.sup.c Ni, 12 g Al 34.29 5.75 1.13WSCA in t-butoxideNMP10 g ethyl-amine______________________________________ .sup.a elemental analyses were done in duplicates in all cases; .sup.b th .sup.1 H NMR analysis of the product in this run indicated the degree of amination to be 0.048 amino group per glucoside ring; .sup.c the .sup.1 H NMR analysis of the product in this run indicated the degree of amination to be 0.038 amino group per glucoside ring.
The results shown in Table 2 indicate that the amination process using ethylamine and Raney Ni and aluminum t-butoxide as reagents is reproducible with consistent results. The degree of amination increases with temperature, with 75° C. giving the best results. The percentages of elements in the product were determined by elemental analysis.
The amount of reagent contamination in the product was reduced by dissolving the product in a minimal volume of HCl and precipitating out the product in acetone. The HCl reacts with the Raney Ni and aluminum t-butoxide thereby removing them from the product.
The amination of water soluble cellulose acetate with ethylamine to produce N-ethyl chitosan was confirmed by elemental analysis. This amination process may be performed with WSCA and other alkylamines such as methylamine, propylamine, butylamine, pentylamine, and hexylamine to produce respectively the N-methyl, N-propyl, N-butyl, N-pentyl, and N-hexyl chitosans. The amination can also be carried out using ammonia as the aminating agent wherein the resulting product is a synthetic analog of chitosan. The process could also be employed in a parallel manner to react WSCA with carboxyalkylamines to generate polymers with amphoteric functional groups (see Muzzarelli et al., Carbohydrate Research 107, 199-214 (1982)). Chelation properties and the strength of hydrogen bonding change with the substituent on the amino group, and the general amination process disclosed herein enables the economical production of a number of N-alkyl chitosans with varying plasticities, chelation capabilities, membrane- and fiber-forming characteristics, and other properties. Furthermore, the use of a starting material wherein there is homogeneity at the reaction site, e.g., water soluble cellulose acetate, promotes homogeneity of the end product. On the other hand, chitosan, for example, as starting material is crucially heterogeneous in that it is partially acetylated at the reaction site.
EXAMPLE 3
To a solution of 10 g low viscosity water soluble cellulose acetate in 75 ml NMP, 3.5 g Raney Ni and 12 g of aluminum t-butoxide, both in approximately 30 ml NMP, were added under argon atmosphere with continuous stirring in an ice bath. 10 g of ethylamine was then added slowly and then placed in a 75° C. oil bath with continuous stirring under argon atmosphere overnight. 80 ml of water was then added to decrease solution viscosity (on repeated procedures, sometimes the amount of water was increased in proportion to the amount of viscosity). The pH of the solution was then lowered by using 50% HCl-H 2 O solution added dropwise to the reaction flask. The actual pH was not recorded; the amount of 50% HCl-H 2 O added was determined by the amount of unreacted Ni in the flask. In this case, about 100 ml 50% HCl-H 2 O was added to the flask. Once the release of hydrogen gas diminished, the solution was stirred overnight. The gray gel-like material was dropped into 600 ml of water to lower its viscosity. This was then vacuum filtered and dropped slowly into 600 ml acetone where a fluffy cream color precipitate was obtained. The precipitate was vacuum filtered overnight and vacuum oven dried at 50° C. until a constant weight was obtained. The product was then purified by dissolving it in about 120 ml 50% HCl-H 2 O and vacuum filtering, adding small amounts of water to facilitate filtration. The product was vacuum oven dried at 50° C. until a constant weight was obtained.
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A method is disclosed of preparing amidated water soluble cellulose acetates by amidating water soluble cellulose acetate. Methods are also provided for preparing aminated water soluble cellulose acetates of varying plasticities, film- and fiber-forming characteristics, and other properties by methanolysis of naturally-occurring chitin or by amination of water soluble cellulose acetate.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present disclosure is related to the disclosures provided in the following Japanese patent applications filed prior to the filing of the present application: “METHOD FOR PRODUCING AQUEOUS PIGMENT DISPERSION”, filed as a Japanese Patent Application No. 11-97168; and “PIGMENT COMPOSITION AND AQUEOUS PIGMENT DISPERSION PRODUCT USING THE SAME”, filed as a Japanese Patent Application No. 11-97169; and the disclosures of the aforementioned applications are hereby expressly incorporated by reference herein in their entireties.
The present invention relates to a pigment composition that is easily dispersed in an aqueous medium. Specifically, the present invention relates to a pigment composition that can be produced in a single step without using water and a solvent in large amounts as in the conventional methods; and an aqueous pigment dispersion product comprising the same.
2. Description of the Prior Art
Hitherto, as a method for producing an aqueous dispersion product of a pigment, there has been adopted a method of mixing a pigment treated to be suitable for an aqueous system with dispersing varnish and then dispersing the mixture in an aqueous system in a disperser such as a sand mill or a bead mill with massive energy and time.
The pigment used in such a production of an aqueous dispersion product as above is finished into a pigment that can be used for an aqueous dispersion product after passing through steps requiring a great deal of energy and time. For example, in a pigmentation step based on wet-milling of a crude pigment, the crude pigment is milled in the presence of grinding media by means of a milling apparatus such as a kneader. Such a pigmentation step using mechanical power requires massive kneading energy and time for milling and a great deal of energy and time for separating and purifying the grinding media from the resultant pigment.
Against various processes typically used to produce an aqueous dispersion product of a pigment, as described above, the following methods have been recently suggested: a method of making a milled substance into a pigmentary form in the presence of a surfactant, as disclosed in Japanese Patent Application Laid-Open No. 55-75453; a method of dry-milling a crude pigment and mechanically dispersing a mixture of the dry-milled substance, a resin and an organic solvent, as disclosed in Japanese Patent Application Laid-Open No. 9-217019; and a method of kneading a mixture of crude copper phthalocyanine, a resin and an organic liquid, as disclosed in Japanese Patent Application Laid-Open No. 9-188845.
However, by any one of the above-mentioned methods in the prior art, a pigment composition capable of being dispersed in an aqueous medium with low mechanical energy cannot be economically produced.
SUMMARY OF THE INVENTION
Surprisingly, the present inventors have found out that when, upon the production of the aqueous dispersion of a pigment and a water-soluble resin, a specific surfactant, that is, a nonionic surfactant comprising a compound having in its molecule an acetylenic linkage is added thereto at a suitable timing, the dispersibility of the pigment particles in an aqueous system, particularly in an alkali aqueous solution, can be remarkably improved.
An object of the present invention is to provide a method for producing a pigment composition which is capable of being easily dispersed in an aqueous medium in a single step without using a large amount of water or a solvent.
Another object of the present invention is to provide a pigment composition having an excellent dispersibility as herein-above mentioned, and an aqueous dispersion product thereof.
These and other objects of the invention are satisfied by a pigment composition comprising a dry-milled pigment, a water-soluble resin, and a nonionic surfactant composed of a compound having an acetylenic linkage; and a method for producing a pigment composition, comprising dry-milling a pigment containing coarse particles in the presence of a water-soluble resin and a nonionic surfactant composed of a compound having an acetylenic linkage.
As a production method of the pigment composition, some variations are also possible within the scope of the present invention. One example of such variations is a method comprising the steps of (a) dry-milling a pigment containing coarse particles in the presence of a nonionic surfactant composed of a compound having an acetylenic linkage thereby obtaining an intermediate milled product, and (b) further dry-milling a mixture of the intermediate milled product and a water-soluble resin.
As a method for producing an aqueous pigment dispersion product, one of the most important examples is a method comprising the steps of (a) dry-milling a pigment containing coarse particles in the presence of a water-soluble resin thereby obtaining a milled product, and (b) dispersing the milled product in water in the presence of a nonionic surfactant composed of a compound having an acetylenic linkage.
The water-soluble resin may be water-soluble in the presence of an alkali. Especially, acrylic resin is preferable. One category of pigments applicable to the present invention is those composed of a condensed polycyclic compound. It should be also noted that the present invention can be quite effectively applicable to, though not specifically limited to, a phthalocyanine pigment. The nonionic surfactant may be an acetylene glycol compound such as 2,4,7,9-tetramethyl-5-decyne-4,7-diol or an ethylene oxide adduct thereof.
In the pigment composition according to the invention, the dry-milled pigment may be composed of pigment particles having surfaces coated with the water-soluble resin, which can be readily dispersed into an aqueous medium, especially aqueous solution of sodium hydroxide.
For effectively achieving the objects of the present invention, the water-soluble resin is preferably in an amount of 2 to 50% by weight and the nonionic surfactant is preferably in an amount of 1 to 20% by weight based on an amount of the pigment, in the pigment composition.
The pigment containing coarse particles, which is supposed to be milled, is typically a crude pigment.
In the presence of surfactant, the surfactant produces a surface treating effect on the surface of the pigment particles to improve the hydrophilic properties of the surface thereby significantly improving the affinity of the pigment particles to the resin. In the present invention, a specific compound as above-characterized is used for such surface activating purpose. Along with the surface treating function itself, these compounds also have a high permeability to penetrate into a minute space of material such as pigment particles. Pigment particles are usually composed of smaller particles coagulated each other, namely aggregate of primary particles. Because of this additional property, these compounds can permeate into inside of such an aggregate, and weaken the coagulation force. Wetting and adsorption of the resin to the surface of pigment particles also proceed based on the original surface treating effect. It is reasoned that owing to such double effects produced by the surface treating agent in the present invention, extremely high dispersibility of the pigment composition can be attained.
Therefore, according to the present invention, a pigment can be dispersed in water by a simple operation. According to the present invention, it is possible to provide, at low costs, an aqueous dispersion product having a quality that is equal to or higher than those obtained by the salt milling method using a solvent, which has been adopted as an ordinary pigment-producing method.
DETAILED DESCRIPTION OF THE INVENTION
Examples of the pigment to which the present invention can be applied are, though not specifically limited to, pigments composed of condensed polycyclic compounds such as phthalocyanine pigments, quinacridone pigments, and dioxazine pigments; and azo pigments such as monoazo pigments and bisazo pigments. The pigment that is subjected to dry-milling may be a pigment containing coarse pigment particles, which are not preferable as a final pigmentary form. A preferred example to which the present invention can be applied is a crude pigment composed of a condensed polycyclic compound.
The water-soluble resin may be a resin that is usually used as a resin component or a binder component of an aqueous pigment dispersion product, or a resin that is compatible with other components added to an ink concentrate using the pigment composition of the present invention. Examples of the water-soluble resin that can be preferably used include acrylic resins such as acrylic ester polymers, acryl-styrene copolymers and acryl-α-methylstyrene copolymers. These acrylic resins can be dissolved in water in the presence of an alkali component such as an alkali metal ion, amine or ammonia. From the viewpoint of easy handling, it is preferred that the water-soluble resin added upon dry-milling is in a pellet form.
In the present invention, the amount of the water-soluble resin added upon dry-milling is 2 to 50% and preferably 10 to 25% by weight of the amount of the pigment. When the added amount is more than 50% by weight, the ratio of the resin in the concentrate using the pigment composition obtained by the dry-milling is high, and hence unfavorably the aqueous dispersion product is restrictedly used or cannot be used at all. When the added amount is less than 2% by weight, it is difficult that the pigment composition obtained by the dry-milling is deflocculated in an aqueous medium.
The nonionic surfactant containing an acetylenic linkage may be an acetylene glycol compound. Specific examples thereof include 2,4,7,9-tetramethyl-5-decyne-4,7-diol, 3,6-dimethyl-4-octyne-3,6-diol, 2,5-dimethyl-3-hexyne-2,5-diol, or ethylene oxide adducts thereof. It is preferred to use a mixture of the nonionic surfactant and ether or glycol.
In the present invention, the amount of the nonionic surfactant added upon dry-milling or added upon dispersion of the pigment composition in water is preferably 1 to 20%, more preferably 3 to 10% by weight, based on the amount of the pigment. When the amount of the surfactant is larger than the above-mentioned upper limit, it is highly feared that the milled substance adheres to each other in a dry-milling apparatus, or the use of the resultant aqueous pigment dispersion product may be unfavorably limited. When the amount of the surfactant is smaller than the lower limit, the pigment composition is not deflocculated in the vehicle. In the case that in particular a phthalocyanine pigment is used, the color of the pigment is not developed. It is also possible to use not only the nonionic surfactant having an acetylene group, but also a different surfactant together with the nonionic surfactant.
In the dry-milling of the present invention, a milling apparatus having therein grinding media such as beads may be used. The milling apparatus pulverizes materials to be milled in their powder form without flocculation of the pigment with the aid of water or a solvent. Examples of such a milling apparatus include a dry attritor, a ball mill, and vibration mill. In view of productivity, the attritor is preferred. The dry-milling may be conducted in a manner such that all of the three components, that is, the pigment to be milled, the nonionic surfactant, and the water-soluble resin are milled simultaneously in their mixed state. However, It is more preferable that the nonionic surfactant is added to the pigment firstly and milling is conducted to the mixture as a first step, and subsequently the water-soluble resin is added thereto and dry-milling further conducted as a second milling step. As the case may be, it is also possible to add, to the pigment containing coarse particles, only the water-soluble resin firstly, and dry-mill the mixture of the pigment and resin.
It is necessary to set suitable conditions for the dry-milling in accordance with the specific milling apparatus to be used. Milling temperature is preferably 30 to 150° C. When the milling temperature is higher than the softening temperature of the water-soluble resin that is present together, it is highly feared that the milled materials adhere to each other in the milling apparatus. Therefore, it is necessary to set the temperature to a value lower than the softening point of the water-soluble resin if possible. The milling is preferably conducted for 10 min to 6 hours. When the milling time is shorter, particles milled in an insufficient extent may be unfavorably contained in the pigment. When the milling time is longer, productivity of sufficiently milled pigment unfavorably deteriorates.
The pigment composition of the present invention is in a powder form wherein the surfaces of the finely-milled pigment particles are coated with the water-soluble resin or with the surfactant and the water-soluble resin, and is easily deflocculated and dispersed in water in the presence of an alkali. The pigment composition of the present invention can be made into an aqueous pigment dispersion product in the presence of the alkali by a simple operation, for example, by mixing the composition with a vehicle prepared for use of making aqueous pigment dispersion and stirring the mixture. According to the present invention, the particle size of the dispersed pigment particles contained in the pigment composition can be made substantially equal to that of pigment particles obtained by the salt milling method using a solvent.
The aqueous pigment dispersion product of the present invention can be used, for example, as aqueous paint, textile printing agents, aqueous ink, ink for inkjet printing, dispersing solution for a color filter, or the like.
EXAMPLES
The present invention will be in more detail described by way of examples hereinafter. A pigment used as a standard pigment in the examples is a pigment prepared from a crude pigment by the salt milling method using a solvent. For measurement of crystal types, a X-ray diffraction device was used. Particle sizes and particle forms were observed with a transmission electron microscope.
Example 1
A dry attritor was charged with 83 parts by weight of crude copper phthalocyanine, and 5 parts by weight of “Olfine STG” made by Nissin Chemical Industry as a nonionic surfactant having an acetylenic linkage, and the mixture was milled at 90° C. for 30 minutes. Next, 12 parts by weight of an acrylic resin “Johncryl J-683” made by Johnson Polymer Co., Ltd. were added thereto, and the mixture was further milled at 90° C. for 20 minutes to obtain a pigment composition.
The resultant pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
Next, 18 parts by weight of the obtained pigment composition were added to 20 parts by weight of an aqueous solution containing sodium hydroxide for dissolving the resin, and the mixture was gently stirred at room temperature to obtain a concentrated dispersion product. To the resultant concentrated dispersion product were added 62 parts by weight of an aqueous styrene acrylic emulsion, to prepare a final ink.
As compared with a standard ink containing the same content of the standard pigment, the ink of Example 1 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 140%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 2
A pigment composition was obtained in the same way as in Example 1 except that 5 parts by weight of “Surfynol TG” made by Nissin Chemical Industry were used as a nonionic surfactant having an acetylenic linkage. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then performed to obtain a final ink. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 2 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 130%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 3
A pigment composition was obtained in the same way as in Example 1 except that 5 parts by weight of “Surfynol 504” made by Nissin Chemical Industry were used as a nonionic surfactant having an acetylenic linkage. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then performed to obtain a final ink. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 3 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 110%. The average dispersion particle size of the final ink was 80 to 120 nm.
Comparative Example 1
A pigment composition was obtained in the same way as in Example 1 except that 5 parts by weight of a nonionic surfactant having no acetylenic linkage, i.e., “Newcol 723” made by Nippon Nyukazai Co., Ltd. were used instead of the nonionic surfactant having an acetylenic linkage. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then tried in order to obtain a final ink. However, its color was hardly developed.
Comparative Example 2
A pigment composition was obtained in the same way as in Example 1 except the omission of the step wherein 12 parts by weight of the acrylic resin Johncryl J-683 made by Johnson Polymer Co., Ltd. were added and the mixture was milled at 90° C. for 20 minutes. The content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then performed to obtain a final ink. As compared with the standard ink containing the same content of the standard pigment, the final ink lacked clearness, and the tinting strength was about 70%.
Example 4
A pigment composition was obtained in the same way as in Example 1 except that 3.8 parts by weight of “Olfine STG” made by Nissin Chemical Industry, which were a reduced amount, were used as a nonionic surfactant having an acetylenic linkage. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then performed to obtain a final ink. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 4 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 130%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 5
A pigment composition was obtained in the same way as in Example 1 except that 6.5 parts by weight of “Olfine STG” made by Nissin Chemical Industry, which were an increased amount, were used as a nonionic surfactant having an acetylenic linkage. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was 2% or less.
The same way as in Example 1 was then performed to obtain a final ink. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 5 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 140%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 6
A dry attritor was charged with 84 parts by weight of crude copper phthalocyanine and 16 parts by weight of an acrylic resin “Johncryl J-679” made by Johnson Polymer Co., Ltd., and the mixture was milled at 90° C. for 20 minutes to obtain a pigment composition. The obtained pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the pigment was about 50%.
Next, 18 parts by weight of the obtained pigment composition, together with 1.0 part by weight of “Olfine STG” made by Nissin Chemical Industry as a nonionic surfactant having an acetylenic linkage, were added to 20 parts by weight of an aqueous solution containing sodium hydroxide for dissolving the resin, and the mixture was gently stirred at room temperature to obtain a concentrated dispersion product. To the resultant concentrated dispersion product were added 61 parts by weight of an aqueous styrene acrylic emulsion, to prepare a final ink.
As compared with a standard ink containing the same content of the standard pigment, the ink of Example 6 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 140%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 7
A final ink was obtained in the same way as in Example 6 except that 1.0 part by weight of “Surfynol TG” made by Nissin Chemical Industry was used as a nonionic surfactant having an acetylenic linkage. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 7 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 130%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 8
A final ink was obtained in the same way as in Example 6 except that 1.0 parts by weight of “Surfynol 504” made by Nissin Chemical Industry were used as a nonionic surfactant having an acetylenic linkage. As compared with the standard ink containing the same content of the standard pigment, the ink of Example 8 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 110%. The average dispersion particle size of the final ink was 80 to 120 mn.
Comparative Example 3
A concentrated dispersion product was obtained in the same way as in Example 6 except that 1.0 part by weight of “Olfine STG” made by Nissin Chemical Industry was not used at all as a nonionic surfactant having an acetylenic linkage. Further, 62 parts by weight of an aqueous styrene acrylic emulsion were added to the resultant concentrated dispersion product, to try to prepare a final ink. However, its color was hardly developed.
Comparative Example 4
By means of a dry attritor, crude copper phthalocyanine was milled at 90° C. for 20 minutes. The milled pigment had a content by percentage of α-type crystal of about 30%.
Next, 15 parts by weight of the resultant pigment, together with 1.0 part by weight of “Olfine STG” made by Nissin Chemical Industry as a nonionic surfactant having an acetylenic linkage, were added to 20 parts by weight of water. The mixture was then gently stirred at room temperature to obtain a concentrated dispersion product. To the resultant concentrated dispersion product were added 64 parts by weight of an aqueous styrene acrylic emulsion, to try to prepare a final ink. However, its color was hardly developed.
Example 9
A dry attritor was charged with 84 parts by weight of crude copper phthalocyanine and 16 parts by weight of an acrylic resin “Johncryl J-679” made by Johnson Polymer Co., Ltd., and the mixture was milled at 90° C. for 20 minutes. The resultant pigment composition was in a powder form wherein the surfaces of the milled pigment particles were coated with the acrylic resin, and the content by percentage of α-type crystal in the milled pigment was about 50%.
Next, 18 parts by weight of the resultant pigment composition, together with 0.5 part by weight of “Olfine STG” made by Nissin Chemical Industry as a nonionic surfactant having an acetylenic linkage, were added to 20.5 parts by weight of an aqueous solution containing sodium hydroxide for dissolving the resin. The mixture was then gently stirred at room temperature to obtain a concentrated dispersion product. To the resultant concentrated dispersion product were added 61 parts by weight of an aqueous styrene acrylic emulsion, to prepare a final ink.
As compared with a standard ink containing the same content of the standard pigment, the ink of Example 9 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 120%. The average dispersion particle size of the final ink was 80 to 120 nm.
Example 10
The same way as in Example 9 was performed except that 2.0 parts by weight of “Olfine STG” made by Nissin Chemical Industry, which were an increased amount, were used as a nonionic surfactant having an acetylenic linkage and accordingly 19 parts by weight of an aqueous solution containing sodium hydroxide for dissolving the resin, which were an reduced amount, were used. In this way, a concentrated dispersion product was obtained, and then a final ink was obtained.
As compared with the standard ink containing the same content of the standard pigment, the ink of Example 10 was superior to the standard ink in tinting strength, transparency, clearness and the like. The tinting strength had a quality of about 150%. The average dispersion particle size of the final ink was 80 to 120 nm.
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There are disclosed a pigment composition comprising a dry-milled pigment, a water-soluble resin, and a nonionic surfactant composed of a compound having an acetylenic linkage; and a method for producing a pigment composition, comprising dry-milling a pigment containing coarse particles in the presence of a water-soluble resin and a nonionic surfactant composed of a compound having an acetylenic linkage. The production method is also possible in the form of comprising (a) dry-milling a pigment containing coarse particles in the presence of a nonionic surfactant composed of a compound having an acetylenic linkage thereby obtaining an intermediate milled product, and (b) further dry-milling a mixture of the intermediate milled product and a water-soluble resin. For producing an aqueous pigment dispersion product, there is also disclosed herein a method comprising the steps of (a) dry-milling a pigment containing coarse particles in the presence of a water-soluble resin thereby obtaining a milled product, and (b) dispersing the milled product in water in the presence of a nonionic surfactant composed of a compound having an acetylenic linkage.
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FIELD OF THE INVENTION
[0001] The present invention relates generally to hot melt adhesive dispensing systems, and more particularly to a new and improved hot melt adhesive dispensing system wherein in order to achieve desired and accurate variable output volumes of dispensed hot melt adhesives or other thermoplastic materials, from at least two different fluid flows, so as to satisfy predetermined distribution or application pattern parameters, the at least two different fluid flows are subjected to predetermined pressure modifications.
BACKGROUND OF THE INVENTION
[0002] Multi-plate and other types of hot melt adhesive or other thermoplastic material dispensing systems are well known in the fluid dispensing art and industry. Examples of United States patents disclosing such hot melt adhesive or other thermoplastic material dispensing systems include U.S. Pat. No. 6,051,180 which issued to Kwok on Apr. 18, 2000, U.S. Pat. No. 5,904,298 which issued to Kwok et al. on May 18, 1999, U.S. Pat. No. 5,902,540 which issued to Kwok on May 11, 1999, U.S. Pat. No. 5,882,573 which issued to Kwok et al. on Mar. 16, 1999, and U.S. Pat. No. 5,862,986 which issued to Bolyard, Jr. et al. on Jan. 26, 1999. It is noted further that these patents are directed toward different types of hot melt adhesive dispensing systems, such as, for example, meltblowing, spray pattern dispensing, and the like.
[0003] As exemplified by means of U.S. Pat. No. 5,904,298 which issued to Kwok et al., the disclosed hot melt adhesive or other thermoplastic material dispensing system comprises a dual-component hot melt adhesive or other thermoplastic material dispensing system wherein two fluid flows are able to have their fluids dispensed from a plurality of output nozzles or orifices which are arranged within a transversely disposed array of output nozzles or orifices extending across the lateral extent of the nozzle or die assembly which is fluidically connected to a common manifold or head. In conjunction with such dual-component hot melt adhesive or other thermoplastic material dispensing systems, it is sometimes desired to dispense different volumes of one or both of the fluid flows depending upon the particular or predetermined hot melt adhesive or other thermoplastic material distribution or application pattern parameters to be achieved. In connection with such a dual-components variable volume hot melt adhesive or other thermoplastic material dispensing system, the two fluid flows to the transversely arrayed dispensing nozzles or orifices are respectively controlled by means of two volume control valves. Accordingly, it can be appreciated that with respect to volume deposition of the hot melt adhesive or other thermoplastic material onto an underlying substrate, six potential volume deposition states are possible. The first volume deposition state that can occur is where both of the volume control valves are closed whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate is zero. The second volume deposition state that can occur is where the first volume control valve is open while the second volume control valve is closed whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate is the volume of fluid controlled by means of the first volume control valve. The third volume deposition state that can occur is where the first volume control valve is closed while the second volume control valve is open whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate is the volume of fluid controlled by means of the second volume control valve. The fourth volume deposition state that can occur is where the first volume control valve is maintained open while the second volume control valve is cyclically opened and closed whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate comprises the volume of fluid controlled by means of the first volume control valve to which is added or superimposed in a cyclical or intermittent manner, onto the volume of hot melt adhesive or other thermoplastic material controlled by means of the first volume control valve, the volume of hot melt adhesive or other thermoplastic material controlled by means of the second volume control valve. The fifth volume deposition state that can occur is where the second volume control valve is maintained open while the first volume control valve is cyclically opened and closed whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate comprises the volume of fluid controlled by means of the second volume control valve to which is added or superimposed in a cyclical or intermittent manner, onto the volume of hot melt adhesive or other thermoplastic material controlled by means of the second volume control valve, the volume of hot melt adhesive or other thermoplastic material controlled by means of the first volume control valve. Lastly, the sixth volume deposition state that can occur is where both of the volume control valves are open whereby the volume of hot melt adhesive or other thermoplastic material that is dispensed onto the substrate comprises the combined volumes of the hot melt adhesive or other thermoplastic material as controlled by both of the volume control valves.
[0004] While this conventional system admittedly functions satisfactorily, some operational difficulties and drawbacks have been experienced and noted. More specifically, during the aforenoted fourth and fifth operational states, hydraulic conditions can be such as to effectively be detrimental to the desired depositional results. For example, in connection with the fourth operative state, a first volume of hot melt adhesive is being continuously supplied from the first fluid flow path as a result of the first control valve being maintained open, however, a second volume of hot melt adhesive is effectively being superimposed onto the first volume of hot melt adhesive, from a second fluid flow path, as a result of the cyclical opening and closing of the second control valve. It has been experienced that when the second control valve is closed such that the flow of the second volume of hot melt adhesive is stopped or terminated, the inertial flow of the second volume of hot melt adhesive effectively undergoes, creates, or results in a negative pressure spike or drop which can negatively impact the volume flow of the first hot melt adhesive from the first fluid flow path. This negative impact upon the volume flow of the first hot melt adhesive from the first fluid flow path has in fact manifested itself as a momentary cessation in the dispensed volume of hot melt adhesive from the lateral or transverse array of dispensing dies or nozzle assemblies, whereby a gap in the hot melt adhesive, dispensed from the lateral or transverse array of dispensing dies or nozzle assemblies, appears upon the underlying substrate. A positive pressure spike will likewise occur when one of the fluid flows, having been previously taken off-line as a result of its control valve having been closed, again comes back on-line as a result of its control valve again being opened, whereby it is needed to effectively accommodate such positive pressure spikes in order to maintain the proper volumetric fluid flow of the hot melt adhesive.
[0005] A need therefore exists in the art for a new and improved variable volume hot melt adhesive or other thermoplastic material dispensing nozzle or die assembly wherein structure is incorporated therein such that the aforenoted negative or positive pressure spikes are, in effect, isolated, reduced, or effectively attenuated over a period of time whereby gaps in the dispensed volumes of hot melt adhesive do not occur when the system experiences a negative pressure spike, and in the instance of the system experiencing a positive pressure spike, the flow of the hot melt adhesive is nevertheless likewise controlled and stabilized such that the flow of the hot melt adhesive or other thermoplastic material can continue at the desired volumetric level until the normal line pressure has again been achieved over the requisite period of time.
SUMMARY OF THE INVENTION
[0006] The foregoing and other objectives are achieved in accordance with the teachings and principles of the present invention through the provision of a new and improved dual, variable volume hot melt adhesive dispensing nozzle or die assembly wherein a pair of choke slots are provided within a first fluid control plate. The provision of the choke slots within the first fluid control plate effectively restricts and retards the flow of the fluid through such choke slots whereby volumes of the fluids are effectively built up and stored upstream of the choke slots so as to effectively delay the reaction of pressure spikes upon the fluid flows under both positive and negative conditions. This buildup in pressure and volume is then dispersed or effectively attenuated over a period of time so as to cause the fluid flow to smoothly transition between positive and negative spiked fluid flow conditions and normal fluid flow conditions. Accordingly, the pressure spikes do not adversely affect the resulting fluid flows whereby, for example, under conventional negative pressure spike conditions, gaps in the dispensed hot melt adhesive would otherwise occur.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Various other features and attendant advantages of the present invention will be more fully appreciated from the following detailed description when considered in connection with the accompanying drawings in which like reference characters designate like or corresponding parts throughout the several views, and wherein:
[0008] FIG. 1 is a perspective view of a new and improved variable volume hot melt adhesive dispensing nozzle or die assembly as constructed in accordance with the principles and teachings of the present invention;
[0009] FIG. 2 is an exploded perspective view of the new and improved variable volume hot melt adhesive dispensing nozzle or die assembly, as shown in FIG. 1 , wherein the various plates comprising the dispensing nozzle or die assembly are disclosed; and
[0010] FIGS. 3 a - 3 n are front elevational views of the individual plates comprising the new and improved variable volume hot melt adhesive dispensing nozzle or die assembly as shown in FIGS. 1 and 2 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0011] Referring now to the drawings, and more particularly to FIG. 1 thereof, a new and improved variable volume hot melt adhesive dispensing nozzle or die assembly, constructed in accordance with the principles and teachings of the present invention, is disclosed and is generally indicated by the reference character 100 . It is seen that the dispensing nozzle or die assembly 100 comprises a first interior assembly cover plate 102 , a second exterior assembly cover plate 104 , and a plurality of fluid control plates 106 - 128 interposed between the first interior assembly cover plate 102 and the second exterior assembly cover plate 104 . The plurality of fluid control plates 106 - 128 are adapted to control or determine the flow of the hot melt adhesive or other thermoplastic material and heat air fluids to be conducted through the dispensing nozzle or die assembly 100 , wherein the specific details of the plurality of fluid control plates 106 - 128 will be more fully appreciated from FIGS. 2 and 3 a - 3 n , as well as from the detailed description of the same which follows hereinafter. As can best be seen from FIGS. 1-3 n , a plurality of screw bolts 130 are adapted to pass through the first interior assembly cover plate 102 , the second exterior assembly cover plate 104 , and the plurality of fluid control plates 106 - 128 so as to fixedly secure all of the plates together, while a plurality of fasteners 132 are adapted to mount the assembled dispensing nozzle or die assembly 100 onto a suitable support surface, not shown. More particularly, it is seen that the upper edge portion of the first interior assembly cover plate 102 is provided with a plurality of apertures 134 for accommodating the plurality of fasteners 132 , the upper edge portion of the second exterior assembly cover plate 104 is provided with a plurality of apertures 136 for accommodating the plurality of fasteners 132 , and the upper edge portions of each one of the fluid control plates 106 - 128 are likewise provided with a plurality of apertures 138 - 160 for accommodating the plurality of fasteners 132 . In a similar manner, it is seen that the central portion of the first interior assembly cover plate 102 is provided with a plurality of apertures 162 for accommodating the plurality of screw bolts 130 , the central portion of the second exterior assembly cover plate 104 is provided with a plurality of apertures 164 for accommodating the plurality of screw bolts 130 , and the central portions of each one of the fluid control plates 106 - 128 are likewise provided with a plurality of apertures 166 - 188 for accommodating the plurality of screw bolts 130 .
[0012] With reference continuing to be made to FIGS. 2-3 n , it is to be appreciated that in accordance with the principles and teachings of the present invention, it is desired to develop a hot melt adhesive or other thermoplastic material dispensing nozzle or die assembly for dispensing or depositing hot melt adhesives or other thermoplastic materials onto a substrate in accordance with particularly desired or required deposition patterns comprising variable volumes of, for example, two hot melt adhesives or other thermoplastic materials to be dispensed or deposited onto the substrate at particular or specified locations. More particularly, it is seen that a first volumetric fluid flow of a first hot melt adhesive or other thermoplastic material, denoted by means of the flow arrow 190 , passes through the first interior assembly cover plate 102 and exits from a first fluidsupply port 191 , and that the first fluid flow 190 subsequently passes through a first fluid aperture 192 defined within a lower portion of the first fluid control plate 106 . The first fluid aperture 192 is fluidically connected to a first horizontally oriented choke slot 194 also defined within the lower portion of the first interior assembly cover plate 102 . In a similar manner, it is noted that a second volumetric fluid flow of a second hot melt adhesive or other thermoplastic material, denoted by means of the flow arrow 196 , also passes through the first interior assembly cover plate 102 and exits from a second fluid supply port 197 , and that the second fluid flow 196 subsequently passes through a second fluid aperture 198 also defined within the lower portion of the first fluid control plate 106 . The second aperture 198 is similarly fluidically connected to a second horizontally oriented choke slot 200 also defined within the lower portion of the first interior assembly cover plate 102 . It is noted that the first and second fluid apertures 192 and 198 are disposed transversely remote from each other, while the first and second choke slots 194 and 200 are disposed somewhat adjacent to each other. In this manner, the first and second fluid flows will flow from the transversely remote first and second fluid apertures 192 , 198 and through the first and second choke slots 194 , 200 such that the resulting fluid flow outputs will effectively exit from the first fluid control plate 106 at a substantially central portion of the first fluid control plate 106 . Accordingly, it is further seen that a third fluid flow aperture 202 is defined within a lower central portion of the second fluid control plate 108 such that a single fluid flow, effectively comprising the combined flow of the first and second fluid flows 190 , 196 , exits the third fluid flow aperture 202 as the combined fluid flow which is denoted by means of the fluid flow arrow 204 .
[0013] Continuing further, the combined fluid flow 204 will next flow toward the third fluid control plate 110 within which there is defined, at a relatively central region within the lower portion of the fluid control plate 110 , a first transversely extending primary fluid distribution slot 206 which serves to effectively distribute the fluid flow 204 in a transversely balanced manner. The fluid flow 204 will then exit the third fluid control plate 110 and flow toward the fourth fluid control plate 112 within which there is defined, within the lower portion of the fluid control plate 112 , a pair of laterally spaced, transversely extending secondary fluid distribution slots 208 , 210 which serve to effectively pass the balanced fluid flow toward a plurality of laterally or horizontally spaced nozzle feed apertures 212 which are disposed within a transversely extending array across the lower edge portion of the fifth fluid control plate 114 . It will be noted that the sixth fluid control plate 116 and the seventh fluid control plate 118 are likewise provided with similar nozzle feed apertures 214 and 216 , respectively, however, it is to be appreciated that the nozzle feed apertures 214 and 216 are progressively changing in aperture size such that the fluid flow of hot melt adhesive or other thermoplastic material flows therethrough in a balanced manner under constant pressure conditions. The fluid flows will then flow toward a plurality of dispensing nozzles 218 , which are disposed within a transversely extending array across the lower edge portion of the eighth fluid control plate 120 , from which the hot melt adhesive or other thermoplastic material will be dispensed under constant volume conditions as determined by means of the volumetric flows originally developed by means of the original first and second fluid flows 190 , 196 .
[0014] Having described substantially all of the major components of the variable volume hot melt adhesive or other thermoplastic material dispensing nozzle or die assembly 100 in order to dispense or deposit a dual-component hot melt adhesive or other thermoplastic material, as a combined flow of the dual-component hot melt adhesive or other thermoplastic material, onto an underlying substrate in accordance with the principles and teachings of the present invention, a brief description of the operation of the dispensing nozzle or die assembly 100 will now be provided. When the control valves controlling the first and second fluid flows 190 , 196 are both closed, there will obviously be no dispensing of any hot melt adhesive or other thermoplastic material. In a similar manner, a partial dispensing of hot melt adhesive or other thermoplastic material can be achieved by opening either one of the control valves controlling one of the first and second volumetric fluid flows 190 , 196 . In addition, assuming that the control valve controlling the first volumetric fluid flow 190 has been opened, the first volumetric fluid flow 190 is permitted to flow continuously. If the control valve controlling the second volumetric fluid flow 196 is then also opened, the second volumetric fluid flow 196 will in effect be superimposed upon the first volumetric fluid flow 190 and in effect cause an increase in the overall volumetric fluid flow as may be desired or required in accordance with predetermined or specified hot melt adhesive or other thermoplastic material dispensing patterns. Subsequently, if the second volumetric fluid flow 196 is terminated as a result of, for example, its fluid control valve being closed, so as to achieve a different particularly specified or predetermined hot melt adhesive or other thermoplastic material dispensing or deposition pattern, the second choke slot 200 will effectively cause a sufficient pressurized volume of the second fluid flow 196 to be retained or stored upstream of the second choke slot 200 whereby this retained or stored pressurized volume of the second fluid flow 196 can be subsequently released over a period of time. This fluidic occurrence or pressurized state has the effect of delaying the reaction of the negative pressure spike, attendant the closing of the second fluid control valve and the stoppage of the second fluid flow, upon the first fluid flow. Accordingly, the first fluid flow will smoothly transition from the combined or dual-fluid flow to the single fluid flow conditions without the dispensing or deposition of the hot melt adhesive or other thermoplastic material experiencing any adverse dispensing or deposition characteristics, such as, for example, a gap or space in the deposited hot melt adhesive or other thermoplastic material.
[0015] More particularly, for the choke slot 200 to work or operate properly, whereby the retained or stored pressurized volume of the second fluid flow 196 can in fact be released over a predetermined period of time with the desired results, the cross-sectional area of the choke slot 200 must be substantially equal to or slightly less than (≦) the cross-sectional areas of all ten of the dispensing nozzles 218 . During this mode of operation, that is, when the second fluid flow 196 has been terminated, it will be appreciated that the volume of the dispensed hot melt adhesive or other thermoplastic material, in the form of dispensed filaments dispensed or deposited from the dispensing nozzles 218 onto the underlying substrate, will effectively smoothly transition from filaments having a relatively large diametrical cross-section, corresponding to that point in time when both fluid flows 190 , 196 were flowing, to filaments having a relatively small diametrical cross-section, corresponding to that point in time when the second fluid flow 196 was terminated and when the retained or stored pressurized volume of the second fluid flow 196 has been released or dissipated over a predetermined period of time.
[0016] Continuing still further, while the aforenoted choke structure can be utilized in conjunction with various different types of hot melt adhesive dispensing or deposition systems, the hot melt adhesive or other thermoplastic material dispensing nozzle or die assembly, as illustrated within FIGS. 1-3 n , is particularly utilized or adapted for use as a hot melt adhesive or other thermoplastic material spray device, and accordingly, requires an attendant supply of heated air to be used in conjunction with the fluid flows of the hot melt adhesive or other thermoplastic material being dispensed from the dispensing nozzles and onto the underlying substrate in order to achieve the desired or required hot melt adhesive or other thermoplastic material deposition patterns. More particularly, with reference continuing to be made to FIGS. 2-3 n , first and second hot air flows 220 , 222 are conducted through a first set of apertures 224 , 226 defined within the first interior assembly cover plate 102 . Similar sets of fluid flow apertures 228 - 246 are respectively provided within the fluid control plates 106 - 114 . Fluid control plates 116 - 120 are respectively provided with pairs of laterally spaced, substantially arcuately shaped air slots 248 - 258 for receiving the air flows 220 , 222 from the apertures 244 , 246 within fluid control plate 114 , and for effectively transforming the substantially linearly oriented air flows into laterally or transversely extending air flow arrays. After traversing the arcuately-shaped air slots 256 , 258 defined within the fluid control plate 120 , the air flows 220 , 222 will respectively pass through first and second sets of apertures 260 , 262 which are defined within the ninth fluid control plate 122 so as to be fluidically aligned with the opposite ends of each one of the arcuately-shaped air slots 256 , 258 .
[0017] In turn, the tenth fluid control plate 124 is provided within a pair of laterally spaced substantially arcuately-shaped air slots 264 , 266 for receiving the air flows 220 , 222 from the apertures 260 , 262 and for respectively conducting the air flows 220 , 222 toward the upper end portions or upstanding legs of two substantially U-shaped air distribution passageways 268 , 270 which are defined within the eleventh fluid control plate 126 . It is further seen that the lower portions of the U-shaped air distribution passageways 268 , 270 are integrally provided with and fluidically connected to a pair of laterally spaced, horizontally oriented or transversely extending slots 272 , 274 , and that still yet further, the tenth fluid control plate 124 is likewise provided with a pair of laterally spaced, horizontally oriented or transversely extending slots 276 , 278 adjacent to the lower edge portion thereof. In this manner, it can be appreciated that after the air flows 220 , 222 have passed through the arcuately-shaped apertures 264 , 266 of the tenth fluid control plate 124 , and have entered the upper end portions of the upstanding legs of the air distribution passageways 268 , 270 within the eleventh fluid control plate 126 , the air flows 220 , 222 will be conducted downwardly through the passageways 268 , 270 , into the air flow slots 272 , 274 , and into the air flow slots 276 , 278 defined within the tenth fluid control plate 124 . Continuing still further, it is seen that the ninth fluid control plate 122 is provided with a horizontally disposed, transversely extending array of apertures 280 which are disposed within the vicinity of the lower edge portion of the ninth fluid control plate 122 and which are adapted to be fluidically connected to the air flow slots 276 , 278 of the tenth fluid control plate 124 . In this manner, the air flows 220 , 222 will be conducted from the air flow slots 276 , 278 of the tenth fluid control plate 124 , through the apertures 280 of the ninth fluid control plate 122 , and into pairs of hot air inlets 282 which are respectively defined within lower regions of the eighth fluid control plate 120 and which are disposed upon opposite sides of each one of the dispensing nozzles 218 defined or provided within the lower edge portions of the eighth fluid control plate 120 . It is to be appreciated that the plurality of apertures 280 are defined at height elevations or locations within the ninth fluid control plate 122 such that the exiting air flows 220 , 222 will enter the upper end portions of the hot air inlets 282 of the eighth fluid control plate 120 whereby such air flows 220 , 222 can then flow downwardly toward the dispensing nozzles 218 so as to in fact assist in the hot melt adhesive or other thermoplastic material dispensing or deposition onto an underlying substrate.
[0018] Obviously, many variations and modifications 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 present invention may be practiced otherwise than as specifically described herein.
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A dual, variable volume hot melt adhesive dispensing nozzle or die assembly is provided with a pair of choke slots within a first fluid control plate. The provision of the choke slots within the first fluid control plate effectively restricts and retards the flow of the fluid through such choke slots whereby volumes of the fluids are effectively built up and stored upstream of the choke slots so as to effectively delay the reaction of pressure spikes upon the fluid flows under both positive and negative conditions. This buildup in pressure and volume is then dispensed over time so as to cause the fluid flow to smoothly transition between positive and negative spiked fluid flow conditions and normal fluid flow conditions. Accordingly, the pressure spikes do not adversely affect the resulting fluid flows whereby, for example, under conventional negative pressure spike conditions, gaps in the dispensed hot melt adhesive would otherwise occur.
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BACKGROUND OF THE INVENTION
Cataract surgery generally involves the removal of the natural lens and the implantation of an intraocular lens. Both extracapsular lens removal, which leaves the posterior capsule, and intracapsular removal in which the natural lens is removed, together with the lens capsule, require relatively large incisions in the eye of the order of 7 to 8 millimeters in length. Phacoemulsification, which breaks up the natural lens with ultrasound and removes the pieces, requires a small incision of only about 3 to 31/2 millimeters in length.
A small incision in the eye is greatly preferred because it produces less trauma, minimizes fluid losses, reduces the likelihood of infection and inflammation and minimizes and facilitates the suturing required to close the incision. Although phacoemulsification requires only a small incision for removal of the natural lens, the optic of the intraocular lens is typically of the order of 6 millimeters in diameter and, therefore, is too large to pass through the 3 to 31/2 millimeter incision. Accordingly, even if phacoemulsification is used, it is necessary to enlarge the incision in order to insert the intraocular lens.
In an effort to overcome this, it has been proposed in Kelman U.S. Pat. No. 4,451,938 to construct the intraocular lens in multiple pieces, insert the pieces separately into the eye and then assemble them within the eye. Unfortunately, the surgical techniques required for assembly of the individual pieces of intraocular lens in the eye are extremely difficult.
It has also been proposed in Mazzocco British Patent Application No. 2,144,315 and Kelman European Patent Application No. 83303414.3 to utilize a deformable optic which can be folded for insertion through a small incision into the eye. One problem with this approach is that it has been difficult to find materials which are both adequately deformable and suitable for use as an optic.
SUMMARY OF THE INVENTION
This invention generally overcomes the disadvantages noted above by providing an optic which has at least one dimension which is small enough to pass through a relatively short or small incision, such as a 3 to 3.5 millimeter incision. Unlike the prior art discussed above, the optic can be rigid and be integrally constructed in a single piece so that no folding or assembly of the optic is necessary.
The optic can be provided with a suitably small dimension or dimensions in various different ways. For example, the optic may be circular and have a reduced diameter. However, to increase the area of the optic in a direction transverse to the optical axis of the lens while providing a small dimension to enable insertion through a small incision, the optic is preferably elongated. Preferably, the optic is in the form of a central segment of a circle.
The eye has an active optical region which is approximately 5 to 6 millimeters in diameter and which is transverse to the optical axis of the eye. Light passing through this region of the eye can be focused by the lens on the retina and, therefore, seen. However, because a dimension of the optic is less than 5 to 6 millimeters, light within the active optical region which does not pass through the optic would produce glare.
This invention provides glare-reducing means to reduce or eliminate the glare resulting from light in the active optical region which does not pass through the optic. Generally, the glare-reducing means can be any means or member capable of reducing the glare observed by the patient who wears the intraocular lens. For example, the glare-reducing means may reduce the transmission of light through the active optical region to the retina. For example, the glare-reducing means may transmit no more than about 60 percent of the visible light incident thereon, although preferably it transmits no more than about 10 percent of such light. For optimum glare-reducing results, the glare-reducing means is essentially opaque so that it transmits no more than about 1 percent of such light. However, to achieve this low a percent of transmission, the glare-reducing means would need to be black, and this is undesirable. Accordingly, the overall preferred construction is one which achieves the lowest percent of visible light transmission without making the glare-reducing means black, and this may be about 10 percent transmission.
The glare-reducing means reduces glare resulting from light in that portion of the active optical region which does not pass through the optic. Because the active optical region is generally circular, the glare-reducing means is preferably present in any region of this circle not occupied by the optic. To the extent that the glare-reducing means is not operative in this region, the glare will increase. Accordingly, for optimum results, the glare-reducing means should be effective throughout the active optical region where the optic is not present.
The provision of glare-reducing means, however, increases the dimensions of the intraocular lens so that it will not pass through the relatively short 3 to 3.5 millimeter incision. To solve this problem, this invention provides that at least a portion of the glare-reducing means be deformable to permit a reduction in an overall dimension of the intraocular lens to facilitate implantation.
The glare-reducing means is not part of the optic in that it does not focus light on the retina. In addition, the glare-reducing means transmits a lower percentage of incident visible light than the optic and has a different power than the optic.
The glare-reducing means preferably includes a first glare-reducing section extending along one of the elongated sides of the optic and a joining section which joins the first glare-reducing section to the optic. In a preferred construction, the glare-reducing means includes a second glare-reducing section which extends along the other elongated side of the optic and is coupled to the joining section.
The optic has opposite ends, and the joining section advantageously projects beyond one of the ends to form a lead-in to facilitate implantation. The optic has a posterior face, and the glare-reducing sections overlap the posterior face of the optic along the associated elongated sides to assure that light transmission is reduced or eliminated outside the optic.
The glare-reducing sections are preferably, flexibly joined to the joining section so they can be moved over the optic for implantation. Because the glare-reducing sections are preferably located posteriorly of the posterior face of the optic, they can be moved over the posterior face without interference from the optic. The glare-reducing sections may be rigid.
The invention, together with additional features and advantages thereof, may best be understood by reference to the following description taken in connection with the accompanying illustrative drawing.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front elevational view of an intraocular lens constructed in accordance with the teachings of this invention.
FIG. 2 is an isometric view of the intraocular lens.
FIG. 3 is a side elevational view of the intraocular lens.
FIG. 4 is an enlarged, fragmentary sectional view taken generally along line 4--4 of FIG. 1.
FIG. 5 is an exploded isometric view of the intraocular lens.
FIGS. 6-8 illustrate how the intraocular lens can be inserted through an incision into the eye.
FIG. 9 is a sectional view showing the intraocular lens implanted in the eye.
FIG. 10 is a sectional view taken generally along line 10--10 of FIG. 9.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIGS. 1-5 show an intraocular lens 11 which comprises a rigid optic 13, glare-reducing means in the form of a glare attachment 15 and fixation means in the form of resilient loops 17 and 19 for affixing the intraocular lens within the eye. Although the optic 13 can be of various sizes and configurations, in the embodiment illustrated, it has an optical axis 21, and it is elongated in a direction generally transverse to the optical axis such that the optic has elongated, planar, parallel sides 23 and 25 and opposite ends 27 and 29. In the embodiment illustrated, the optic 13 is in the form of a central segment of circle, and thus the ends 27 are circular. The optic 13 has a posterior face 31 and an anterior face 33, and in the embodiment illustrated, the posterior face is planar, and the anterior face is convex.
The glare attachment 15 reduces glare resulting from light in a zone which extends along the elongated sides 23 and 25 of the optic 13 when the intraocular lens 11 is implanted as described more fully hereinbelow in connection with FIGS. 9 and 10. The glare attachment 15 may be formed by machining and, like the optic 13, may be integrally constructed of polymethylmethacrylate or other suitable material for implantation in the eye.
Generally, the glare attachment in this embodiment comprises glare-reducing sections 35 and 37 and a joining section 39 which joins the glare-reducing sections to each other and to the optic 13. The glare-reducing sections 35 and 37 may be identical, and each of them has a linear, inner edge 41 and a curved part-circular outer edge 43. Each of the glare-reducing sections 35 and 37 forms an outer segment of a circle and is in the form of a thin disc having flat, opposed, parallel faces. As shown in FIG. 5, the inner edges 41 are widely spaced by a slot 45 which extends all the way to the joining section 39. Each of the glare-reducing sections 35 and 37 transmits a substantially lower percent of visible incident light than the optic 13, and in this embodiment, each of them transmits no more than about 10 percent of such incident visible light.
The joining section 39 includes a thin web 47 in the form of a shallow "U" which integrally joins adjacent ends of the glare-reducing sections 35 and 37. The joining section 39 also includes an elongated finger or tab 49 which projects into the slot 45 as shown in FIG. 5 and which projects upwardly out of the plane of the glare-reducing sections 35 and 37 as shown in FIG. 4. The web 47 is resiliently deformable so that the glare-reducing sections can be moved relative to each other. In the unrestrained condition, the web 47 retains the glare-reducing sections 35 and 37 in the position shown in FIGS. 1-5 in which the edges 41 are parallel, and the glare-reducing sections 35 and 37 are co-planar.
Although the glare attachment 15 could be directly or indirectly coupled to the optic 13 in various different ways, in the embodiment illustrated, it is directly coupled to the optic by sonic welding an end portion of the tab 49 to the posterior face 31 adjacent the end 27 as shown in FIGS. 1 and 4. With the glare attachment 15 coupled to the optic 13 in this manner, the optic 13 lies just anteriorly of, and centered on, the slot 45, and the glare-reducing sections 35 and 37 extend along the sides 23 and 25, respectively, of the optic 13.
To facilitate appropriate, inward movement of the glare-reducing sections 35 and 37, they are preferably located in a plane which lies just posterior of the posterior face 31 as best shown in FIG. 3. To assure that there is no gap between the optic 13 and the glare-reducing sections 35 and 37, inner edge portions of the glare-reducing sections along the inner edges 41 overlap outer edge portions of the optic 13 along the sides 23 and 25 of the optic.
The glare-reducing sections 35 and 37 cooperate with the optic 13 to form a circle which may be, for example, 6 millimeters in diameter. The optic 13 forms a central segment of this circle, and the glare-reducing sections 35 and 37 form outer segments of the circle, with the sides 23 and 25 and the edges 41 forming, in effect, chords of the circle. The joining section 39 projects from the periphery of this circle to form a lead-in which facilitates implantation. The width dimension of the optic, i.e., the distance between the sides 23 and 25, may be, for example, about 3 millimeters. The glare-reducing sections 35 and 37 can be moved toward each other over the posterior face 31 against the resilient biasing action of the web 47 to reduce the overall width dimension of the intraocular lens 11 to 3 millimeters or slightly larger than 3 millimeters.
Although the fixation means can take various different forms, in the embodiment illustrated, the fixation means includes loops 17 and 19 of polypropylene or other suitable material. Each of the loops 17 and 19 has a proximal end portion 51 which is received within a bore in one of the ends 27 and 29. Alternatively, the loops may be appropriately coupled to the glare attachment 15. Although the loops 17 and 19 may taken different forms, in the illustrated embodiment, each of them is in the form of a resilient "J" loop which is vaulted anteriorly as best shown in FIGS. 2 and 3.
FIGS. 6-8 show one way in which the intraocular lens 11 can be inserted through a relatively small incision 53 into the eye 55 after removal of the natural lens (not shown) through the incision utilizing phacoemulsification. For example, the incision 53 may be of the order of 3.5 to 4 millimeters in length.
FIG. 6 shows the intraocular lens with the loop 17 being inserted through the incision 53 and with the glare-reducing sections 35 and 37 unfolded.
FIG. 7 shows the intraocular lens 11 advanced further through the incision 53 and with the glare-reducing sections 35 and 37 being moved inwardly toward each other along the posterior face 31 of the optic 13 as a result of the resilient deformation of the web 47. FIG. 7 also shows how the joining section 39 forms a lead-in through the incision 53 and across the interior of the eye to facilitate implantation.
FIG. 8 shows the glare-reducing sections moved toward each other sufficiently such that the end portions thereof overlap slightly. In this position, the glare-reducing sections 35 and 37 project only slightly beyond the sides 23 and 25 of the optic 13. The glare-reducing sections 35 and 37 may be cammed to this position by the ends of the incision or held in this position by the surgeon. Accordingly, the intraocular lens 11 can be inserted through the incision 53, even though the incision is only slightly longer than the width of the optic 13.
FIGS. 9 and 10 show the intraocular lens 11 implanted in the eye 55. Although the intraocular lens 11 could be implanted within the capsular bag 57, in the embodiment illustrated, the loops 17 and 19 are vaulted anteriorly to engage the ciliary sulcus 59. When so mounted, the intraocular lens 11 is in the posterior chamber 61 coaxial with the pupil 63.
As shown in FIGS. 10, the intraocular lens 11 is implanted so that the optic 13 has its long axis vertical. When implanted, the resilience of the web 47 returns the glare-reducing sections 35 and 37 to the position shown in FIGS. 1-4.
The optic 13 is at the active optical region of the eye 55, and it focuses light passing through it from the pupil 63 on the retina. Because the optic 13 is narrower than the diameter of the active optical region and has an area less than the area of the active optical region, the light outside the optic cannot be focused on the retina. Accordingly, but for the presence of the glare-reducing sections 35 and 37, this light would pass unfocused to the retina and produce glare. However, the glare-reducing sections 35 and 37 substantially reduce transmission of this light to substantially reduce the glare.
Although an exemplary embodiment of the invention has been shown and described, many changes, modifications and substitutions may be made by one having ordinary skill in the art without necessarily departing from the spirit and scope of this invention.
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An intraocular lens comprising an elongated optic and first and second glare-reducing sections extending along the elongated sides of the optic. The glare-reducing sections are joined to each other and to the optic by a joining section. The joining section is flexible so that the glare-reducing sections can be moved over the optic to reduce the overall dimensions of the intraocular lens for implantation. Fixation members fix the intraocular lens in the eye.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 USC §119(a) of a Korean Patent Application No. 10-2015-0165869 filed on Nov. 25, 2015, the subject matter of which is hereby incorporated by reference.
BACKGROUND
[0002] Field of the Invention
[0003] It has been required in pharmaceutical and cosmetic fields before to develop a formulation that can effectively act on the skin to improve the skin conditions, while stably loading various kinds of materials with efficacy on the skin into the product.
[0004] However, there was a problem that most of drugs are sparingly soluble or unstable so as to make the whole system unstable by combining or reacting with other materials.
[0005] Thus, various techniques for loading effective drugs into formulations more stably and also easily have been developed, and for example, nanoemulsions preparing emulsified particles by a nano unit, liposome using self-assembly characteristic of phospholipids, solid lipid nanoparticluates nano-microparticulating solid lipids or polymer type nanoparticulates stabilizing interfaces with a surfactant, and the like may be illustrated.
[0006] However, such nanoparticulates had still a difficult problem in improving a problem of poor solubility in target drugs and the percutaneous absorption effect according to the dispersion property.
BACKGROUND ART
[0007] JP Laid-open Patent Publication No. 2009-155282
SUMMARY OF THE INVENTION
Technical Problem
[0008] The present application provides a micelle which is encapsulated by an amphiphilic polymer to have an excellent dispersion property and a process for preparing the same.
[0009] The present application also provides a composition comprising such micelles.
Technical Solution
[0010] The present application relates to a micelle comprising a drug which is encapsulated by an amphiphilic polymer and a process for preparing the same.
[0011] In addition, the present application relates to a composition comprising the micelles.
[0012] The present application may provide a micelle having an excellent dispersion property by effectively encapsulating a drug with a block copolymer which may represent a phase separation property using its self-assembly characteristic and also encapsulating a subject material using an amphiphilic polymer having an excellent dispersion property in a composition, where the formulation comprising these micelles may exhibit an excellent percutaneous absorption characteristic.
[0013] In the present application the term “amphiphilic polymer” may mean a polymer comprising areas having different physical properties from each other, for example different solubility parameters from each other at the same time, for example, a polymer comprising a hydrophilic area and a hydrophobic area at the same time.
[0014] In the present application the term “hydrophilic or hydrophobic area” means an area included in a polymer in a state such that it is ascertainable for each area to be phase-separated, for example, with forming a block, where each degree of hydrophilicity or hydrophobicity is relative.
[0015] In the present application the term “self-assembly characteristic” means a phenomenon that the amphiphilic polymer voluntarily causes fine phase separation in oil or in water to have a predetermined size of regularity.
[0016] The micelle of the present application comprises a drug; and an amphiphilic polymer encapsulating the drug and having a first block (A) and a second block (B) which is phase-separated with the first block (A). In addition, the second block (B) comprises a polymerization unit of an acrylic monomer or a vinylic monomer.
[0017] In the present application the term “micelle” may mean a particle of several nano to tens of thousands nano size having a core/shell structure by the self-assembly characteristic of the amphiphilic polymer.
[0018] The micelle of the present application comprising the amphiphilic polymer encapsulating the drug may have an excellent dispersion property in oil or in water, and also have an excellent stability to be effectively applied to the formulation having an excellent percutaneous absorption characteristic.
[0019] In one example, as depicted in FIG. 1 , the micelle of the present application may be a structure comprising a drug ( 100 ) and an amphiphilic polymer ( 200 ) encapsulating the drug ( 100 ). In addition, the amphiphilic polymer ( 200 ) may comprise a first block ( 201 ) and a second block ( 202 ) to have a structure that the second block ( 202 ) of the amphiphilic polymer ( 200 ) is adjacent to the drug ( 100 ). The encapsulation above, as in FIG. 1 , is a term meaning a structure that the amphiphilic polymer wraps around the drug, and is used in the same meaning as the “loading” herein.
[0020] Typically, the drug is sparingly soluble, but the drug of the present application may be encapsulated by the amphiphilic polymer having a hydrophobic area and a hydrophilic area at the same time to secure an excellent dispersion property of the drug in oil or in water.
[0021] In addition, in the case of the micelle of the present application, it may be effectively dispersed in oil or in water, in a state securing stability, by including the amphiphilic polymer having an excellent interaction with certain drug.
[0022] The drug contained in the micelle of the present application is not particularly limited, but may include, for example, physiologically active substances.
[0023] In one example, the physiologically active substance may be sparingly soluble.
[0024] Such a physiologically active substance may be any one selected from the group consisting of, for example, genistein, daidzein, cucurbitasin, prangenidin or a derivative thereof; a polyphenol; or a mixture thereof.
[0025] By way of example of the physiologically active substance, genistein, daidzein, cucurbitasin, prangenidin or a derivative thereof above, means a phenolic compound or a glycoside thereof contained in soybean, which has a structure similar to estrogen of a female hormone, and an excellent antioxidant effect, and the like, so that is used in various applications from skin care to anticancer treatment.
[0026] Specifically, the isoflavone may be genistein or a glycoside of the genistein, for example acetyl genistein or malonyl genistein, and the like, but is not limited thereto.
[0027] Isoflavone such as genistein, daidzein, cucurbitasin, prangenidin or a derivative thereof above is a phenolic compound, which includes intramolecular —H, wherein the intramolecular —H may form a hydrogen bond with a functional group being capable of forming the hydrogen bond contained in the second block (B) of the amphiphilic polymer to improve stability of the drug located inside the micelle.
[0028] The drug contained in the micelle may be included in an amount such that the physiological activity may be expressed, when the micelle has been prepared in a formulation.
[0029] In one example, the content of the drug may be in a range of 1 to 60% by weight, 1 to 50% by weight, 1 to 40% by weight or 1 to 20% by weight relative to the total weight of the micelle. When the content of the drug exceeds 60% by weight, the effective loading cannot be achieved, and the drug may be effused out of the micelle to be agglomerated into a crystal form or modified.
[0030] Such a micelle may have an average particle diameter in a range of 1 nm to 10,000 nm. The average particle diameter of the micelle is a value measured by a dynamic light scattering method, which may be a range covering a particle diameter of a single micelle or micelle aggregates themselves.
[0031] The micelle of the present application comprises the amphiphilic polymer encapsulating the drug.
[0032] The amphiphilic polymer of the present application comprises a first block (A) and a second block (B) that is phase-separated with the first block (A), and also the second block (B) comprises a polymerization unit (B1) of an acrylic monomer or a vinylic monomer having a solubility parameter of a single polymer of less than 10.0 (cal/cm 3 ) 1/2 .
[0033] The amphiphilic polymer of the present application may include two blocks which are phase-separated from each other to effectively load a drug.
[0034] The term “phase-separated from each other” in the present application means a state that the first block and the second block are not mixed with each other in the absence of external action to form each block.
[0035] The amphiphilic polymer of the present application comprises the first block (A) and the second block (B) that is phase-separated with the first block (A).
[0036] The first block (A) means a hydrophilic area of the amphiphilic polymer, which may comprise, for example, a polymer having a solubility parameter of 10 (cal/cm 3 ) 1/2 or more.
[0037] Methods to obtain the solubility parameter are not particularly limited, and may follow methods known in the art. For example, the parameter may be calculated or obtained according to the method known in the art as so-called HSP (Hansen solubility parameter).
[0038] In another example, the first block (A) may comprise a polymer having a solubility parameter of has a solubility parameter of 13 (cal/cm 3 ) 1/2 or more, 14 (cal/cm 3 ) 1/2 or more, 15 (cal/cm 3 ) 1/2 or more, 16 (cal/cm 3 ) 1/2 or more or 17 (cal/cm 3 ) 1/2 or more. The upper limit of the solubility parameter of the first block (A) is not particularly limited, and may be, for example, 25 (cal/cm 3 ) 1/2 or less, or 23 (cal/cm 3 ) 1/2 or less.
[0039] The first block (A) may comprise the known polymers without any limitation, if they satisfy the abovementioned solubility parameter and may form a hydrophilic area of the amphiphilic polymer being capable of including a drug, according to the present invention.
[0040] In one example, the first block (A) may be any one selected from the group consisting of polyethylene glycol, a polyethylene glycol-propylene glycol copolymer, polyvinyl pyrrolidone and polyethyleneimine.
[0041] Specifically, the first block (A) may be polyethylene glycol having a number average molecular weight in a range of 500 to 100,000, but is not limited thereto. The term “number average molecular weight” in the present application may mean an analytical value measured by a nuclear magnetic resonator (NMR), and unless particularly specified otherwise, the molecular weight of any polymer may mean a number average molecular weight of the polymer.
[0042] The second block (B) comprises a polymerization unit (B1) of an acrylic monomer or a vinylic monomer having a solubility parameter of a single polymer of less than 10.0 (cal/cm 3 ) 1/2 .
[0043] In the present application the term “acrylic monomer” means (meth)acrylic acid or a derivative thereof. In addition, the term “(meth)acrylic acid” means acrylic acid or methacrylic acid.
[0044] The second block (B) of the amphiphilic polymer of the present application is a site that serves to form a micelle shape by adjoining the drug and encapsulating around the drug.
[0045] Thus, the second block (B) refers to the relatively hydrophobic site within the amphiphilic polymer.
[0046] In another example, the second block (B) may comprise a polymerization unit (B1) of an acrylic monomer or a vinylic monomer having a solubility parameter of a single polymer of less than 9.8 (cal/cm 3 ) 1/2 or less than 9.5 (cal/cm 3 ) 1/2 . The lower limit of the solubility parameter of the acrylic monomer or the vinylic monomer is not particularly limited, and may be, for example, 2 (cal/cm 3 ) 1/2 or more, or 4 (cal/cm 3 ) 1/2 or more.
[0047] As the acrylic monomer, a compound may be illustrated, which is represented by Formula 1 or 2 below, without being limited thereto.
[0000]
[0048] In Formulas 1 and 2, Q is hydrogen or an alkyl group, B in Formula 1 is a straight or branched alkyl group having at least one carbon atom, an alicyclic hydrocarbon group, an aromatic substituent or a carboxyl group, and R 1 and R 2 in Formula 2 are each independently hydrogen, a linear or branched alkyl group having at least one carbon atom, an alicyclic hydrocarbon group, or an aromatic substituent.
[0049] In Formulas 1 and 2, the alkyl group present in Q may use an alkyl group of 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms. The alkyl group may be of straight-chain, branched-chain or cyclic. In addition, the alkyl group may be optionally substituted by one or more substituents.
[0050] In Formulas 1 and 2, B, R 1 and R 2 may be each independently a straight or branched alkyl group of at least 1 carbon atom, at least 3 carbon atoms, at least 5 carbon atoms, at least 7 carbon atoms or at least 9 carbon atoms, which may be substituted or un-substituted. The compound comprising such a relatively long-chain alkyl group is known as a hydrophobic compound. The upper limit of the number of carbon atoms in the straight-chain or branched-chain alkyl group is not particularly limited, and for example, the alkyl group may be an alkyl group having up to 20 carbon atoms.
[0051] In Formulas 1 and 2, B, R 1 and R 2 may be, in another example, an alicyclic hydrocarbon group, for example, an alicyclic hydrocarbon group of 3 to 20 carbon atoms, 3 to 16 carbon atoms or 6 to 12 carbon atoms, and examples of such a hydrocarbon group may include an alicyclic alkyl group of 3 to 20 carbon atoms, 3 to 16 carbon atoms or 6 to 12 carbon atoms, and the like, such as a cyclohexyl group or an isobornyl group. The compound having such an alicyclic hydrocarbon group is also known as a relatively hydrophobic compound.
[0052] In Formulas 1 and 2, B, R 1 and R 2 may be, in another example, an aromatic substituent, for example, an aryl group or an arylalkyl group, and the like.
[0053] The aryl group above may be, for example, an aryl group of 6 to 24 carbon atoms, 6 to 18 carbon atoms or 6 to 12 carbon atoms. In addition, the alkyl group of the arylalkyl may be, for example, an alkyl group of 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms. As the aryl group or arylalkyl group a phenyl group, a phenylethyl group, a phenylpropyl group or a naphthyl group may be illustrated, without being limited thereto.
[0054] In Formulas 1 and 2 above herein, as a substituent being capable of being optionally substituted on the alkyl group, the aryl group or the hydrocarbon group, halogen such as chlorine or fluorine, an epoxy group such as a glycidyl group, an epoxyalkyl group, a glycidoxyalkyl group or an alicyclic epoxy group, an acryloyl group, a methacryloyl group, an isocyanate group, a thiol group, an alkyl group, an alkenyl group, an alkynyl group or an aryl group, and the like, may be illustrated, without being limited thereto.
[0055] The compound represented by Formula 1 above may be, for example, alkyl (meth)acrylate. The term “(meth)acrylate” above refers to acrylate or methacrylate. The alkyl (meth)acrylate may include, for example, methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, t-butyl (meth)acrylate, sec-butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, n-octyl (meth)acrylate, isobornyl (meth)acrylate, isooctyl (meth)acrylate, isononyl (meth)acrylate or lauryl (meth)acrylate, and the like, but is not limited thereto.
[0056] In the present application the appropriate type may be selected among monomers as above, considering the desired physical properties of amphiphilic polymers and used.
[0057] In one example, Q in Formula 1 above may be hydrogen or an alkyl group of 1 to 4 carbon atoms, and B may be an alkyl group of at least 7 carbon atoms or an alicyclic hydrocarbon group of 6 to 12 carbon atoms, without being limited thereto.
[0058] The second block (B) may comprise a polymerization unit (B1) of a vinylic monomer having a solubility parameter of a single polymer of less than 10 (cal/cm 3 ) 1/2 .
[0059] The vinylic monomer may be, for example, a compound represented by Formula 3 or 4 below.
[0000]
[0060] where, X is a nitrogen atom or an oxygen atom, Y is a carbonyl group or a single bond, R 3 and R 5 are each independently hydrogen or an alkyl group, or R 3 and R 5 are linked together to form an alkylene group, and R 4 is an alkenyl group (provided that R 3 is not present, if X is an oxygen atom);
[0000]
[0061] where, R 6 , R 7 and R 8 are each independently hydrogen or an alkyl group, and R 9 is a cyano group or an aromatic substituent.
[0062] When Y in Formula 3 is a single bond, no separate atom is present in the portion indicated by Y, and a structure directly linking R 5 and X may be established.
[0063] In Formula 3, R 4 may be, for example, a straight, branched or cyclic alkenyl group of 2 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms or 2 to 4 carbon atoms, which may be optionally substituted or un-substituted. Generally, as the alkenyl group a vinyl group or an aryl group, and the like may be used.
[0064] In Formula 3, R 3 and R 5 may be each independently hydrogen or a straight, branched or cyclic alkyl group of 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms, or linked together to form an alkylene group of 1 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 12 carbon atoms or 2 to 8 carbon atoms. When R 3 and R 5 above form an alkylene group, the compound of Formula 3 may be a cyclic compound.
[0065] As the vinylic monomer represented by Formula 3 or 4 above, a styrenic monomer such as styrene, or methyl styrene; acrylonitrile; an amide-based monomer such as N-vinyl amide compound; an ester-based monomer such as vinyl ester compound; or an ether-based monomer such as vinyl ether compound; and the lie, may be illustrated, without being limited thereto, and if the monomer satisfies the aforementioned solubility parameter of a single polymer, it may be used as the vinylic monomer contained as a polymerization unit in the amphiphilic polymer of the present application, without any limitation.
[0066] In addition, the second block (B) may further comprise, in addition to the aforementioned polymerization unit (B1) of the acrylic monomer or the vinylic monomer, a polymerization unit (B2) of a polymerizable monomer having a functional group being capable of forming a hydrogen bond.
[0067] The amphiphilic polymer of the present application may improve the loading ability for the targeted drug and stably locate in the inside (core) of the micelle, by including the aforementioned polymerization unit (B1) of the acrylic monomer or the vinylic monomer and the polymerization unit (B2) of the polymerizable monomer having a functional group being capable of forming a hydrogen bond in the second block (B) at the same time.
[0068] The polymerizable monomer having a functional group being capable of forming a hydrogen bond above is a polymerizable monomer except for the above-mentioned acrylic monomers and vinyl monomers, which may refer to a monomer having a functional group being capable of forming a hydrogen bond.
[0069] In one example, as the functional group of the polymerizable monomer, a hydroxy group, an amine group, a nitro group, an amino group, an imide group, an alkoxysilane group or a cyano group, and the like may be illustrated, without being limited thereto, and if it is a functional group serving as an electron donor which may improve the loading ability of drugs by forming an interaction with —H, specifically a hydrogen bond, in the drug to be described later and more stably locate the drug in the inside (core) of the micelle, there is no limitation.
[0070] As the polymerizable monomer containing an amine group, for example, 2-aminoethyl (meth)acrylate, 3-aminopropyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate or N,N-dimethylaminopropyl (meth)acrylate, and the like may be illustrated, without being limited thereto.
[0071] As the polymerizable monomer containing an alkoxysilane group, for example, vinyl alkoxysilane, allyl alkoxysilane, (meth)acryloxyalkyl alkoxysilane or vinylacryloxysilane, and the like may be illustrated. In addition, the (meth)acryloxyalkyl alkoxysilane may include, for example, 3-(meth)acryloxypropyl methyldimethoxysilane, 3-(meth)acryloxypropyl methyldiethoxysilane, 3-(meth)acryloxy trimethoxysilane, 3-(meth)acryloxypropyl triethoxysilane, (meth)acryloxymethyl triethoxysilane or (meth)acryloxymethyl tris(trimethylsiloxy)silane, and the like, but is not limited thereto.
[0072] As the polymerizable monomer containing a cyano group, for example, cyanomethyl (meth)acrylate, cyanoethyl (meth)acrylate or cyanopropyl (meth)acrylate, and the like may be illustrated, without being limited thereto.
[0073] Such a polymerizable monomer having a functional group being capable of forming a hydrogen bond forms a polymerization unit (B2) to the second block (B), and the polymerization units (B2) is located, for example, on the outside of the polymer, so that it may serve for loading the drug.
[0074] In addition, the second block (B) may comprise the aforementioned polymerization unit (B1) of the acrylic monomer or the vinylic monomer and the polymerization unit (B2) of the polymerizable monomer having a functional group being capable of forming a hydrogen bond in a predetermined weight ratio.
[0075] For example, the weight ratio (B1:B2) of the polymerization unit (B1) of the acrylic monomer or the vinylic monomer having a solubility parameter of a single polymer of less than 10.0 (cal/cm 3 ) 1/2 and the polymerization unit (B2) of the polymerizable monomer having a crosslinkable functional group being capable of forming a hydrogen bond, in the second block (B), may be the same or different. For example, the weight ratio (B1:B2) may be in a range of 1:9 to 9:1. In another example, the weight ratio (B1:B2) may be in a range of 2:8 to 8:2, 3:7 to 7:3 or 4:6 to 6:4. In the range of such a weight ratio (B1:B2), the drug may be effectively loaded, and the amphiphilic polymer safely dispersed in an aqueous solution may be formed.
[0076] The second block (B) may have, for example, a number average molecular weight in a range of 500 to 100,000. In such a range, the desired hydrophobic properties and loading ability for the drug may be secured.
[0077] In the amphiphilic polymer of the present application, the block ratio (A:B) of the first block (A) and the second block (B) may be the same or different.
[0078] In one example, the amphiphilic polymer may have a different block ratio (A:B) of the first block (A) and the second block (B).
[0079] Specifically, in the amphiphilic polymer of the present application the block ratio (A:B) of the first block (A) and the second block (B) may be adjusted in a range of 1:9 to 9:1. The term block ratio (A:B) above refers to the weight ratio between the respective blocks.
[0080] In another example, the block ratio (A:B) of the first block (A) and the second block (B) may be 2:8 to 8:2, 3:7 to 7:3 or 4:6 to 6:4.
[0081] In the range of such a block ratio (A:B), the desired dispersion property may be effectively secured, and also the percutaneous absorption characteristic of the formulation may be improved.
[0082] The amphiphilic polymer may have a number average molecular weight (Mn) in a range of 1,000 to 500,000.
[0083] The micelle according to the present application may have a different block ratio (A:b) of the first block (A) and the second block (B), as described above, and also include the amphiphilic polymer comprising a functional group allowing for a certain interaction with the drug to have an excellent encapsulation characteristic, a dispersion property in an aqueous solution and a superior percutaneous absorption characteristic, and the like.
[0084] The present application relates also to a composition comprising such micelles.
[0085] In one example, the present application relates to a composition for preparing particles comprising a drug and a micelle comprising the amphiphilic polymer encapsulating the drug.
[0086] The composition for preparing particles of the present application comprises a micelle formed due to the self assembly characteristic of the amphiphilic polymer. In addition, such amphiphilic polymers forming the micelle encapsulate, for example, the drug.
[0087] In addition, the present application relates to a pharmaceutical or cosmetic composition comprising the micelles comprising the amphiphilic polymer.
[0088] Specifically, the micelle contained in the pharmaceutical or cosmetic composition comprises an amphiphilic polymer and a drug that is encapsulated by the amphiphilic polymer.
[0089] In one example, if the composition is a pharmaceutical composition, the drug in the micelle can be included in the composition as a pharmaceutically acceptable form. In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.
[0090] In addition, the pharmaceutical composition may be in various oral or parenteral dosage forms.
[0091] When the pharmaceutical composition is formulated, it may be prepared using diluents or excipients, such as fillers, extenders, binders, humectants, disintegrators and surfactants, as commonly used.
[0092] In one example, a solid formulation for oral administration includes tablets, pills, powders, granules, or capsules, and such a solid formulation may be prepared by mixing one or more compounds at least with one or more excipients, for example, starch calcium carbonate, sucrose or lactose, gelatin, and the like.
[0093] In one example, a liquid formulation for oral administration corresponds to suspensions, internal solutions, emulsions, or syrups and the like, in which various excipients, for example, wetting agents, sweeteners, aromatics, or preservatives, and the like may be included, other than water or liquid paraffin as the commonly used simple diluents. A formulation for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, or suppositories.
[0094] The pharmaceutical composition may be formulated in any form suitable for pharmaceutical preparations, including oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, or aerosols; external preparations such as ointments or creams; suppositories; sterile injection solutions, and the like, in accordance with each conventional method.
[0095] In another example, the composition may be a cosmetic composition that can be included in external preparations for skin having formulations, for example, emollients, astringent lotions, nourishing lotions, nourishing creams, cleansing foams, essences, packs, and the like.
[0096] In the cosmetic compositions and external preparations for skin, the known additive components, for example, powdery bases or carriers (binders, disintegrators, excipients or lubricants and the like), oily bases or carriers (animal and vegetable oils, waxes, Vaseline, paraffin oils, silicone oils, higher fatty acid esters or higher fatty acids, etc.), aqueous bases or carriers (gel bases, such as xanthan gum), preservatives, chelating agents, antioxidants, algefacients, stabilizers, fluidizers, emulsifiers, thickeners, buffering agents, dispersing agents, absorbents, moisturizing agents, wetting agents, desiccants, antistatic agents or other resins (polyamide-based resins, olefinic resins such as hydrogenated polybutene, etc.), and the like may be included.
[0097] Such a pharmaceutical composition or cosmetic composition may be in a water-in-oil type or oil-in-water type of emulsion form.
[0098] The micelle in the composition may form, for example, aggregates. Such micelle aggregates may be formed due to van der Waals force between the hydrophobic areas or the like. The size of such micelle aggregates may be, for example, in a range of 10 nm to 10,000 nm.
[0099] The present application relates also to a process for preparing the aforementioned micelle.
[0100] That is, the present application relates to a process for preparing the micelle comprising a step of polymerizing a polymer forming a first block (A) and an acrylic monomer or a vinylic monomer having a solubility parameter of a single polymer of less than 10.0 (cal/cm 3 ) 1/2 to prepare an amphiphilic polymer; and a step of mixing the amphiphilic polymer and a drug.
[0101] Specifically, in the process for preparing the amphiphilic polymer of the present application, the method of polymerizing the polymer forming the first block (A) and the aforementioned monomer is not particularly limited, but may utilize a living radical polymerization, for example, atom transfer radical polymerization (ATRP) for effectively achieving narrow molecular weight distribution and the desired molecular weight.
[0102] More specifically, the amphiphilic polymer of the present application may be prepared by reacting a polymer which comprises a halogen atom and forms the first block (A) with a transition metal complex catalyst to generate a radical, and giving such a radical with an electron from a double bond site of the acrylic monomer or the vinylic monomer for forming the second block to form the second block (B) having the polymerization unit (B1) of the acrylic monomer or the vinylic monomer, but is not limited thereto.
[0103] The polymer forming the first block is, for example, a polymer, with or without a halogen atom, having a solubility parameter of 10 (cal/cm 3 ) 1/2 or more, and when the polymer without a halogen atom for forming the first block is used, a step of preparing an initiator for ATRP through a reaction with a compound containing a halogen atom may be further included.
[0104] The step of mixing the amphiphilic polymer prepared as above with a drug may comprise, for example, dissolving the amphiphilic polymer in a certain organic solvent, for example ethanol, and the like, and then mixing the prepared solution and the drug.
[0105] In addition, after the above process, the subsequent process may include a process of removing the solvent, without being limited thereto, and the known further process may be entailed between the processes above or to the subsequent process.
[0106] The temperature in the step of removing the solvent varies depending on the boiling point of each solvent, and for example, the solvent may be removed at a temperature of 50° C. or more, but is not limited thereto.
Effect of the Invention
[0107] The present application may provide the micelles which are effectively dispersed in the composition and comprise the drug encapsulated by the amphiphilic polymer having high stability for the drug, and the process for preparing the same.
[0108] In addition, the formulation containing such micelles can exhibit excellent percutaneous absorption properties.
BRIEF DESCRIPTION OF DRAWINGS
[0109] FIG. 1 is a schematic view about the micelle comprising the amphiphilic polymer according to the present application.
[0110] FIG. 2 is images confirming precipitation of the amphiphilic polymer according to Examples and Comparative Examples and the drug encapsulated by the polymer through an optical microscope.
[0111] FIG. 3 is a schematic view about a Franz cell for the percutaneous absorption experiment.
DETAILED DESCRIPTION OF THE INVENTION
[0112] Hereinafter, the present application will be explained in more detail through Examples, but the Examples are restricted only to the gist of the present application. Furthermore, the present application is not limited to the process conditions suggested in the following Examples, and it is obvious to those having ordinary knowledge in the art that it can be optionally selected within the range of conditions necessary for achieving the object of the present application.
Examples
Example 1—Preparation of Amphiphilic Polymer (P1)
[0113] After dissolving a polyethylene glycol monomethyl ether polymer (molecular weight: 5,000, manufacturer: Aldrich) forming the first block in dichloromethane with a 30% concentration, 3 equivalents of triethylamine and 2 equivalents of 2-bromoisobutyryl bromide are added, relative to the —OH functional group, and reacted to prepare the initiator for ATRP. Then, the precipitation and loading process is twice repeated in diethyl ether solvent and dried to obtain the polyethylene glycol polymer having bromine terminals without impurities. 100 parts by weight of the obtained polyethylene glycol polymer having bromine terminals was dissolved in 250 parts by weight of anisole reaction solvent on a flask, 150 parts by weight of methyl methacrylate (solubility parameter: 9.5 (cal/cm 3 ) 1/2 ), and the flask was sealed with a rubber stopper. Then, the dissolved oxygen was removed through nitrogen purging and stirring at room temperature for 30 minutes, and the reaction was progressed by dipping it in an oil bath set to 60° C. and introducing a cupric bromide complex and a catalyst reducing agent. If the desired molecular weight was obtained, the reaction was completed to prepare the amphiphilic polymer (PI). The molecular weight and block ratio (A:B) of the amphiphilic polymer (P1) are shown in Table 1 below.
Example 2—Preparation of Amphiphilic Polymer (P2)
[0114] The amphiphilic polymer (P2) was prepared in the same manner as Example 1 except that the polyethylene glycol polymer having bromine terminals as prepared in the same manner as Example 1 was dissolved in the anisole reaction solvent on the flask, and methyl methacrylate (solubility parameter: 9.5 (cal/cm 3 ) 1/2 ) and N,N-dimethylaminoethyl methacrylate (solubility parameter: 9.6 (cal/cm 3 ) 1/2 ) were introduced in a weight ratio of 80:20. The molecular weight and block ratio (A:B) of the amphiphilic block polymer (P2) and the weight ratio (B1:B2) of polymerization units in the second block (B) are shown in Table 1 below.
Example 3—Preparation of Amphiphilic Polymer (P3)
[0115] The amphiphilic polymer (P3) was prepared in the same manner as Example 1 except that the polyethylene glycol polymer having bromine terminals as prepared in the same manner as Example 1 was dissolved in the anisole reaction solvent on the flask, and methyl methacrylate (solubility parameter: 9.5 (cal/cm 3 ) 1/2 ) and N,N-dimethylaminoethyl methacrylate (solubility parameter: 9.6 (cal/cm 3 ) 1/2 ) were introduced in a weight ratio of 60:40. The molecular weight and block ratio (A:B) of the amphiphilic block polymer (P3) and the weight ratio (B1:B2) of polymerization units in the second block (B) are shown in Table 1 below.
Comparative Example 1—Preparation of Amphiphilic Polymer (P4)
[0116] The polyethylene glycol (A)-polycaprolactone (B) copolymer (P4) applied by polycaprolactone (solubility parameter: about 10 (cal/cm 3 ) 1/2 ) being a polyester-based polymer, was prepared by the following method.
[0117] Specifically, it was synthesized via a ring-opening polymerization using polyethyleneglycol monomethyl ether polymer (molecular weight: 5000, manufacturer: Aldrich) as an initiator. Stannous 2-ethyl-hexanoate (Sn(Oct) 2 ) was used as a reaction catalyst. Polyethylene glycol monomethyl ether and Sn(Oct) 2 were dried in a 2-neck round flask at 110° C. for 4 hours under vacuum to remove water and then, the reactor was cooled to room temperature. Polyethyleneglycol monomethyl ether and the same amount of ε-caprolactone were added to the reactor in a nitrogen atmosphere and vacuum dried for 1 hour at 60° C. The reactor was gradually raised to 130° C. in a nitrogen atmosphere, reacted for 18 hours, and the reaction was terminated by cooling to room temperature. Methylene chloride was added to the reactor cooled to room temperature to dissolve the reactant, and then the copolymer was precipitated while slowly adding it to the cold ethyl ether. The precipitated block copolymer was filtered and then vacuum dried at 40° C. for 48 hours to finally obtain the polyethylene glycol (A)-polycaprolactone (B) copolymer (P4).
Comparative Example 2—Preparation of Amphiphilic Polymer (P5)
[0118] The amphiphilic polymer (P5) was synthesized and prepared in the same manner as Comparative Example 1 except that on synthesizing the polyethylene glycol (A)-polycaprolactone (B) copolymer applied by polycaprolactone (solubility parameter: about 10 (cal/cm 3 ) 1/2 ) being a polyester-based polymer two-fold amount of ε-caprolactone was added, relative to polyethyleneglycol monomethyl ether.
Experimental Example 1—Evaluation of Block Ratio (A:B) and Molecular Weight of the Prepared Amphiphilic Polymers
[0119] Block ratios and molecular weights of the prepared amphiphilic polymers (P1 to P5) were evaluated by the following method and shown in Table 1.
[0120] Specifically, the polymer solution completely removing the catalyst was solidified via the purification step, and then the block ratio of the amphiphilic polymer was confirmed through 1 H NMR analysis. In the purification of the polymer solution, the polymer solution is passed through an alumina column to remove the copper complex catalyst and then falls in drops to an excess of diethyl ether with stirring to remove the residual monomer, and is solidified. The solidified polymer is dried for 24 hours in a vacuum oven. The amphiphilic polymer purified by the above method is dissolved in CDCl 3 solvent and measured by 1 H-NMR analysis equipment. In the case of Examples 1 to 3, from the analyzed result, no 1H peaks derived from CH 2 ═C(CH 3 )— of the double bond terminal were confirmed, whereby it can be confirm that the unreacted monomer is not present. In addition, in the case of Examples 1 to 3 and Comparative Examples 1 and 2, 3H peaks derived from —OCH 3 of the ethylene glycol block terminal were identified near 3.2 ppm and on the base of this, the ratio and molecular weight of each polymer block was calculated. Since about 450 of H peaks (4H×113 repeating units) derived from —CH 2 CH 2 O— of ethylene glycol forming the polymer appeared in the region of 3.6 to 3.8 ppm, 3H peaks derived from —CH 3 adjacent to the backbone of methyl methacrylate forming the polymer in the case of Examples 1 to 3 appeared in the region of 3.5 to 3.6 ppm, and 2H peaks derived from —OCH 2 — adjacent to —COO— of the dimethylamonoethyl methacrylated side chain forming the polymer appeared in the region of 4.0 to 4.2 ppm, the contents of the constituent monomers each were calculated as a mass fraction through their area ratios. Since 2H peaks derived from the first right —CH 2 — of —CO— in —(CO—CH 2 CH 2 CH 2 CH 2 CH 2 —O—) n being the chain of caprolactone forming the polymer in the case of Comparative Examples 1 and 2, appeared in the region of 2.3 to 2.4 ppm, the molecular weight was identified through the 3H peak area derived from —OCH 3 of the ethylene glycol block terminal and the 2H peak area derived from the first right —CH 2 — of —CO— in caprolactone.
[0000]
TABLE 1
Weight ratio of
Molecular weight
polymerization
(Mn,
Block
unit in
first block:
ratio
second block (B)
second block)
(A:B)
(B1:B2)a
Example 1
11,000 (5,000:6,000)
4.55:5.45
100:0
Example 2
11,000 (5,000:6,000)
4.55:5.45
80:20
Example 3
11,000 (5,000:6,000)
4.55:5.45
60:40
Comparative
9,900 (5,000:4,900)
5.05:4.95
—
Example 1
Comparative
14,700 (5,000:9,700)
0.34:0.66
—
Example 2
amethyl methacrylate (B1):N,N-dimethylaminoethyl methacrylate (B2) mass ratio
Experimental Example 2—Preparation of Micelle and Determination of Dissolved Concentration of Drug
[0121] Using the synthesized amphiphilic polymers (P1 to P5), genistein of a sparingly soluble material was encapsulated. First, a solution of the amphiphilic polymer (10 g) dissolved in 30 mL of ethanol was mixed with a solution of genistein (2 g) dissolved in 20 g of dipropylene glycol (DPG). The solution was slowly added to 100 mL of 0.5% aqueous polyvinyl alcohol solution while stirring. After standing the solution for a certain time with stirring in order to evaporate the ethanol solvent, the remaining ethanol was removed using a rotary evaporator to prepare a solution such that the content of genistein is 2%. The prepared solution was diluted with purified water of ten times and then stored at room temperature (25° C.) for 7 days, where it was confirmed with an optical microscope whether the change over time was and shown in FIG. 2 . In addition, the liquid was filtered through a syringe filter (pore size: 1 μm) to remove the precipitated genistein and then the content of the genistein encapsulated in the amphiphilic polymer micelle particles was measured from a liquid chromatography (HPLC). Drug loading capacity and drug loading efficiency of the amphiphilic polymer were calculated by the following equations, and the particle size of the micelle comprising the amphiphilic polymer loading the drug was measured using Zetasizer 3000 from Malvern Instruments.
[0000]
Drug
loading
capacity
=
Drug
impregnation
amount
Drug
impregnation
amount
+
Block
copolymer
content
100
(
%
)
[
Equation
1
]
Drug
loading
efficiency
=
Drug
impregnation
amount
Initial
drug
input
amout
100
(
%
)
[
Equation
2
]
[0122] The results measuring the size of the micelle particles, and drug loading capacity and drug loading efficiency according to these were showed in Table 2 below.
[0000]
TABLE 2
Compar-
Compar-
Exam-
Exam-
Exam-
ative
ative
ple 1
ple 2
ple 3
Example 1
Example 2
Particle Size
110
125
135
100
150
(nm)
Drug loading
2.4
10.7
16.1
1.2
1.8
capacity (%)
Drug loading
13
60
96
6
9
efficiency (%)
Experimental Example 3—Percutaneous Absorption Experiment
[0123] The percutaneous absorption of genistein was evaluated from the above prepared amphiphilic polymer solution loading genistein us porcine skin (2×2 cm, thickness 1000 μm) and Franz diffusion cell. The sink condition for genistein was maintained using the PBS (phosphate buffered saline) solution containing 30% by weight of dipropylene glycol (DPG) as an acceptor solution. After loading 0.2 g of the amphiphilic polymer solution loading genistein on the Franz diffusion cell equipped with the porcine skin, the experiment was carried out at 32° C. similar to the skin temperature for 24 hours. The skin tissues absorbing genistein were crushed and extracted to analyze the genistein content absorbed in the skin tissues and the genistein content in the acceptor solution through HPLC, which were shown in Table 3.
[0000]
TABLE 3
Compar-
Compar-
Exam-
Exam-
Exam-
ative
ative
ple 1
ple 2
ple 3
Example 1
Example 2
Skin permeation
0.66
1.85
3.70
0.22
0.35
amount (μg/cm 2 )
Skin perme-
0.38
1.05
2.10
0.13
0.20
ability (%)
EXPLANATION OF CODES
[0000]
100 : Drug
200 : Amphiphilic polymer
201 : First block
202 : Second block
|
The present application relates to a micelle comprising a drug encapsulated by an amphiphilic polymer and a composition comprising the same.
The micelle of the present application has an excellent dispersion property on an aqueous solution and a superior percutaneous absorption characteristic on preparing a formulation.
| 0 |
CROSS-REFERENCE TO RELATED APPLICATION
The present application is a division of copending Application Ser. No. 333,497, filed Feb. 20, 1973, now U.S. Pat. No. 3,935,214; issued Jan. 27, 1976, and entitled 2- OR 3-KETO-C-PHENYL-1,4-DISUBSTITUTED PIPERAZINES, said application Ser. No. 333,497 in turn being a continuation-in-part application of copending Application Ser. No. 848,395, filed July 23, 1969, and entitled 1,4-DISUBSTITUTED PHENYL PIPERAZINE COMPOUNDS, COMPOSITIONS CONTAINING SAME, AND PROCESS OF MAKING AND USING SAME, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new and valuable phenyl piperazine compounds and more particularly to 1,4-substituted phenyl piperazine compounds of noteworthy therapeutic utility and to a process of making and using same.
2. Description of the Prior Art
ARCHER in U.S. Pat. No. 3,062,821 discloses 1,4-disubstituted-2-piperazinones of Formula I ##STR1## In said formula R represents lower alkyl;
X and X' represent hydrogen, lower alkoxy, or hydroxyl; and
Y hydrogen or lower alkyl.
Said 1-[2-(phenyl lower alkyl)]-4-lower alkyl-2-piperazinone compounds are useful intermediates in the preparation of compounds of Formula II ##STR2## in which R, X, X', and Y represent the same substituents as given hereinabove. These 1-[2-(phenyl lower alkyl)]-4-lower alkyl piperazine compounds are useful hypotensive agents.
DE BENNEVILLE in U.S. Pat. No. 3,390,139 discloses N-vinyl-2-piperazinones of Formula III ##STR3## in which R 1 is hydrogen, alkyl, cycloalkyl, aralkyl, alkyl substituted aralkyl, diaminoalkyl, or furfuryl;
R 2 is hydrogen or methyl;
R 3 is hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, alkyl, chloro, or alkoxy substituted phenyl or naphthyl, aralkyl, alkyl substituted aralkyl, or 2-furyl;
R 4 is hydrogen or alkyl; and
R 5 is hydrogen or alkyl.
These compounds are polymerizable or copolymerizable compounds, the resulting polymers or copolymers are useful for many purposes. Higher members of the monomeric N-vinyl-2-piperazinones of Formula III show fungistatic and bacteriostatic activity and are useful for other purposes.
DE BENNEVILLE in U.S. Pat. No. 2,653,153 describes 4-N-substituted-2-ketopiperazines of Formula IV ##STR4## in which R is alkyl, tertiary aminoalkyl, or aralkyl; and
R' and R" are hydrogen or lower alkyl. These 4-N-substituted-2-ketopiperazines are valuable activators and synergists for insecticidal agents.
None of these compounds has found any noteworthy application in veterinary and human therapy.
SUMMARY OF THE INVENTION
It is one object of the present invention to provide valuable 1,4-substituted phenyl piperazine compounds which have a surprising and pronounced effect upon blood coagulation and are useful, for instance, in the treatment of thrombotic diseases, especially those of the arterial system.
Another object of the present invention is to provide a simple and effective process of producing such valuable novel 1,4-substituted phenyl piperazine compounds.
A further object of the present invention is to provide pharmaceutical compositions containing, as active pharmaceutical agent, said novel 1,4-substituted phenyl piperazine compounds
Still another object of the present invention is to provide a method of therapeutically affecting blood coagulation by administering the novel 1,4-substituted phenyl piperazine compounds.
Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.
In principle, the new 1,4-substituted phenyl piperazine compounds according to the present invention correspond to the following formula V ##STR5## In said formula X, Y, and Z are the same or different substituents and may be either hydrogen, halogen, trifluoro lower alkyl, preferably trifluoro methyl, hydroxyl, lower alkoxy, preferably methoxy or ethoxy, or phenyl substituted lower alkoxy, such as benzyloxy;
R is di-(lower)alkylamino (lower)alkyl, and preferably dimethylamino ethyl, diethylamino ethyl, dipropylamino ethyl, dimethylamino propyl, diethylamino propyl, di-n-propylamino propyl, or lower alkyl substituted by one or two saturated monocyclic heterocyclic rings such as piperidino, pyrrolidino, piperazino, N-lower alkyl piperazino, 3-ketopiperazino, morpholino, or the like, preferably piperidino ethyl, morpholino ethyl, or dimorpholino propyl;
R 1 is lower alkyl with 1 to 3 carbon atoms; and ##STR6## is the group ##STR7##
The term "lower alkyl" in said substituents indicates alkyl with 1 to 5 carbon atoms. Thus the substituent in N 1 -position of the piperazine ring may be benzyl, phenyl ethyl, or phenyl propyl, or substituted benzyl, phenyl ethyl, phenyl propyl. Preferred substituents in the N 1 -aralkyl group are
One halogen atom in 2-; 3-; or 4-position.
Two halogen atoms in 2,3-; 2,4-; 2,5-; or 3,4- position and, if desired, also in 2,6-position.
Such halogen substituted compounds may also carry hydroxyl or lower alkoxy, preferably methoxy groups.
One lower alkoxy group, preferably one methoxy or ethoxy group in 4-position.
Three lower alkoxy groups, preferably in 3,4,5-position.
One phenyl lower alkoxy group, preferably the benzyloxy group in 2- or 4-position.
Two phenyl lower alkoxy groups, preferably the benzyloxy groups in 3,4-position.
Two hydroxyl groups, preferably in 2,3, and/or 4-position.
One trifluoro lower alkyl group, preferably the trifluoromethyl group in 3-position. addition
The phenyl radical in position 2 or 3 of the piperazine ring is always unsubstituted.
The basic lower alkylamino group in N 4 -position is preferably a group of the Formula VI ##STR8## in which R 2 is lower alkyl;
R 3 is hydrogen or a saturated five- or six-membered heterocyclic ring, preferably the morpholino ring attached by its heterocyclic nitrogen atom to the lower alkyl R 2 ; and
R 4 and R 5 are lower alkyl or, together with the nitrogen atom to which they are attached, form a saturated five- or six-membered heterocyclic ring, such as the pyrrolidino, piperidino, piperazino, or morpholino ring. The piperazino ring may be substituted at its other nitrogen atom by lower alkyl or by hydroxy lower alkyl to represent the N 4 -lower alkyl or N 4 -hydroxy lower alkyl piperazino ring or it may be substituted by a keto group to represent the 3-keto piperazino ring.
It is evident that the compounds according to the present invention represent two groups of compounds, namely
a. The N 1 -phenyl lower alkyl substituted 2- or 3-phenyl substituted N 4 -basically substituted 3- or 2-piperazone compounds of Formulas VII or VIII: ##STR9## and b. the N 1 -phenyl lower alkyl substituted 2- or 3-phenyl substituted N 4 -basically substituted piperazine compounds of Formulas IX and X: ##STR10##
In said Formulas VII to X the symbols R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, and Z represent the same substituents as indicated hereinabove.
Especially valuable compounds according to the present invention are compounds of the following Formula XI and XII: ##STR11## In said Formulas X 1 is hydrogen or lower alkoxy.
Y 1 and Z 1 are hydrogen, halogen, trifluoromethyl; hydroxyl, lower alkoxy, and phenyl lower alkoxy, whereby X 1 is lower alkoxy only if Y 1 and Z 1 are lower alkoxy;
R 1 is lower alkyl with 1 to 3 carbon atoms;
R 2 is lower alkyl;
R 3 is hydrogen or a saturated five- or six-membered heterocyclic ring, said heterocyclic ring being attached by its heterocyclic nitrogen atom to the lower alkyl R 2 ;
R 4 and R 5 are lower alkyl or, together with the nitrogen atom to which they are attached, form a saturated five- or six-membered heterocyclic ring.
According to the present invention the 1,4-substituted phenyl piperazine compounds of the above given Formulas have a pronounced effect upon the blood coagulation system. They act upon all processes which play an essential role in the formation of thromboses, such as their coagulation promoting effect due to their power of releasing the thrombocyte factor 3, their coagulation inhibiting effect, and their trombocytes aggregation and adhesion inhibiting effect. Thus the novel compounds of the present invention or their pharmaceutically acceptable acid addition salts are highly effective anticoagulants. They prolong the clotting time of blood on oral or parenteral administration of the required dose and have been found to inhibit platelet aggregation, such as induced by the addition of adenosine diphosphate, when added to platelet-rich plasma.
The compounds according to the present invention can be administered for their anticoagulant effect over a wide dosage area. For instance, a dosage of about 0.5 mg./kg. to 100 mg./kg. of body weight orally administered daily or on parenteral administration has proved to be highly effective.
The new compounds according to the present invention may find particular application in the treatment of thrombotic disease, especially of the arterial system, for instance, to inhibit thrombosis of the coronary or cerebral arteries.
The following new piperazine compounds according to the present invention have been found to be useful in therapy:
1-(4-chloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine
1-(3,4-dichloro benzyl)-2-phenyl-4-(diethylamino ethyl)piperazine;
1-[(4-methoxy phenyl)-ethyl]-2-phenyl-4-(diethylaminoethyl)-piperazine;
1-[3-phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl)-piperazine;
1-(4-chloro benzyl)-2-phenyl-4-(piperidino ethyl) piperazine;
1-(4-chloro benzyl)-2-phenyl-4-[1,3-dimorpholino propyl-(2)]piperazine;
1-(4-chloro benzyl)-3-phenyl-4-(diethylamino ethyl) piperazine.
The new piperazine compounds of the above given Formulas are obtained according to the present invention, for instance, by reacting a 1-R-substituted phenyl piperazine of Formula XIII. ##STR12## wherein ##STR13## and R represent the above given groups and substituents, with an aralkyl halogenide of Formula XIV ##STR14## wherein X, Y, Z, and R 1 represent the same substituents and numerals as given hereinabove, while
Hal is halogen.
Another method of producing the 1,4-substituted phenyl piperazine compounds according to the present invention comprises reacting a 1-aralkyl phenyl piperazine of Formula XV. ##STR15## wherein ##STR16## X, Y, Z, and R 1 represent the above given substituents, with a basically substituted alkyl halogenide of Formula XVI ##STR17## wherein
Hal is halogen and R represents the above given substituent.
A further method of producing the 1,4-substituted phenyl piperazine compounds according to the present invention comprises reacting a 1-aralkyl phenyl piperazine, substituted in the ω-position by a reactive group Q, preferably by a halogen atom, and having the general Formula XVII ##STR18## wherein ##STR19## X, Y, Z, and R 1 have the above given meaning, and R 6 is lower alkyl, with a corresponding secondary amine of the group consisting of a di-lower alkyl amine, such as dimethylamine, diethylamine, dipropylamine, or with piperidine, morpholine, pyrrolidine, piperazine, 3-ketopiperazine, or a lower N-alkyl piperazine.
If desired, the keto group in the resulting reaction product of Formula V, wherein ##STR20## is either ##STR21## is reduced to the methylene group, so as to yield compounds of Formula V wherein ##STR22## represents either ##STR23##
The resulting basically substituted phenyl piperazine compounds of Formula V may be converted, if desired, into their substantially non-toxic, pharmaceutically acceptable acid addition salts by methods well known to the art. Not only physiologically tolerable salt-forming inorganic acids, such hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and others, but also organic acids, such as acetic acid, propionic acid, benzoic acid, salicyclic acid, succinic acid, malonic acid, citric acid, tartaric acid, fumaric acid, and others can be used in the preparation of therapeutically valuable salts.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples serve to illustrate the present invention without, however, limiting the same thereto.
EXAMPLE 1
1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine ##STR24## Method A:
1-(4'-Chloro benzyl)-2-phenyl piperazine
44 g. of 1-(4'-chloro benzyl)-2-phenyl-3-keto piperazine obtained according to Example 1, Method A (a) of Application Ser. No. 333,497, are dissolved in 350 cc. of dioxane. The solution is added drop by drop to a suspension of 15 g. of lithium aluminum hydride LiAlH 4 in 800 cc. of ether while stirring thoroughly. After addition is completed, the reaction mixture is boiled under reflux for 12 hours. Thereafter, the lithium complex compound is decomposed and excess lithium aluminum hydride is destroyed by successively treating the reaction mixture with 15 cc. of a 15% sodium hydroxide solution, with 15 cc. of water, with 45 cc. of a 15% sodium hydroxide solution, and with 30 cc. of water. The inorganic precipitate is removed by filtration and the filtered solution is evaporated to dryness. The residue is recrystallized from isopropanol. 37 g. of pure white crystals of the melting point 103°-104° C. are obtained.
Method B:
1-(4'-Chloro benzyl)-2-phenyl piperazine
142.4 g. of 1(4'-chloro benzyl)-2-phenyl-3-keto piperazine prepared according to Example 1, Method A (a) of Application Ser. No. 333,497, are suspended in 400 cc. of benzene while stirring vigorously. 800 cc. of a 1.5 molar solution of dibutyl aluminum hydride are then allowed to run slowly to said suspension. Thereby the reaction mixture is caused to boil under reflux. Half an hour after the addition is completed, the mixture is cooled to 5° C. Excess dibutyl aluminum hydride is decomposed by careful addition of water. The precipitated aluminum hydroxide is dissolved in 40% sodium hydroxide solution. The separated organic layer is washed with 40% sodium hydroxide solution and then with water and is freed of its organic solvent by evaporation. The residue is recystallized from 1.5 l. of isopropanol.
Pure white crystals of the melting point 103°-104° C. are obtained in a yield corresponding to the theoretical yield. The resulting compound is identical with the compound obtained according to Method A given hereinabove as is proved by chromatography and infrared spectroscopy.
b. 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine
30 g. of the base prepared according to Methods A or B as described hereinabove are dissolved in 100 cc. of toluene. The solution is boiled under reflux with 20 g. of diethylamino ethylchloride and 20 g. of finely pulverized anhydrous potassium carbonate for 8 hours. By treating the reaction mixture with water, separating the toluene layer, extracting the base with hydrochloric acid, setting the base free from its hydrochloride solution by addition of ammonia, and dissolving it in benzene, the base is purified. After distilling off the solvent and repeated distillation in a vacuum, 34 g. of a yellow oil of the boiling point 188°-199° C./0.09 mm. Hg are obtained. Yield: 81% of the theoretical yield.
EXAMPLE 2
1-(3',4'-Dichloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine ##STR25##
a. 1-(3',4'-Dichloro benzyl)-2-phenyl-3-keto piperazine
140 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 163 g. of 3,4-dichloro benzylchloride in 1,600 cc. of acetone for 6 hours while 330 cc. of triethylamine are added. The hot reaction mixture is filtered to remove precipitated triethyl ammonium chloride and is concentrated by fractional distillation. The resulting crystal fractions are twice recrystallized from 4 l. of 96% ethanol.
162 g. of the above given reaction product of the melting point 195°-208° C. (with decomposition) are obtained. Yield: 52% of the theoretical yield.
b. 1-(3',4'-Dichloro benzyl)-2-phenyl piperazine
132 g. of the keto piperazine prepared as described hereinabove under (a) are dissolved in 200 cc. of dioxane. Said solution is added drop by drop to a suspension of 21 g. of lithium aluminia hydride LiAlH 4 in 900 cc. of absolute ether while the suspension is exposed to vibration. After the addition is completed, the mixture is boiled under reflux for 12 hours. Successively 20 cc. of 15% sodium hydroxide solution, 20 cc. of water, 60 cc. of 15% sodium hydroxide solution, and 40 cc. of water are added to the reaction mixture to cause decomposition of the complex compound formed. The filtrate is freed of solvent, the residue is distilled, and a viscous oil, boiling between 170° C./0.02 Torr. and 178° C./0.02 Torr., is obtained. The oil crystallizes on trituration with heptane. It is twice recrystallized from heptane. Yield: 110 g. corresponding to 87% of the theoretical yield.
c. 1-(3',4'-Dichloro benzyl)-2-phenyl-4-diethylamino ethyl) piperazine
40 g. of the piperazine compound prepared according to the method described hereinabove under (b), are boiled under reflux with 18.5 g. of diethylamino ethylchloride in 250 cc. of acetone with the addition of 52 cc. of triethylamine for 12 hours. The triethyl ammonium-chloride formed thereby is filtered off. The resulting solution is concentrated by evaporation. Absolute ethanolic hydrochloric acid is added to the residue. The precipitated hydrochloride is washed with ethanol and is dissolved in water. The base is set free from its aqueous solution by the addition of ammonia and is extracted by means of benzene. After drying over anhydrous potassium carbonate and removing the solvent, 34 g. of a light yellow oil of the boiling point 192° C./0.03 mm. Hg are obtained. The yield is 65% of the theoretical yield.
EXAMPLE 3
1-[(4'-Methoxy phenyl) ethyl]-2-phenyl-4-(diethylamino ethyl) piperazine ##STR26##
a. 1-[(4'-Methoxy phenyl)ethyl]-2-phenyl-3-keto piperazine
140 g. of 2-phenyl-3-keto piperazine, 148.5 g. of 4-methoxy phenyl ethylchloride, and 330 cc. of triethylamine in 1.6 l. of acetone are boiled under reflux for 12 hours. The acetone is distilled off. 300 cc. of dimethylformamide are added to the residue and the mixture is heated on the water bath for 36 hours. The major part of the dimethylformamide is distilled off in a vacuum. About 500 cc. of acetone and 150 cc. of triethylamine are added to the residue. The mixture is freed of triethylammoniumchloride by filtration while still boiling, and is cooled. After again distilling off the solvent, the remaining crystals are washed with petroleum ether and are triturated with water. The resulting solution is again filtered. On rendering the solution alkaline, the reaction product is precipitated initially in oily form. It crystallizes very rapidly. After recrystallizing the crystals three times from isopropanol pure white crystals of the melting point 142°-147° C. (with decomposition) are obtained. The yield is 110 g. corresponding to 44.7 % of the theoretical yield.
When carrying out the reaction from the beginning on in a mixture of dimethylformamide and triethylamine, the yield is lower than when proceeding as described hereinabove. This is due to formylation reaction taking place thereby.
b. 1-[(4'-Methoxyphenyl)-ethyl]-2-phenyl piperazine
29 g. of the keto piperazine prepared as described hereinabove under (a), are dissolved in 200 cc. of absolute dioxane. A suspension of 8 g. of lithium aluminum hydride LiAlH 4 in 700 cc. of absolute ether is added drop by drop to said solution while stirring vigorously. Thereafter, the mixture is boiled under reflux for 12 hours. After decomposing the reaction mixture by successive addition of 10 cc. of 15 % sodium hydroxide solution, 10 cc. of water, 30 cc. of 15 % sodium hydroxide solution, and finally of 20 cc. of water in the order given, the mixture is freed from the precipitated inorganic salts by filtration and the filtrate is concentrated by evaporation. Ethanolic hydrochloric acid is added to the residue and the hydrochloride precipitated thereby is filtered off by suction. The base is set free from the hydrochloride by the addition of sodium hydroxide solution. 23 g. of a viscous oil are obtained. The oil crystallizes after standing for some time. It has a boiling point of 180°-185° C./0.01 mm. Hg. The yield is 83 % of the theoretical yield.
c. 1-[(4'-Methoxy phenyl)-ethyl]-2-phenyl-4-(diethylamino ethyl) piperazine
18 g. of the base obtained as described hereinabove under (b) are boiled under reflux with 30 g. of triethylamine and 12 g. of diethylamino ethylchloride in 120 cc. of acetone for 15 hours. The reaction solution is cooled, filtered, and freed of the solvent by concentration by evaporation. The residue is dissolved in dilute hydrochloric acid. The base is set free from its hydrochloride solution by the addition of ammonia, is extracted with benzene, and the benzene extract is again freed of its solvent. A mixture of acetone in ethanolic hydrochloric acid is added to the residue. The precipitated hydrochloride is filtered off by suction. The base is again set free from its hydrochloride by the addition of ammonia and is distilled in a vacuum. 17 g. of a viscous oil of the boiling point 215° C./0.002 mm. Hg are obtained. The yield is 70 % of the theoretical yield.
EXAMPLE 4
1-[3'-Phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl) piperazine ##STR27##
a. 1-[3'-Phenyl propyl-(1)]-2-phenyl-3-keto piperazine
140 g. of 2-phenyl-3-keto-piperazine and 135 g. of 3-phenyl propylchloride(1) are heated on the water bath in 350 cc. of dimethylformamide with the addition of 330 cc. of triethylamine for 48 hours. The major portion of the dimethylformamide and the triethylamine are distilled off in a vacuum. The residue is dissolved in 2 l. of acetone. 150 cc. of triethylamine are added to said acetone solution. The mixture is boiled under reflux for 10 minutes. The solution is then cooled to 30° C. and is freed from triethyl ammoniumchloride by filtration. The keto-piperazine crystallizes from the resulting filtrate on cooling in a mixture of ice and sodium chloride. The crystals are purified by recrystallization from isopropanol and 50 % ethanol. 110 g. of white crystals of the melting point 114°-116° C. are obtained. The yield is 47 % of the theoretical yield.
b. 1-[3'-Phenyl propyl-(1)]-2-phenyl piperazine
43 g. of the keto-piperazine obtained as described hereinabove under (a) are dissolved in 200 cc. of dioxane and are reduced by the addition of 10 g. of lithium aluminum hydride LiAlH 4 suspended in 800 cc. of ether as described in the preceding examples. After decomposing the reaction mixture and recovering the base by purification via its hydrochloride, 30 g. of a viscous oil of the boiling point 155°-160° C./0.01 mm. Hg are obtained. The yield is 73 % of the theoretical yield.
c. 1-[3'-Phenyl propyl-(1)]-2-phenyl-4-(diethylamino ethyl) piperazine
23 g. of the base prepared as described hereinabove under (b) are boiled under reflux with 13.5 g. of diethylamino ethylchloride, 35 cc. of triethylamine, and 150 cc. of acetone for 10 hours. After recovering the base as described in the preceding examples and purifying it via its hydrochloride, 22 g. of a colorless oil of the boiling point 187°-189° C./0.01 mm. Hg are obtained. The yield is 70.5 % of the theoretical yield.
EXAMPLE 5
1-(4'-Chloro benzyl)-2-phenyl-4-(piperidino ethyl) piperazine ##STR28##
31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according to Example B), 25 g. of piperidino ethylchloride, 20 g. of triethylamine, and 250 cc. of acetone are boiled under reflux for 18 hours. The filtered reaction solution is freed of its solvent by concentration by evaporation. The residue is dissolved in benzene. The benzene solution is washed with water. After drying and distilling off the solvent, the base is obtained in the form of a viscous, yellow oil on distillation at 210° C./0.06 Torr. The oil crystallizes on trituration with isopropanol. After twice recystallizing the crystals from n-heptane (41 g. of yellow crystals of the melting point 85°-87° C.) are obtained. The yield is 95 % of the theoretical yield.
In place of acetone there may also be used other solvents, for instance, benzene, toluene, or xylene and, in place of triethylamine, for instance, pyridine, dimethylaniline, potassium carbonate, sodium amide or sodium hydride.
In a similar manner as described in Example 6 are obtained:
1-(4'-Chloro benzyl)-2-phenyl-4-pyrrolidino ethyl) piperazine, boiling point 200°-205° C./0.05 mm. Hg; melting point of the hydrochloride 254°-258° C. (decomposition), by reaction of 1-(4'-chloro benzyl)-2-phenyl piperazine and pyrrolidino ethyl chloride.
1-(4'-Chloro benzyl)-2-phenyl-4-[4'-methyl piperazino ethyl-(1)]piperazine, boiling point 215°-217° C./0.005 mm. Hg; melting point of the hydrochloride 252°-270° C. (decomposition), by reaction of 1-(4'-chloro benzyl)-2-phenyl piperazine and 1-(3-chloro ethyl)-4-methyl piperazine.
EXAMPLE 6
1-(4'-Chloro benzyl)-2-phenyl-4-[1",3"-dimorpholino propyl(2")]-piperazine ##STR29##
31 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine prepared according to Example B, 52 g. of 1,3-dimorpholino propylchloride-(2), prepared by chlorinating 1,3-dimorpholino propanol-(2), 25 g. of triethylamine, and 250 cc. of acetone are boiled under reflux for 48 hours. The base remaining after filtration and evaporation of the solvent is purified by dissolving it in hydrochloric acid and setting it free from its hydrochloride solution by the addition of ammonia. The base is dissolved in benzene, and the benzene solution dried over anhydrous potassium carbonate. After distilling off the solvent, the residue is distilled in a vacuum of 0.1 Torr. The first fraction distilling over at a temperature up to 110° C. consists mainly of unreacted dimorpholino propylchloride. The remaining residue is dissolved in petroleum ether and is separated from undissolved matter by filtration after cooling. The solvent is distilled off and the remaining compound is purified by distillation in a vacuum. 34 g. of an oil of the boiling point 230° C./0.001 mm. Hg are obtained. The oil solidifies on standing.
EXAMPLE 7
1-(4'-Chloro benzyl)-3-phenyl-4-(diethylamino ethyl) piperazine ##STR30##
a. 1-(Diethylamino ethyl)-2-phenyl piperazine
1-(Diethylamino ethyl)-2-phenyl-3-keto piperazine is prepared by reacting N 1 -(diethylamino ethyl) ethylenediamine with α-chloro phenyl acetylchloride and isolating the above mentioned reaction product from the resulting mixture of isomers.
89 g. of said keto piperazine dissolved in 200 cc. of dioxane are added drop by drop to a suspension of 20 g. of lithium aluminum hydride LiAlH 4 in 800 cc. of ether. After addition of the keto piperazine, the reaction mixture is boiled under reflux for 6 hours. It is then decomposed by successively adding 20 cc. of 15% sodium hydroxide, 20 cc. of water, 60 cc. of 15% sodium hydroxide solution, and finally 40 cc. of water. The filtered solution is concentrated by evaporation and the residue is distilled in a vacuum. The resulting oil which distills at a temperature between 102° C. and 115° C./0.05 mm. Hg, is dissolved in benzene and is extracted therefrom by shaking in 10 % hydrochloric acid. The base is set free from its hydrochloride solution by the addition of 10 % sodium hydroxide solution and is repeatedly distilled in a vacuum. An almost colorless oil of the boiling point 114°-117° C./0.07 mm. Hg is obtained. The yield corresponds to the theoretical yield. The compound contains a small amount of 3-phenyl-1-(diethylamino ethyl) piperazine.
b. 1-(4'-Chloro benzyl)-3-phenyl-4-diethylamino ethyl) piperazine
26 g. of the base prepared as described hereinabove under (a) are boiled under reflux with 17.7 g. of 4-chloro benzylchloride and 42 cc. of triethylamine in 200 cc. of acetone for 10 hours. After filtration and distilling off the solvent, the base is purified in the manner described hereinabove via its hydrochloride and is set free from said hydrochloride by the addition of ammonia. The residue is freed of the solvent and is dissolved in acetic acid ethyl ester. The hydrochloride is precipitated from said solution by the addition of absolute ethanolic hydrochloric acid. The hydrochloride is recrystallized from acetic acid ethyl ester. The base is set free from said hydrochloride by means of ammonia and is distilled in a vacuum. An almost colorless oil of the boiling point 180° C./0.01 mm. Hg is obtained. The yield is 30 g. corresponding to 78 % of the theoretical yield.
This compound can be distinguished by means of its infrared spectrum from the isomeric 1-(4'-chloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine by directly comparing both compounds.
EXAMPLE 8
1-(Diethylamino ethyl)-2-phenyl-4-(p-ethoxy benzyl) piperazine ##STR31##
(a) 1-Diethylamino ethyl-2-phenyl-3-keto piperazine
144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g. of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. of acetone for 24 hours. The cooled solution is filtered to remove triethylamine hydrochloride and the filtrate is evaporated to dryness. The residue is dissolved in water, 40 % sodium hydroxide solution is added thereto, and the oil which forms as upper layer, is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the benzene is removed by distillation, and the residue is distilled in a vacuum. A light yellow, viscous oil of the boiling point 175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized from n-heptane. 145 g. of the above mentioned compound melting at 53°-56° C. are obtained. The yield is 64 % of the theoretical yield.
b. 1-Diethylamino ethyl-2-phenyl piperazine
89 g. of the keto piperazine prepared as described hereinabove under (a), are dissolved in 200 cc. of absolute dioxane. The solution is added to a suspension of 20 g. of lithium aluminum hydride LiAlH 4 in 800 cc. of absolute ether while exposing the mixture to vibration. After addition of the keto piperazine solution is completed, the reaction mixture is boiled under reflux for 6 hours. Thereafter it is decomposed by successive treatment with 21 cc. of 15 % sodium hydroxide solution, 21 cc. of water, 63 cc. of 15 % sodium hydroxide solution, and 42 cc. of water. The decomposed reaction mixture is filtered, the solvent is removed by distillation, and the residue is distilled in a vacuum. 65 g. of a light yellow oil of the boiling point 114°-117° C./0.05 mm. Hg are obtained. This oil corresponds to the above given compound. The yield is 77 % of the theoretical yield.
c. 1-Diethylamino ethyl-2-phenyl-4-(p-ethoxy benzyl) piperazine
40 g. of the piperazine derivative prepared as described hereinabove under (b) are boiled under reflux with 27 g. of p-ethoxy benzylchloride in 400 cc. of acetone with the addition of 50 cc. of triethylamine for 12 hours. The triethyl ammonium hydrochloride formed thereby is filtered off. The acetone is removed by distillation. The residue is dissolved in benzene and the base is dissolved therefrom in the form of its hydrochloride by extraction with dilute hydrochloric acid. The base is set free from its hydrochloride solution by the addition of ammonia and is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate. The solvent is distilled off and the residue is distilled in a vacuum. 39 g. of a light yellow viscous oil of the boiling point 200° C/0.05 mm. Hg are obtained. The yield is 64 % of the theoretical yield.
EXAMPLE 9
1-Diethylamino ethyl-3-phenyl piperazine
1-Diethylamino ethyl-2-keto-3-phenyl piperazine prepared according to Example 1 B (a) of application Ser. No. 333,497, is reduced by following the procedure described hereinabove in Example 7 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-diethylamino ethyl-2-keto-3-phenyl piperazine is reduced. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 102° C./0.02 mm. Hg.
EXAMPLE 10
1-Benzyloxy benzyl-2-phenyl piperazine
1-Benzyloxy benzyl-2-phenyl-3-keto piperazine prepared according to Example 12, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-benzyloxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of white crystals melting at 140-141° C.
EXAMPLE 11
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl piperazine
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-3-keto piperazine prepared according to Example 13, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(3',4',5'-trimethoxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of a yellow oil boiling at 185-195° C./0.08 mm. Hg.
EXAMPLE 12
1-[3'-(4"-Methoxy phenyl) propyl(1) ]-2-phenyl piperazine
1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl-3-keto piperazine prepared according to Example 14, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-[3'-(4"-methoxy phenyl) propyl(1)]-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine is obtained in the form of a light yellow oil boiling at 176° C./0.05 mm. Hg.
EXAMPLE 13
1-(4'-Chloro benzyl)-3-phenyl-4-diethylamino ethyl piperazine
1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine prepared according to Example 10, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(4'-Chloro benzyl)-2-keto-3-phenyl-4-diethylamino ethyl piperazine is used. The resulting 3-phenyl piperazine compound is obtained in the form of a light yellow oil boiling at 180° C./0.01 mm. Hg.
EXAMPLE 14
1-(3',4'-Dichloro benzyl)-2-phenyl-4-dimethylamino ethyl piperazine
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3 (b), is alkylated by following the procedure described in Example 3 (c), whereby, in place of the diethylamino ethylchloride, the equimolecular amount of dimethylamino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 190° C./0.01 mm. Hg.
EXAMPLE 15
1-(3',4'-Dichloro benzyl)-2-phenyl-4-morpholino ethyl piperazine
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 3 (b), is akylated by following the procedure described in Example 3 (c) whereby, in place of diethylamino ethylchloride, the equimolecular amount of morpholino ethylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 230° C./0.04 mm. Hg.
EXAMPLE 16
1-(3',4'-Dichloro benzyl)-2-phenyl-4-diethylamino propyl piperazine
1-(3',4'-Dichloro benzyl)-2-phenyl piperazine prepared according to Example 2 (b), is alkylated by following the procedure described in Example 2 (c) whereby, in place of the diethylamino ethylchloride, the equimolecular amount of diethylamino propylchloride is used. The resulting reaction product is obtained in the form of a light yellow oil boiling at 210° C./0.04 mm. Hg.
EXAMPLE 17
1-(4'-Benzyloxy benzyl)-2-phenyl-4-diethylamino ethyl piperazine
1-(4'-Benzyloxy benzyl)-2-phenyl piperazine prepared according to Example 10, is alkylated by means of diethylamino ethylchloride by following the procedure described in Example 2 (c). The resulting reaction product is obtained in the form of a light yellow oil boiling at 235° C./0.01 mm. Hg.
EXAMPLE 18
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-4-diethylamino ethyl piperazine
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl piperazine prepared according to Example 11, is alkylated by means of diethylamino ethylchloride by following the procedure described in Example 2 (c). The resulting reaction product is obtained in the form of yellow oil boiling at 200° C./0.03 mm. Hg.
EXAMPLE 19
1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl-4-diethylamino ethyl piperazine
1-[3'-(4"-Methoxy phenyl) propyl(1)]-2-phenyl piperazine prepared according to Example 12, is alkylated by means of diethylamino ethylchloride by following the procedure described in Example 2 (c). The resulting reaction product is obtained in the form of a yellow oil boiling at 130°-190° C./0.01 mm. Hg.
EXAMPLE 20
1-(4'-Ethoxy benzyl)-3-phenyl-4-diethylamino ethyl piperazine
1-Diethylamino ethyl-2-phenyl piperazine prepared according to Example 7 (a), is reacted with 4-ethoxy benzylchloride by following the procedure described in Example 7 (b) and using, in place of 4-chloro benzylchloride, the equimolecular amount of 4-ethoxy benzylchloride. The resulting reaction product is obtained in the form of a yellow oil boiling at 200° C./0.05 mm. Hg.
EXAMPLE 21
1-(4'-Chloro benzyl)-2-phenyl-4-(diethylamino ethyl) piperazine ##STR32##
A. 1-(4-Chloro benzyl)-2-phenyl-4-(β-hydroxy ethyl) piperazine ##STR33##
a. 30 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine, prepared according to Example 1 A), 20 g. of ethylene chlorohydrin, 20 g. of triethylamine and 250 cc. of methyl ethyl ketone are boiled under reflux for 24 hours. After cooling, the triethylamine hydrochloride formed thereby is removed by filtration, the filtrate is evaporated in a vacuum, the residue is dissolved in benzene, the benzene solution is washed with water and dried over anhydrous potassium carbonate. The benzene is removed by distillation and the residue is distilled in a vacuum. A yellow, viscous oil of the boiling point 195° C./0.01 mm. Hg is obtained. The oil is twice recrystallized from isopropanol and then from n-heptane. Melting point 91-94° C.; yield 22 g.
b. A mixture of 28.6 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine, 6.0 g. of ethylene oxide and 200 cc. of methanol is let standing for 4 days in a closed flank at room temperature. Then the methanol is distilled off and the residue is distilled at 193° C./0.01 mm. Hg. The base is twice recrystallized from n-heptane, whereby a product having a melting point of 91°-94° C. is obtained. Yield 19 g.
c. 50 g. of 1-(4'-chloro benzyl)-2-phenyl piperazine are dissolved in 100 cc. of dioxane. To this solution are added 31 g. of acetylglycolic acid chloride, dissolved in 50 cc. of dioxane. The mixture boiled for 2 hours under reflux. The dioxane is distilled off in a vacuum and the residue is dissolved in benzene; the benzene solution is washed with an aquous 10 % sodium hydroxide solution and is dried over anhydrous potassium carbonate. The solvent is distilled off and the residue is recrystallized three times from isopropanol. Melting point 136°-137° C.; yield 46 g.
44 g. of the piperazine derivative obtained as above are dissolved in 120 cc. of absolute dioxane and added slowly drop to drop to a suspension of 10 g. of LiAlH 4 in 700 cc. of absolute ether. The mixture is boiled under reflux for 2.5 hours. It is then decomposed by adding 10 cc. of 15 % sodium hydroxide solution, 10 cc. of water, 30 cc. of 15 % sodium hydroxide solution and 20 cc. of water. The precipitated inorganic material is separated by filtration and the solvent is distilled in a vacuum. The residue is recrystallized three timed from n-heptane. The obtained compound has a melting point of 91°-94° C. Yield 17 g.
B. 1-(4'-Chloro benzyl)-2-phenyl-4-(2-chloro ethyl)pierazine hydrochloride. ##STR34##
24 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-hydroxy ethyl) piperazine are dissolved in 150 cc. of chloroform and added drop by drop to a solution of 15 g. of thionyl chloride in 150 cc. of chloroform. The mixture is boiled under reflux for 5 hours and the solvent is removed in a vacuum by heating the mixture in a water bath. Excess of absolute ethanolic hydrochloric acid is added and the remaining acid is distilled off. The crystalline residue obtained is recrystallized from absolute ethanol. Melting point 178°-195° C. (dec.); yield 30 g.
C. 1-(4'-Chloro benzyl)-2-phenyl-4-(diethylaminoethyl) piperazine.
20 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 14 g. of diethylamine and 200 cc. of acetone are boiled under reflux for 12 hours. After cooling, the precipitated diethylamino hydrochloride is filtered off with suction and the solvent of the filtrate is evaporated in a vacuum. The residue is distilled in a vacuum. 15 g. of a light yellow oil having a boiling point of 190° C./0.06 mm. Hg are obtained. This product is identical with the product as obtained according to Example 1 B.
EXAMPLE 22
1-(4'-Chloro benzyl)-2-phenyl-4-[(4"-methyl)-piperazino ethyl-(1)] piperazine. ##STR35##
47 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 16.5 g. of N-methyl piperazine, 75 cc. of triethylamine and 300 cc. of methyl ethyl ketone are boiled under reflux for 12 hours. After cooling the precipitated triethylamino hydrochloride is filtered off with suction and the solvent is distilled off in a vacuum. The residue is dissolved in benzene, the benzene solution is washed with water and dried over anhydrous potassium carbonate. The solvent is distilled off and the residue is disssolved in absolute ethanol. Absolute ethanolic hydrochloric acid is added to precipitate the hydrochloride salt. After cooling the precipitation is separated by filtration, washed with absolute ethanol and dried. Melting point 250°-269° C. (decomposition). To obtain the free base the hydrochloride is dissolved in water and the base is set free from its hydrochloride solution by the addition of ammonia and extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the solvent is distilled off and the residue is distilled in a vacuum. Boiling point 220-223° C./0.01 mm. Hg. Yield 30 g.
EXAMPLE 23
1-(4'-Chloro benzyl)-2-phenyl-4-[(3"-keto)piperazino ethyl-(1")] piperazino.
25 g. of 1-(4"-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 7.3 g. of mono keto piperazine, 200 cc. of methyl ethyl ketone and 200 cc. of triethylamine are boiled for 24 hours under reflux. The precipitated triethylamine hydrochloride is filtered off with suction. Then, the solvent is evaporated, the residue is dissolved in benzene and the benzene solution is washed with water and dried over anhydrous potassium carbonate. The solvent is distilled off and the residue is distilled at 230°-250° C./0.06 mm. Hg (minor decomposition). The distilled product is dissolved in ether, washed with 0.5N hydrochloric acid. The extract obtained with the diluted hydrochloric acid is treated with carbon aand after filtration, the base is set free from said solution by use of ammonia. The base is dissolved in benzene, dried over anhydrous potassium carbonate and after evaporation of the solvent, the residue is distilled at 220°-230° C. (air bath temperature)/0.005 mm. Hg. A very viscous, brownish oil is obtained.
The acid addition salts of the bases according to the present invention are prepared in a manner known per se. For instance, anhydrous ethanolic hydrochloric acid is added to the base whereby the hydrochloride precipitates and is isolated by filtration. Or the base is triturated with the equimolecular amount of the respective acid either as such or in aqueous solution or in solution in an organic solvent and, if required, evaporating the solvent.
Specific procedures to prepare the acid addition salts are the following:
To prepare the hydrochlorides, the bases are dissolved in absolute ethanol and an equimolecular amount of abslute ethanolic hydrochloric acid is added. After cooling, the precipitated hydrochloride is separated by filtration and recrystallised from absolute ethanol or isopropanol.
The succinates or fumarates, respectively, may be obtained using an equimolar amount succinic acid or fumaric acid, respectively, which is added and to the base dissolved in acetone. After boiling under reflux, e.g. for 2 hours, the mixture is cooled and the precipitated salts are separated. The so obtained salts are pure for analysis. In case that the fumarates or succinates, respectively, are not separated from the mixture in crystalline form, the solvent is evaporated and the remaining syrup is triturated to induced crystallization. Recrystallization may be effected by use of ethyl acetate.
To prepare the sulfates, the base is dissolved in absolute ethanol and an equimolecular amount of dilute sulfuric acid is added. The obtained sulfates may be recrystallized from ethanol.
The preparation of the phosphates may be effected by dissolution of the base in absolute ethanol, and addition of an equimolecuar amount of dilute phosphoric acid. The phosphate may be precipitated by use of acetic acid ethyl ester and may be recrystallized by use of isopropanol.
The following acid addition salts have been prepared and isolated:
__________________________________________________________________________Ex- Acid addi-ampleBase tion salt Melting point__________________________________________________________________________24 1-(4'-Chloro benzyl)-2-phenyl- Dihydro- 255-1270° C. with4-diethylamino ethyl piperazine chloride decomposition25 1-(3',4'-Dichloro benzyl)-2- Dihydro- 220-222° C.phenyl-4-diethylamino ethyl chloridepiperazine26 1-(3',4'-Dichloro benzyl)-2- o-Phos- 220-226° C.phenyl-4-diethylamino ethyl phatepiperazine27 1-(3',4'-Dichloro benzyl)-2- Sulfate 210-214° C.phenyl-4-diethylamino ethylpiperazine28 1-(4'-Chloro benzyl)-2-phenyl- Succinate 156-158° C.4-piperidino ethyl piperazine29 1-(4'-Chloro benzyl)-2-phenyl-4- Fumar- 190° C. sublimatespiperidino ethyl piperazine ate 250-251° C. with de- composition30 1-[(4'-Methoxy phenyl)ethyl]- Hydro- 190-201° C.2-phenyl-4-diethylamino ethyl chloridepiperazine31 1-[3"-Phenyl propyl(1)]-2- Hydrochloride 185-192° C.piperazine32 1-(4'-Chloro benzyl)-3-phenyl- Hydrochloride 241-255° C.4-diethylamino ethyl piperazine with decom- position33 1-(4'-Chloro benzyl)-2-phenyl- Succin- 95-101° C.4-diethylamino ethyl piperazine ate__________________________________________________________________________
EXAMPLE 34
4-Diethylaminoethyl-3-phenyl-1-o-hydroxy benzyl) piperazine ##STR36##
a. 4-Diethylaminoethyl-3-phenyl-1-(o-acetoxy benzoyl)piperazine is prepared by boiling under reflux 15 g. of 1-diethylaminoethyl-2-phenyl-piperazine dissolved in 100 ml. of methyl ethyl ketone with 11 g. of acetyl salicyclic acid chloride dissolved in 50 ml. methyl ethyl ketone, for 6 hours. The solvent is removed by distillation. The residue is dissolved in water. The aqueous solution is extracted with benzene. Ammonia is added to the aqueous layer until its reaction is alkaline and the thus precipitated oil is extracted with benzene. The benzene extract is dried by means of potassium carbonate and the benzene is distilled off. The residue is distilled in a vacuum. Boiling point: 190° C./0.01 mm. (bath temperature). Light yellow, viscous oil.
b. 4-Diethylaminoethyl-3-phenyl-1-(o-hydroxy benzoyl) piperazine is obtained by dissolving the reaction product prepared as described hereinabove under (a) in 100 ml. of dilute hydrochloric acid (2 : 100). The solution is heated to 50° C. for one hour an is then rendered alkaline by the addition of ammonia. The precipitated viscous product is extracted with benzene, the benzene solution is dried by means of potassium carbonate. The benzene is removed by distillation and the residue is distilled in a vacuum. Boiling point: 180° C./0.001 mm. (bath temperature). Light yellow, vitreous product.
c. 4-Diethylaminoethyl-3-phenyl-1-(o-hydroxy benzyl) piperazine is obtained by dissolving 40 g. of 4-diethylaminoethyl-3-phenyl-1-(o-hydroxy benzoyl) piperazine in 150 ml. of dioxane and slowly adding said solution to a suspension of 6 g. of lithium aluminum hydride in 800 ml. of absolute ether. The reaction mixture is boiled under reflux for two hours. The resulting complex compound is decomposed by a treatment with 5 ml. of 15% sodium hydroxide solution followed by 5 ml. of water, 15 ml. of 15% sodium hydroxide solution, and finally 10 ml. of water. The resulting precipitate is filtered off and the solvent is distilled off from the filtrate. The residue is distilled in a vacuum. Boiling point: 180° C./0.001 mm. (bath temperature). Yellow oil.
EXAMPLE 35
1-(p-Hydroxy benzyl)-2-phenyl-4-diethylaminoethyl piperazine ##STR37##
a. 1-(4-Benzyloxy benzyl)-2-phenyl-3-keto piperazine is obtained by boiling under reflux 48 g. of 4-benzyloxybenzyl chloride, 35 g. of 2-phenyl-3-keto piperazine, 500 ml. of acetone, and 50 ml. of triethylamine for 14 hours. Thereafter, the acetone is distilled off and the residue is treated with water. The precipitated crystals are filtered of and are recrystallized from dioxane and thereafter from a mixture of dimethylformamide and water (1 : 1). Melting point: 207°-211° C. White crystals.
b. 1-(4-Benzyloxybenzyl)-2-phenyl piperazine is obtained by suspending 39 g. of the compound prepared according to (a) hereinabove in 150 ml. of dioxane. The suspension is added to a suspension of 10 g. of lithium aluminum hydride (LiAlH 4 ) in 900 ml. of ether. The resulting mixture is boiled under reflux for two hours. The complex compound formed thereby is decomposed by treatment with 10 ml. of 15% sodium hydroxide solution, followed by a treatment with 10 ml. of water, 30 ml. of 15% sodium hydroxide solution, and finally with 20 ml. of water. The decomposed mixture is filtered. The filter residue is discarded. The filtrate is evaporated to dryness and the evaporation residue is recrystallized from dioxane. melding point: 140°-141° C., white crystals.
c. 1-(4-Benzyloxybenzyl)-2-phenyl-4-diethylaminoethyl piperazine is obtained by boiling under reflux 25 g. of the compound prepared according to (b) hereinabove with 10.5 g. of diethylaminoethyl chloride, 30 ml. of triethylamine. and 200 ml. of acetone for six hours. The precipitated triethylamine hydrochloride is filtered off. The acetone is distilled of and the residue is dissoved in benzene. The benzene solution is extracted with dilute hydrochloric acid (1 : 10). The acid solution is made alkaline by the addition of ammonia and the precipitated oil is extracted with benzene. After distilling off the benzene, the residue is distilled in a vacuum. Boiling point: 235° C./0.01 mm. Yellow oil.
d. 1-(p-Hydroxybenzyl)-2-phenyl-4-diethylamino ethyl piperazine is obtained by dissolving 15 g. of the compound prepared as described under (c) in 500 ml. of toluene. 5 g. of palladium deposited on asbestos are added thereto. Hydrogen is passed into the solution under a positive pressure of 15 mm. mercury. Progress of the hydrogenating debenzylation is ascertained by thin-layer chromatography. Introduction of hydrogen is discontinued after 20 hours. The catalyst is filtered off. The toluene is distilled off and the residue is triturated with petroleum ether. The precipitated crystals are filtered off by suction. The filter residue is dissolved in warm acetone and is precipitated by the addition of petroleum ether. After filtering off by suction the precipitate and drying it, white crystals of the melting point 108°-112° C. are obtained.
EXAMPLE 36
1-(3,4-Dihydroxy benzyl)-2-phenyl-4-diethylaminoethyl piperazine ##STR38## The compound is prepared in an analogous manner as described in Example 35 by using as starting material 1-(3,4-dibenzyloxybenzyl)-2-phenyl-3-keto piperazine. Light yellow, very viscous oil. Boiling point: 245° C./0.001 mm.
EXAMPLE 37
4-Diethylaminoethyl-3-phenyl-1-(3,4-dibenzyloxy benzyl) piperazine hydrochloride. ##STR39## 30 g. of 3,4-dibenzyloxy benzylchloride, 23 g. of 1-diethylamino ethyl-2-phenyl piperazine, 20 ml. of triethylamine, and 200 ml. of methylethylketone are boiled under reflux for 12 hours. The precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off and the residue is dissolved in benzene. The benzene solution is extracted with dilute hydrochloric acid (1 : 8). The hydrochloric acid extract is rendered alkaline by the addition of ammonia and is extracted with benzene. The benzene is removed from the benzene extract by distillation. Water-free alcoholic hydrochloric acid is added to the residue, and the hydrochloride of the resulting base is precipitated by the addition of a mixture of petroleum ether and acetone (1 : 1). The hydrochloride is redissolved in alcohol and is again precipitated by the addition of petroleum ether and acetone. Melting point of the hydrochloride: It starts to sublimate at 203° C. and melts at 235°-239° C. with decomposition. White crystals.
EXAMPLE 38
1-(p-Chloro benzyl)-2-phenyl-4-morpholino ethyl-3-keto piperazine ##STR40##
45 g. of 1-(4-chloro benzyl)-2-phenyl-3-keto piperazine,
56 g. of morpholino ethylchloride,
50 g. of potassium carbonate, and
500 ml. of toluene
are boiled under reflux for 20 hours. Water is added to the reaction mixture and undissolved matter is filtered off therefrom. The clear toluene solution is extracted with 250 ml. of N hydrochloric acid. The extract is rendered strongly alkaline by the addition of ammonia and the precipitated base is extracted with benzene. After drying the benzene extract, the solvent is distilled off and the residue is recrystallized from isopropanol, yielding a first crystal fraction. The mother lye is concentrated by evaporation to a small volume and is cooled. Precipitated crystals are filtered off by suction. They represent the second crystal fraction. Since both fractions still contain unreacted starting material, they are triturated with 60 ml. of N acetic and undissolved matter is filtered off. The clear acetic acid solution is rendered strongly alkaline by the addition of ammonia and is extracted with benzene. The benzene is distilled off after drying the extract. The remaining residue is recrystallized from isopropanol. Melting point: 117°-119° C. Yield: 10 g.
EXAMPLE 39
1-(2-Chloro benzyl)-2-phenyl-4-morpholino ethyl-3-keto piperazine ##STR41## 45 g. of 1-(2-chloro benzyl)-2-phenyl-3-keto piperazine obtained as described in Example 46 (a),
56 g. of morpholino ethyl chloride,
50 g. of potassium carbonate, and
500 ml. of toluene
are boiled under reflux for 20 hours. The reaction mixture is poured into water. Undissolved matter is separated. The toluene solution is extracted with 250 ml. of N hydrochloric acid. The hydrochloric acid extract is rendered strongly alkaline by the addition of ammonia and the precipitated base is extracted with benzene. After drying, the solvent is distilled off from the extract. The residue is dissolved in 100 ml. of N acetic acid. The crystals formed after allowing the solution to stand for a short period of time, are separated. The acetic acid filtrate is rendered strongly alkaline by the addition of ammonia and the precipitated base is extracted with benzene. After drying the benzene extract and distilling off the solvent, the residue is recrystallized from ispropanol. Melting point: 104°-106° C. Yield: 8.5 g.
EXAMPLE 40
1-(p-Chloro benzyl)-2-phenyl-4-dimethylamino propyl piperazine ##STR42## 28.6 g. of 1-(p-chloro benzyl)-2-phenyl piperazine, 15.0 g. of dimethylaminopropylchloride,
50 ml. of triethylamine, and
100 ml. of methyl ethyl ketone
are boiled under reflux for 20 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off. The residue is dissolved in 100 cc. of N hydrochloric acid. The hydrochloric acid extract is twice washed with benzene and is then rendered alkaline by the addition of ammonia. The oily base is separated in a separating funnel and is dissolved in 100 ml. of isopropanol. Solid potassium hydroxide is added to the isopropanol solution in order to remove the water present therein. The isopropanol solution is then filtered through a layer of potassium carbonate. After distilling off the solvent, a yellow viscous oil is obtained. The oil is dissolved in 1.5 liters of petroleum ether. Small amounts of impurities are filtered off and the petroleum ether is distilled off. The crude base is dissolved in benzene and is extracted with 25% acetic acid. The base is set free from said extract by the addition of ammonia. The base is again dissolved in benzene and dried by means of potassium carbonate. The solvent is distilled off and the residue is distilled in a vacuum. Boiling point: 180°-184° C./0.08 mm. Yield: 14 g.
EXAMPLE 41
1-(3,4-Dibenzyloxy benzyl)-2-phenyl-4-diethylamino ethyl piperazine fumarate ##STR43##
a. 23.2 g. of 2-phenyl-3-keto piperazine,
50.0 g. of 3,4-dibenzyloxy benzylchloride,
30 ml. of triethylamine, and
300 ml. of methyl ethyl ketone
are boiled under reflux for 3 hours. After cooling, precipitated triethylamine hydrochloride is filtered off by suction. The solvent is then distilled off. The residue is dissolved in 50 ml. of acetone. The acetone solution is poured into 500 ml. of water. The precipitated crystallized product is filtered off and is twice recrystallized from isopropanol. Melting point: 108°-110° C. Yield 46 g.
b. 44 g. of the compound as described hereinabove under (a) are suspended into
250 ml. of dioxane.
The suspension is added drop by drop to a suspension of
7 g. of lithium aluminum hydride in
500 ml. of ether.
Thereafter the reaction mixture is boiled under reflux for one hour. After decomposing the lithium aluminum hydride complex compound, the ethereal solution is separated, the ether is distilled off, and the residue is recrystallized from isopropanol. Melting point: 54°-55° C. Yield: 25 g.
c. 25 g. of the compound obtained as described hereinabove under (b),
9 g. of diethylamino ethylchloride,
15 ml. of triethylamine, and
150 ml. of methyl ethyl ketone
are boiled under reflux for 10 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The filtrate is evaporated by distillation to dryness and the residue is dissolved in benzene. The benzene solution is washed with 20% sodium hydroxide solution. The washed benzene layer is separated and extracted with 150 ml. of N hydrochloric acid. The base is set free from said hydrochloric acid extract by the addition of ammonia. It is extracted therefrom with benzene. The benzene solution is dried and the solvent is distilled off. The residue is dissolved in 100 ml. of acetone. 5 g. of fumaric acid are added to said solution which is heated to boiling on the water bath. Small amounts of insoluble matter are filtered off and the solution is cooled. The precipitated fumarate is recrystallized from 96% ethanol. Melting point: 152°-154° C. Yield: 22 g.
EXAMPLE 42
1-(o-benzyloxy-benzyl)- 2-phenyl-4-diethylamino ethyl piperazine ##STR44##
a. 38 g. of 2-phenyl-3-keto piperazine,
52 g. of o-benzyloxy benzylchloride,
50 ml. of triethylamine, and
400 ml. of methyl ethyl ketone
are boiled under reflux for four hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The methyl ethyl ketone is distilled off. The residue is dissolved in isopropanol and water is added thereto, while heating, until crystallization sets in. Melting point: 159°-160° C. Yield: 50 g.
b. 39 g. of the compound prepared as described hereinabove under (a) are dissolved in
100 ml. of anhydrous dioxane.
The solution is added drop by drop to a suspension of
10 g. of lithium aluminum hydride in 900 ml. of absolute ether. Thereafter the mixture is boiled under reflux for one and a half hours. The resulting lithium aluminum hydride complex compound is decomposed by a treatment with 10 ml. of 15% sodium hydroxide solution followed by a treatment with 10 ml. of water, 30 ml. of 15% sodium hydroxide solution, and finally 20 ml. of water. The solution is filtered. The solvent is distilled off. The residue is dissolved in benzene and the benzene solution is extracted with 300 ml. of N/2 hydrochloric acid. The hydrochloric acid extract is rendered strongly alkaline by the addition of ammonia. The precipitated base is extracted with benzene. The benzene solution is dried and the benzene is distilled off. The remaining base is distilled in a vacuum. Boiling point: 205° C./0.03 mm. The base is then recrystallized twice from n-heptane. Melting point: 82°-85° C. Yield: 35 g.
c. 30 g. of the compound prepared as described hereinabove under (b),
12.5 g. of diethylamino ethylchloride,
30 ml. of triethylamine, and
150 ml. of methyl ethyl ketone
are boiled under reflux for 12 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off from the filtrate. The residue is dissolved in benzene. The benzene solution is extracted with 300 ml. of N hydrochloric acid. The base is precipitated from the hydrochloric acid extract by the addition of ammonia. The precipitated base is then extracted with benzene. The benzene solution is dried by means of potassium carbonate and the solvent is distilled off. The residue is distilled in a vacuum. Boiling point: 230°-235° C./0.03 mm. Yield: 25 g.
EXAMPLE 43
1-(p-Methoxy benzyl)-2-phenyl-4-diethylamino propyl piperazine ##STR45##
28 g. of 1-(p-methoxy benzyl)-2-phenyl piperazine obtained as described hereinabove in Example 3 (b),
20 g. of diethylamino propylchloride,
50 ml. of triethylamine, and
200 ml. of methyl ethyl ketone
are boiled under reflux for 12 hours. Precipitated triethylamine hydrochloride is filtered off. The solvent is removed by distillation. The residue is dissolved in benzene. The benzene solution is extracted with an acetic acid-water mixture 1 : 7). The acetic acid solution is separated from the benzene solution and is rendered alkaline by the addition of ammonia. The precipitated oily base is extracted in benzene, dried by means of potassium carbonate, and the benzene is distilled off. The remaining base is distilled in a vacuum. Boiling point: 200° C./0.01 mm.
The crude base is dissolved in 100 ml. of absolute ethanol and the solution is acidified by the addition of absolute alcoholic hydrochloric acid to a pH of 1.0. The precipitated hydrochloride is filtered off by suction and dried. The salt starts to sublimate at 200° C. and melts at 228°-231° C. with decomposition. The hydrochloride is dissolved in water. The base is set free by the addition of ammonia and is extracted with benzene. The benzene is distilled off from the benzene solution. The remaining base is again distilled in a vacuum. Boiling point: 210° C./0.02 mm. Colorless oil. Yield: 21 g.
EXAMPLE 44
1-(3-Chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine ##STR46##
a. 17.5 g. of 1-(3-chloro benzyl)-2-phenyl-3-keto piperazine obtained as described in Example 44 (a) of Application Ser. No. 333,497
are suspended in 50 ml. of absolute dioxane. The suspension is added drop by drop, while stirring, to a suspension of
4.5 g. of lithium aluminum hydride in
400 ml. of absolute ether.
Thereafter, the reaction mixture is boiled under reflux for one and a half hours. The resulting complex compound is decomposed by a treatment first with
4.5 ml. of 15% sodium hydroxide followed by a treatment with 4.5 ml. of water,
14.5 ml. of 15% sodium hydroxide solution, and finally 9.0 ml. of water.
The hydroxide precipitate is filtered off and the solvent is distilled off from the filtrate. The residue is dissolved in 20 ml. of N acetic acid. After allowing the solution to stand for 24 hours, the solid precipitate is filtered off. The filtrate is rendered alkaline by the addition of ammonia and the precipitated base is extracted with benzene. After drying the benzene solution, the solvent is distilled off. The residue is dissolved in 30 ml. of absolute ethanol and is adjusted to a pH of 1.0 by the addition of absolute alcoholic hydrochloric acid. The precipitated hydrochloride is filtered off by suction and dried. Melting point: 239°-242° C. The hydrochloride is dissolved in water. The base is set free by the addition of ammonia and is extracted with benzene. After drying the benzene solution and distilling off the benzene, the oily residue is distilled in a vacuum. Boiling point: 145° C./0.05 mm. Colorless oil.
b. 10 g. of the base obtained as described hereinabove under (a),
150 ml. of acetone,
9.0 g. of diethylamino ethylchloride, and
10 ml. of triethylamine
are boiled under reflux for 14 hours. The reaction mixture is cooled and the precipitated triethylamine hydrochloride is filtered off by suction. The filtrate is evaporated to dryness. The residue is dissolved in benzene. The benzene solution is extracted with 100 ml. of N hydrochloric acid. The hydrochloric acid extract is rendered alkaline. The precipitated base is extracted with benzene. The benzene solution is then dried by means of potassium carbonate and the benzene is distilled off. The remaining residue is distilled in a vacuum. Boiling point: 170° C./0.07 mm. Yellowish, mobile oil. Yield: 12 g.
EXAMPLE 45
1-(2-Chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine ##STR47##
a. 51 g. of 1-(2-chloro benzyl)-2-phenyl-3-keto piperazine prepared as described in Example 46 (a) of Application Serial No. 333,497 are suspended in
100 ml. of dioxane.
The suspension is added to a suspension of
11 g. of lithium aluminum hydride in
700 ml. of absolute ether and
50 ml. of dioxane,
while stirring. Thereafter, the reaction mixture is boiled under reflux for one and a half hours. The resulting complex compound is decomposed first by a treatment with
11 ml. of 15% sodium hydroxide solution followed by a treatment with
11 ml. of water,
33 ml. of 15% sodium hydroxide solution, and finally with
22 ml. of water.
After filtering off by suction the hydroxide precipitate, the solvent is distilled off from the filtrate. The residue is dissolved in 100 ml. of absolute ethanol and 35 ml. of alcoholic hydrochloric acid (about 8 N) are added thereto. The precipitated hydrochloride is filtered off by suction, washed, and dried. Melting point: 276°-277° C. The hydrochloride is dissolved in water. The base is set free therefrom by the addition of ammonia and is extracted with benzene. The benzene solution is dried and the solvent is distilled off. The remaining base is distilled in a vacuum. Boiling point: 136° C./0.08 mm. Yield: 38 g.
b. 10 g. of the base obtained as described hereinabove under (a),
150 ml. of acetone,
9 g. of diethylamino ethylchloride, and
10 ml. of triethylamine
are boiled under reflux for 14 hours. The reaction mixture is cooled and the precipitated triethylamine hydrochloride is filtered off by suction. The filtrate is then evaporated to dryness. The residue is dissolved in water and is extracted with benzene. The benzene solution is separated from the aqueous phase and is extracted with 50 ml. of N hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia and the base set free thereby is extracted with benzene. The benzene solution is dried by means of potassium carbonate and the solvent is distilled off. The residue is distilled in a vacuum. Boiling point: 160° C./0.05 mm. Yield: 11.5 g.
EXAMPLE 46
1-(3-Trifluoromethyl benzyl)-2-phenyl-4-diethylamino ethyl piperazine ##STR48##
a. 60 g. of 1-(3-trifluoromethyl benzyl)-2-phenyl-3-keto piperazine prepared as described in Example 51 (a) of Application Serial No. 333,497 are dissolved in
120 ml. of dioxane.
The solution is added drop by drop to a suspension of
14 g. of lithium aluminum hydride in
700 ml. of absolute ether and
50 ml. of dioxane,
while stirring. Thereafter, the reaction mixture is boiled under reflux for two hours. The resulting complex compound is decomposed first by a treatment with
14 ml. of 15% sodium hydroxide solution followed by a treatment with
14 ml. of water,
42 ml. of 15% sodium hydroxide solution, and finally
28 ml. of water.
The hydroxide precipitate is filtered off and the solvent is distilled off from the filtrate. The residue is dissolved in 200 ml. of absolute ethanol and 35 ml. of an absolute alcoholic solution of hydrochloric acid (8 N) added thereto. The precipitated hydrochloride is filtered off by suction. It is washed with a mixture of acetic acid ethyl ester and alcohol (1 : 1) and is dried. The resulting hydrochloride is dissolved in a small amount of water. The base is set free from said solution by the addition of ammonia and is extracted with benzene. The benzene solution is dried and the solvent is distilled off. The remaining base is distilled in a vacuum. Boiling point: 120° C./0.05 mm. Yield: 40 g.
b. 10 g. of the base obtained as described hereinabove under (a),
150 ml. of acetone,
9 g. of diethylamino ethylchloride, and
10 ml. of triethylamine
are boiled under reflux for 14 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off from the filtrate. The residue is dissolved in benzene. The benzene solution is washed once with water and is then extracted with 50 ml. of N hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia. The base set free thereby which forms the upper layer is extracted with benzene. The benzene solution is dried and the solvent is distilled off. The remaining base is distilled in a vacuum. Boiling point: 147° C./0.05 mm. Yellowish, mobile oil. Yield: 12.5 g.
EXAMPLE 47
1-(p-Chloro benzyl)-2-phenyl-4-piperazino ethyl piperazine ##STR49##
5 g. of 1-(p-chloro benzyl)-2-phenyl-4-[(3-keto)piperazino ethyl] piperazine obtained as described hereinabove in Example 23 are dissolved in
100 ml. of absolute dioxane.
The solution is added drop by drop to a suspension of 5 g. of lithium aluminum hydride in 500 ml. of absolute ether. After addition is completed, the reaction mixture is boiled under reflux for two hours. The resulting complex compound is then decomposed first by the addition of
5 ml. of 15% sodium hydroxide solution followed by the addition of
5 ml. of water,
5 ml. of 15% sodium hydroxide solution, and finally
10 ml. of water.
The inorganic hydroxides are filtered off from the reaction mixture and the solvent is distilled off. The residue is dissolved in benzene. The benzene solution is extracted with dilute acetic acid (1 : 10). Ammonia is added to the acetic acid solution. The precipitated base is extracted with benzene. The benzene solution is dried and the benzene is distilled off. The remaining base is distilled in a vacuum. Boiling point: 190° C./0.05 mm. Very viscous yellow oil. Yield: 3 g.
EXAMPLE 48
1-(p-Methoxy benzyl)-2-phenyl-4-piperidino ethyl piperazine ##STR50##
13 g. of 1-(p-methoxy benzyl)-2-phenyl piperazine obtained as described hereinabove in Example 4 (b),
10 g. of piperidino ethylchloride,
40 cc. of triethylamine, and
100 cc. of methyl ethyl ketone
are boiled under reflux for 18 hours. Without separating the precipitated triethylamine hydrochloride the solvent is distilled off. The residue is dissolved in benzene and water. The aqueous phase is separated and the benzene solution is extracted with dilute acetic acid (1 : 6). The acetic acid solution is then precipitated by the addition of ammonia. The precipitated base is extracted with benzene, dried by means of potassium carbonate, and the benzene is distilled off. The base is distilled in a vacuum. Boiling point: 210° C./0.001 mm. Light yellow, viscous oil. Yield: 15 g.
EXAMPLE 49
4-Diethylamino ethyl-3-phenyl-(3,4,5-trimethoxy benzyl) piperazine ##STR51##
20 g. of 1-diethylamino ethyl-2-phenyl piperazine prepared as described hereinabove in Example 8 (b),
17 g. of 3,4,5-trimethoxy benzylchloride,
250 ml. of acetone, and
20 ml. of triethylamine
are boiled under reflux for 8 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The acetone is distilled off in a vacuum. The residue is dissolved in benzene, and the benzene solution is extracted with 50 ml. of N hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia. The precipitated base is extracted with benzene. After drying by means of potassium carbonate, the solvent is distilled off. The remaining base is distilled in a vacuum. Boiling point: 210° C./0.05 mm. Yellowish, viscous oil. Yield: 19 g.
EXAMPLE 50
4-Diethylamino ethyl-3-phenyl-1-(p-chloro phenyl ethyl) piperazine ##STR52##
20 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as described hereinabove in Example 8 (b),
17 g. of p-chloro phenyl ethylchloride,
20 ml. of triethylamine, and
100 ml. of dimethylformamide
are heated on the water bath for 12 hours. The dimethylformamide is then distilled off in a vacuum. The residue is dissolved in acetone. The precipitated triethylamine hydrochloride is filtered off by suction and the acetone is distilled off from the filtrate. The resulting base is dissolved in benzene and extracted with 50 ml. of N hydrochloric acid. The hydrochloric acid extract is precipitated by the addition of ammonia. The precipitated base is extracted with benzene. The benzene solution is dried by means of potassium carbonate and the benzene is distilled off therefrom. The remaining base is distilled in a vacuum. Boiling point: 190° C./0.02 mm. Yield: 13 g.
EXAMPLE 51
4-Diethylamino ethyl-3-phenyl-1-(o-benzyloxy benzyl) piperazine ##STR53##
27 g. of 1-diethylamino ethyl-2-phenyl piperazine prepared as described hereinabove in Example 8 (b),
27 g. of 2-benzyloxy benzyl chloride,
25 ml. of triethylamine, and
250 ml. of acetone
are boiled under reflux for 4 hours. The precipitated triethylamine hydrochloride is filtered off by suction. The acetone is removed by distillation. The residue is dissolved in benzene and water. The benzene solution is separated from the aqueous phase and is extracted with 100 ml. of 0.5 N hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia and the precipitated base is extracted with benzene. After drying the benzene extract, the solvent is distilled off. Boiling point: 232° C./0.03 mm. Yellowish oil. Yield: 26 g.
EXAMPLE 52
4-Diethylamino ethyl-3-phenyl-1-(p-benzyloxy benzyl) piperazine ##STR54##
30 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as described hereinabove in Example 8 (b),
100 ml. of methyl ethyl ketone,
50 ml. of triethylamine, and
24 g. of p-benzyloxy benzylchloride
are boiled under reflux for 12 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The methyl ethyl ketone is distilled off from the filtrate. The residue is dissolved in benzene and water. The benzene solution is separated from the aqueous phase and is extracted with 250 ml. of 0.1 N hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia. The precipitated base is extracted with benzene. The benzene solution is dried and the solvent is distilled off. Boiling point of the remaining base: 245° C./0.005 mm. Yellow, very viscous oil. The base is dissolved in a small amount of ethanol and its hydrochloride is precipitated from the solution by the addition of absolute alcoholic hydrochloric acid. The hydrochloride is filtered off by suction and is dried. The hydrochloride is dissolved in water. The base is set free by the addition of ammonia, extracted with benzene, dried, and the solvent is distilled off. The residue is recrystallized from petroleum ether. Melting point: 58° C. Yield: 33 g.
EXAMPLE 53
4-Diethylamino ethyl-3-phenyl-1-(p-hydroxy benzyl) piperazine ##STR55## 25 g. of 1-diethylamino ethyl-3-phenyl-4-(p-benzyloxy benzyl) piperazine obtained as described hereinabove in Example 52 are dissolved in 500 ml. of toluene. 4 g. of palladium asbestos are added thereto and hydrogen is introduced into the solution at room temperature under a positive pressure of 50 mm. Hg. A white, crystalline compound starts to precipitate on the catalyst after 15 hours. Introduction of hydrogen is discontinued. The catalyst is filtered off by suction and is washed with 500 ml. of 60° C. toluene. The toluene is distilled off and the remaining residue is recrystallized first from n-heptane and subsequently from isopropanol. Melting point: 144° C. Yield: 11 g.
EXAMPLE 54
4-Diethylamino ethyl-3-phenyl-1-benzyl piperazine ##STR56##
15 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as described hereinabove in Example 8 (b),
8 g. of benzylchloride,
150 ml. of methyl ethyl ketone, and
20 ml. of triethylamine
are boiled under reflux for 8 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The acetone is distilled off and the residue is dissolved in benzene. The benzene solution is extracted with 100 ml. of N-hydrochloric acid. The hydrochloric acid extract is rendered alkaline by the addition of ammonia. The precipitated base is extracted with benzene. The benzene solution is dried and the solvent is distilled off therefrom. The residue is distilled in a vacuum. Boiling point: 160° C./0.01 mm. Yellowish oil. Yield: 10 g.
EXAMPLE 55
4-Diethylamino ethyl-3-phenyl-1-(3,4-dibenzyloxy benzyl) piperazine hydrochloride ##STR57##
23 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as described hereinabove in Example 8 (b),
30 g. of 3,4-dibenzyloxy benzylchloride,
20 ml. of triethylamine, and
200 ml. of methyl ethyl ketone
are boiled for 12 hours under reflux. The precipitated triethylamine hydrochloride is filtered off by suction. The solvent is distilled off. The residue is dissolved in benzene. The benzene solution is extracted with 100 ml. of N hydrochloric acid. The hydrochloric acid extract is precipitated by the addition of ammonia. The precipitated base is dissolved in benzene, the benzene solution is dried and the solvent is distilled off. Absolute alcoholic hydrochloric acid is added to the residue in an amount to yield a pH of 1.0 and a mixture of petroleum ether and acetone (1:1) is slowly added thereto. The hydrochloride precipitates and is filtered off by suction. It is dissolved in alcohol and is again precipitated by careful addition of a mixture of petroleum ether and acetone (1:1).
The compound obtained after filtering and drying starts to sublimate at 203° C. and has a melting point of 235°-239° C. with decomposition. Yield: 39 g.
EXAMPLE 56
4-Diethylamino ethyl-3-phenyl-1-(p-methoxy benzyl) piperazine ##STR58##
64 g. of 1-diethylamino ethyl-2-phenyl piperazine obtained as described hereinabove in Example 8 (b),
39 g. of p-methoxy benzylchloride,
75 g. of triethylamine, and
500 ml. of acetone
are boiled under reflux for 7 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off by suction. The filtrate is evaporated to dryness. The residue is dissolved in benzene and is extracted with 200 ml. of N hydrochloric acid. Ammonia is added to the hydrochloric acid extract and the precipitated base is extracted with benzene. The benzene solution is dried by means of potassium carbonate and the solvent is distilled off. The residue is distilled in a vacuum. Boiling point: 180°-182° C./0.005 mm. Yellowish oil. Yield: 24 g.
The new 1,4-substituted phenyl piperazine compounds to the present invention and their pharmaceutically acceptable acid addition salts can be administered orally, parenterally, or rectally. Compositions containing said compounds as used in therapy, comprise, for instance, tablets, pills, dragees, lozenges, and the like shaped preparations to be administered orally. Said compounds may also be administered in powder form, preferably enclosed in gelatin or the like capsules. Oral administration in liquid form, such as in the form of solutions, emulsions, suspensions, sirups, and the like is also possible. Such solid or liquid preparations are produced in a manner known to the art of compounding and processing pharmaceutical compositions whereby the conventional diluting, binding, and/or expanding agents, lubricants, and/or other excipients, such as lactose, cane sugar, dextrins, starch, talc, kaolin, magnesium hydroxide, magnesium carbonate, pectin, gelatin, agar, bentonite, stearic acid, magnesium stearate, and others may be employed.
The following examples serve to illustrate the preparation of pharmaceutical compositions as they are used in therapy without, however, limiting the same thereto.
EXAMPLE 57
Tablets:
20 g. of the dihydrochloride of 1-(4'-chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine, 128 g. of lactose, and 2 g. of magnesium stearate are intimately mixed with each other and are compressed without preceding granulation to tablets weighing 150 mg. Each tablet contains 20 mg. of the anticoagulant agent according to the present invention.
EXAMPLE 58
The mixture of ingredients as given in Example 57 is compressed to biconvex dragee cores of 150 mg. each. These cores are repeatedly sugar-coated by rotating in a coating pan with sugar sirup. Each dragee contains 20 mg.
EXAMPLE 59
Capsules:
500 g. of 1-(3',4'-dichloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine dihydrochloride are intimately mixed with 200 g. of starch and the mixture is sieved. Portions of 700 mg. each of said mixture are filled in gelatin capsules. Each capsule contains 500 mg. of the anticoagulant agent.
EXAMPLE 60
Suppositories:
400 g. of the molten suppository base Adeps solidus and 10 g. of the succinate of 1-(4'-chloro benzyl)-2-phenyl-4-piperidino ethyl piperazine are thoroughly triturated while maintaining in the molten state. The molten mixture is cast into suppository molds, each of which contains 2.05 g. of the mixture. The molds are then cooled to cause solidification. Each suppository contains 50 mg. of the anticoagulant agent.
EXAMPLE 61
25 mg. of 1-(4'-chloro benzyl)-2-phenyl-4-diethylamino ethyl piperazine dihydrochloride are dissolved in 2.2 cc. of bidistilled water. This solution is filled in ampoules which are sterilized in an autoclave at 120° C.
Ampoules containing 5 mg. to 250 mg. of base may be prepared as follows: The base is dissolved in water by the addition of a stoichiometrically equivalent amount of the desired acid. As an acid, there may be used e.g. hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, succinic acid, fumaric acid, lactic acid, and the like.
The effect which 1,4-disubstituted phenyl piperazine compounds according to the present invention have on blood coagulation, was determined according to standard test methods in vitro with human blood. The results of such tests are given in the following Table. The test mixture was prepared by adding one part of the aqueous solution of the compound to be tested to 9 parts of plasma. The compound to be tested was used in the form of its hydrochloride. Thus 0.1 millimole (mM) as given in the Table indicates 9 ml. of plasma plus 1 ml. of a millimolar (mM) aqueous solution of the compound to be tested.
The effect of the compounds according to the present invention was determined by measuring the recalcification time as well as the stypven time.
The determination of the recalcification time is based on the fact that free calcium + + ions are required to cause coagulation. Because the calcium ions are bound in the blood which has been rendered non-coagulable by the addition of citrate or oxalate, excess calcium chloride solution is added in this test and the period of time calculated from the additon of the calcium chloride to the onset of coagulation is measured. This period of time is the recalcification time.
For determining the stypven time, there is added, in addition to the calcium ions, the viper poison stypven to the citrate or oxalate blood. The stypven test is an especially sensitive test for detecting lipides set free from the thrombocytes.
In order to determine the effect of the compounds according to the present invention upon thrombocytes which are principal features with respect to coagulation of blood, the recalcification time and the stypven time were determined in blood rich in thrombocytes as well as in blood poor in thrombocytes.
It is assumed that the formation of blood clots is initiated by thrombocyte aggregation. Therefore, the compounds according to this invention were also tested for their thrombocyte aggregation, inhibiting effect by the method described by Klaus Breddin in "Schweizerische Medizinische Wochenschrift" vol. 20, p. 655 (1965).
The following Table shows those concentrations of the tested compounds, determined by means of their recalcification time and their stypven time, which indicate a pronounced blood coagulation promoting effect as well as a pronounced blood coagulation inhibiting effect. These concentrations are given in millimoles of the respective compound. The concentrations at which inhibition of the thrombocyte aggregation sets in, are also given for some of the compounds. That one and the same compound can have a blood coagulation promoting as well as a blood coagulation inhibiting effect, is due to the fact that it acts upon various coagulation factors at the same time. Thus a compound is able to set free from the thrombocytes coagulation activating material at a low concentration while at a higher concentration certain coagulation factors have an inhibiting effect.
o in said Table indicates that no effect has been found within the tested concentration range.
The recalcification time was determined according to the method of E. DEUTSCH ET AL. in "Thrombosis et Diathesis Haemorrhagica" vol. XXVI, page 145(1971) and the stypven time according to the method of McKENZIE ET AL. in "Amer. Journ. Clin. Path." vol. 55, pages 551-554.
It has also been found that a number of the compounds according to the present invention possess fibrinolytic activity, i.e. they are capable of dissolving thrombi which have been formed.
TABLE__________________________________________________________________________ Coagulation promoting Coagulation inhibiting Inhibition of effect effect thrombocytes Plasma rich Plasma poor Plasma rich Plasma poor aggregationExam- in in in in according tople Molecular thrombocytes thrombocytes BreddinNo. Compound weight mM mM mM mM mM__________________________________________________________________________ 1-(4-Chloro benzyl)-2- phenyl-4-diethylamino- ethyl-3-keto-piperazine 399.9 1 1 55 5 0.11 4-Diethylaminoethyl-2- phenyl-1-(4-chloro benzyl) piperazine 386.0 1 1 5 5 12 1-(3,4-Dichloro benzyl)-2- phenyl-4-diethylaminoethyl- piperazine 420.4 0.1 - 1 1 2.5 2.5 0.13 1-(p-Methoxyphenyl-ethyl)- 2-phenyl-4-Methylamino ethyl piperazine 395.5 1 1 10 5 0.1-0.54 1-(3-Phenylpropyl)-2- phenyl-4-diethylamino- ethyl piperazine 379.5 0.1 - 1 1 5 2.5 0.1-0.55 1-(4-Chloro benzyl)-2- phenyl-4-(2-piperidino ethyl) piperazine 397.9 1 1 5 2.5-5 0.15 1-(p-chloro benzyl)-2- phenyl-4-[(4-methyl)-pip- erazine ethyl-(1)]piper- azine 413.01 0.1 0.1 2.5 2.5 0.15 1-(p-Chloro benzyl)-2-phenyl- 4-pyrrolidino ethyl pipera- zine 383.97 0.1 1 5 2.5 0.56 1-(4-Chloro benzyl)-2-phenyl- 4-(1,3-bis-(morpholino propyl) piperazine 499.08 1 1 5 2.5 0.1-17 1-(p-Chloro benzyl)-3-phenyl- 4-diethylamino ethyl piper- azine 386.1 0.1 1 5 2.5 0.01-0.18 4-Diethylaminoethyl-3-phenyl- 1-(p-ethoxy benzyl)piperazine 395.6 0.1-1 1 5 1-2.5 0.01-0.1 4-Diethylaminoethyl-3-phenyl- 2-keto-1-(p-chloro benzyl) piperazine 399.95 1 1 5 2.5-5 0.114 4-Dimethylaminoethyl-2-phenyl- 1-(3,4-dichloro benzyl)-pip- erazine 392,38 0.1 1 2.5 2.5 0.1-0.515 4-β-Morpholinoethyl-2-phenyl- (3,4-dichloro benzyl)pipera- zine 434.42 1 1 -- -- 0.116 4-Diethylaminopropyl-2-phen- yl-1-(3,4-dichloro benzyl) piperazine 434,462 0.1 1 2.5 2.5 0.0117 1-(4-Benzyloxy benzyl)-2- phenyl-4-diethylaminoethyl piperazine 457,66 0.1 0.1 2.5 2.518 4-Diethylaminoethyl-2-phen- yl-1-(3,4,5-trimethoxy ben- zyl) piperazine 4.41.596. 1 -- -- 5 0.119 1-[(p-Methoxy phenyl propyl)]- 2-phenyl-4-diethylaminoethyl piperazine 409,626 0.1 1 5 5 0.1-0.520 4-Diethylaminoethyl-3-phenyl- 1-(p-ethoxy benzyl)pipera- zine 395,6 0.1-1 1 5 1 - 2.5 0.1-0.522 1-(p-Chloro benzyl-2-phen- yl-4-[(4-methyl)piperazino ethyl-(1)]piperazine 413.01 0.1 0.1 5 2.523 1-(p-Chlorobenzyl)-2-phenyl- 4-[3-keto)-piperazinoethyl)- (1)] piperazine 466.99 0.1 0.5 o o5a 1-(p-Chloro benzyl)-2- phenyl-4-pyrrolidino ethyl piperazine 383,97 1 o 5 2.534 4-Diethylaminoethyl-3- phenyl-1-(o-hydroxy benzyl) piperazine 367.5 1 1 5 5 --36 4-Diethylaminoethyl-3-phen- yl-1-(3,4,5-trimethoxybenz- yl) piperazine 441.5 1 o o 2.5 --37 1-(p-Hydroxy benzyl)-2- phenyl-4-diethylaminoethyl piperazine 367.5 1 1 o o -- 1-(p-Ethoxy benzyl)-2-phen- yl-4-pyrrolidinoethyl-3- keto piperazine 407,53 1 1 o 547 1-(p-Chloro benzyl)-2-phen- yl-4-piperazino ethyl piperazine 399.0 0.1 0.1 2.5 548 1-(p-Methoxy benzyl)-2- phenyl-4-piperidinoethyl piperazine 393.55 1 o 5 2.549 4-Diethylaminoethyl-3-phen- yl-1-(3,4,5-trimethoxy)- benzyl piperazine 441,5 1 o o 2.550 4-Diethylaminoethyl-3- phenyl-1-(p-chloro phen- yl)ethyl piperazine 400.00 0.1 o 5 2.5 0.0551 4-Diethylamino ethyl-3- phenyl-1-(o-benzyloxy benzyl) piperazine 457.66 0.1 o 5 0.152 4-Diethylaminoethyl-3- phenyl-1-(p-benzyloxy benzyl) piperazine 457.66 0.1 1 2.5 2.5 153 4-Diethylaminoethyl-3- phenyl-1-(p-hydroxy benzyl)piperazine 367.5 0.1 o 10 5 --54 4-Diethylamino ethyl-3- phenyl-1-benzyl piper- azine 351.54 0.1 0.1 0 o55 4-Diethylaminoethyl-3- phenyl-1-(3,4-dibenzyl- oxy benzyl)piperazine . HC1 563.79 1 0.1 2.5 o 4-Diethylaminoethyl-3- phenyl-2-keto-1-(p-ben- zyloxy benzyl) pipera- zine 471.65 1 1 10 2.540 1-(p-Chloro benzyl)-2- phenyl-4-dimethylamino propyl piperazine 371,94 0.01 0.1 2.5 2.541 1-(3,4-Dibenzyloxy benzyl)- 2-phenyl-diethylaminoethyl piperazine fumarate 563.79 1 1 2.5 2.542 1-(o-Benzyloxy benzyl)-2- phenyl-4-diethylaminoethyl piperazine 457.66 0.1 1 5 2.543 1-(p-Methoxybenzyl)-2- phenyl-4-diethylamino propyl piperazine 395,57 0.1 o 5 5__________________________________________________________________________
The starting materials are either commercially available or can be synthesized from commercially available compounds by known methods.
For instance, α-chloro phenyl acetic acid ethyl ester used as the one reactant in Example 1 B (a), is prepared from commercially available α-chloro phenyl acetic acid chloride by esterifying with ethanol. Its boiling point is 123°-125° C./8-10 mm.
N 1 -(diethylamino ethyl) ethylene diamine, the other reactant of Example 1 B (a) is obtained according to the method of H. F. McKay "Canad. J. Chem." vol. 34, pp. 1567-1573 (1956).
1-(β-Chloro ethyl)-4-methyl piperazine used as reactant in Example 6, is prepared by reacting 1(β-hydroxy ethyl)-4-methyl piperazine and thionylchloride.
1,3-Dimorpholino propylchloride (Example 7) is obtained by reacting 1,3-dimorpholino propanol with thionylchloride.
p-Ethoxy benzylchloride (Example 9 c) is produced according to Bergmann and Sulzbacher "J. org. Chem." vol. 16, p. 85 (1951).
3,4,5-Trimethoxy benzylchloride (Example 13) is prepared by reacting 3,4,5-trimethoxy benzyl alcohol with thionylchloride and
3-(4'-Methoxy phenyl) propylchloride (1) by reacting 3-(4'-methoxy phenyl) propanol (1) with thionylchloride.
Acetyl glycolic acid chloride (Example 27 A c) is obtained according to Ghosh "J. Indian Chem. Soc." vol. 24, p. 325 (1947) from acetyl glycolic acid synthesized according to Anschuetz et al. "Ber." vol. 30, p. 467.
1-(3,4-Dibenzyloxy benzyl)-2-phenyl-3-keto piperazine (Example 42 ) is obtained by reacting 2-phenyl-3-keto piperazine with 3,4-dibenzyloxy benzylchloride. Its melting point is 108°-110° C.
3,4-Dibenzyloxy benzylchloride (Example 43) is synthesized by first producing 3,4-dibenzyloxy benzaldehyde according to the method described by Bergmann et al. "J. org. Chem." vol. 16, p. 85 (1951), reducing said aldehyde with sodium boron hydride to the corresponding alcohol, and chlorinating the resulting alcohol with thionylchloride in chloroform. Melting point of the chloride: 42°-44° C.
o-Benzyloxy benzylchloride (Example 55) is obtained in an analogous manner. Boiling point: 118° C./0.05 mm.
Diethylamino propylchloride (Example 56) is prepared by reacting diethylamino propanol with thionylchloride.
p-Chloro phenyl ethylchloride (Example 63) is synthesized according to Depuy et al. "J. Am. Chem. Soc."vol. 79, pp. 3710-11 soc." (1957) and Baddeley et al. "J. Am. Chem. Soc." 1935, p. 1820.
p-Methoxy benzylchloride (Example 69) is prepared as described in "Org. Synth." vol. 36, p. 50.
The following example describes the preparation of a compound in which R 4 and R 5 of Formulas VII to XII form an N 4 -hydroxy lower alkyl piperazine group.
EXAMPLE 62
1-(p-Chloro benzyl)-2-phenyl-4-[β-(4'-hydroxy ethyl piperazino) ethyl ] piperazine ##STR59##
The compound is obtained by reacting 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride as described hereinabove in Example 21 B and C, with N 1 -(2-hydroxy ethyl) piperazine. The resulting reaction product is a yellow oil of the boiling point: 245° C./0.02 mm.
Analogous compounds in which the phenyl ring of the benzyl or phenyl lower alkyl substituent in 1-position is substituted by other substituents than chloro, as well as compounds of the 3-phenyl piperazine type or the 2- or 3-phenyl-3- or -2-keto piperazine type and which have in 4-position a hydroxy lower alkyl piperazino lower alkyl group can, of course, also be produced in a similar manner.
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Novel 1,4-substituted phenyl piperazine compounds have a pronounced effect upon blood coagulation and are useful in the treatment of thrombotic diseases, especially of the arterial system. They are particularly used to inhibit thrombosis of the coronary or cerebral arteries. Examples of such compounds are 1-phenyl (lower) alkyl-2-phenyl-4-di-(lower)alkylamino (lower)alkyl piperazines, 1-phenyl (lower)alkyl-3-phenyl-4-di-(lower)alkylamino (lower)alkyl piperazines and their pharmaceutically acceptable acid addition salts. The phenyl ring in 1-position may be substituted by halogen, trifluoro (lower)alkyl, lower alkoxy, or phenyl lower alkoxy; the di-(lower)alkylamino (lower)alkyl group in 4-position may be replaced by piperidino (lower)akyl, morpholino (lower)alkyl, pyrrolidino (lower)alkyl, piperazino (lower)alkyl, or the like mononuclear nitrogen-containing heterocyclically substituted (lower)alkyl.
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FIELD OF THE INVENTION
[0001] The present invention relates to an apparatus for processing food such as chopping, blending and/or mixing food, and in particular an electric food processing apparatus such as a food processor, a food chopper or a food blender.
BACKGROUND OF THE INVENTION
[0002] There are a variety of conventional food-processing apparatus in the market. One type of food processing apparatus is commonly called “food processor” in which food to be treated may be chopped and mixed in a container provided with the processor. While this type of food processor is effective to a certain extent to chop food, one common problem is that it often does not blend and mix the food efficiently and evenly enough. For instance, when a conventional food processor is used for chopping carrot, the processed carrot will often be uneven and contain larger carrot fragments mixed with smaller carrot fragments. The problem is particularly more noticeable and prominent when different foodstuffs are being treated at the same time, apparently due to different characteristics of the foodstuffs to be treated.
[0003] The present invention seeks to address at least this problem, or to provide an alternative to the public.
SUMMARY OF THE INVENTION
[0004] According to a first aspect of the present invention, there is provided with a food processing apparatus comprising a container defining a cavity and adapted to contain food to be treated, a first blade member rotatable to mix and/or cut food in the container, and a second blade member rotatable to remove food adhered on a sidewall in the container. The provision of the rotatable second blade member may direct foodstuff adhered on the sidewall to the first blade member in order that the foodstuff may be mixed and/or cut more efficiently and evenly.
[0005] Preferably, the container may have a transverse cross section in circular shape. One advantage of providing the container with such a shape is that the second blade member can remove the foodstuff adhered on the sidewall adhered on the sidewall in a relatively simple and rotating manner.
[0006] Suitably, the first blade member and the second blade member may be fixedly connected together. With this arrangement, the blade members are provided in one component. Alternatively, the blade members may be releasably connected together. With this alternative arrangement, the blade members may be separated when not in use for, for example, easier cleaning.
[0007] Advantageously, the second blade member may be relatively thin and/or elongate in shape. A blade member having such characteristics necessarily has a relatively smaller surface area which discourages foodstuff to adhere thereon. Further, a thinner blade may operate more effectively when removing foodstuff adhered on the sidewall than for example a thicker blade. The second blade member may also be relatively narrow such that interference of the mixing or cutting of the food in the container may be minimized.
[0008] Preferably, the second blade member may be arranged vertically adjacent the sidewall and adapted to direct foodstuff adhered thereon to the first blade member, such that the food may be blended more efficiently and mixed more evenly. In one embodiment, the second blade member may abut the sidewall while rotating in the container.
[0009] Suitably, there may be provided with two (or at least two) of the second blade members arranged on opposite sides in the container. The provision of two of the second blade members may be more efficient in assisting the first blade member in mixing or chopping the food than providing just one second blade member. Further, with the two second members, the rotation thereof in the container may be more balanced.
[0010] Advantageously, the second blade member may be manually operable. With this arrangement, the second blade member is being operated only when a user would like to remove foodstuff adhered on the sidewall in the container. For example, the second blade member may be operable by a rotatable handle or knob. Alternatively, the second blade member may be electrically operated. With this alternative arrangement, the operation of the second blade manner may be put to work on press of a button.
[0011] Preferably, the apparatus may be provided with a base member arranged at the bottom in the container and connected to the lower end of the second blade member. In particular, the base member may be sufficiently thick and/or, for safety reason, adapted to prevent access to the cutting edge of the first blade member from below or from opposite sides thereof.
[0012] Suitably, both the first blade member and the second blade member may be rotatable simultaneously. With this arrangement, in use food to be treated may always be directing to the first blade member. Alternatively, both the first blade member and the second blade member may be rotatable independently. In one embodiment, the first blade member may rotate in a clockwise direction and the second blade member may rotate in a counter-clockwise direction.
[0013] The above-described apparatus may be a food processor, a food chopper or a food blender.
BRIEF DESCRIPTION OF DRAWINGS
[0014] Some embodiments of the present invention will now be described by way of example and with reference to the accompanying drawings, in which:—
[0015] FIG. 1 shows a perspective view of a first embodiment of a container of a food processor in accordance with the present invention,
[0016] FIG. 2 shows a cross section view of the container of FIG. 1 taken along line A-A′ in FIG. 1 ,
[0017] FIG. 3 shows another cross section view of the container of FIG. 1 taken at line B-B′ in FIG. 1 ,
[0018] FIG. 4 shows a perspective view of the container of FIG. 1 but in a different configuration,
[0019] FIG. 5 shows a side view of the container of FIG. 4 ,
[0020] FIG. 6 shows a cross section view of the container of FIG. 4 taken at line C-C′,
[0021] FIG. 7 shows a top view of the container of FIG. 4 ,
[0022] FIG. 8 shows an exploded view of the container of FIG. 1 ,
[0023] FIG. 9 shows a perspective view of a second embodiment of a container of a food processor in accordance with the present invention,
[0024] FIG. 10 shows another perspective view of the container of FIG. 9 ,
[0025] FIG. 11 shows a side view of the container of FIG. 9 ,
[0026] FIGS. 12 a to 12 d show top views of the container of FIG. 9 and cross sectional lines D-D′, E-E′, F-F′, G-G′ and H-H′,
[0027] FIGS. 13 to 17 show different cross section views of the container of FIG. 9 taken at lines D-D′, E-E′, F-F′, G-G′ and H-H′, respectively, and
[0028] FIG. 18 shows an exploded view of the container of FIG. 9 .
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0029] Referring firstly to FIGS. 1 to 8 there is shown a first embodiment of a container 2 of a food processor in accordance with the present invention. The food processor is provided with a main body 4 and a lid 6 releasably fitted thereon.
[0030] As shown in FIGS. 1 to 3 and 8 , the body 4 and the lid 6 together define a cavity 8 for containing food to be processed. The body 4 of the container 2 has an upper opening 10 through which food may be deposited in the cavity 8 . The body 4 has a transparent housing such that a user can observe the status of the food being processed. The container 2 is also provided with a pair of handles 12 , 14 adjacent to the opening 10 and on opposite sides of the body 4 .
[0031] As shown in FIGS. 2, 3 and 8 , the body 4 is provided with a tubular member 16 in the center and upwardly extending from the bottom to approximately mid-way in the container 2 . The container 2 is also provided with a first blade means 18 having an enlarged circular head portion 20 arranged near the opening 10 . A cylindrical elongate member 22 is downwardly extending from the center region of the head portion 20 , and an elongate skirt 24 depends from an outer region of the head portion 20 and surrounds the elongate member 22 . The skirt 24 is substantially longer than the elongate member 22 and is comparable in height with the body 4 of the container 2 . A circumferential gap 26 is defined between the skirt 24 and the elongate member 22 , and a cavity in the form of a recess 28 is provided at the lower end of the first blade means 18 . The lower end of the skirt 24 is provided with a pair of steel blade members 30 , 32 with sharp cutting edges laterally extending from opposite sides thereof. The skirt 24 and the elongate member 22 are sized and shaped such that the upwardly extending tubular member 16 is releasably received in the gap 26 therebetween via a lower opening 34 of the skirt. The main body 4 of the food processor (not shown) is provided with a coupler upwardly extending from a conventional stand thereof and the lower end of the tubular member 16 is provided with an opening 36 sized and shaped to receive the coupler when the container 2 sits on the stand at the coupler. As the container 2 sits on the stand of the food processor with the first blade means 18 assembled in the container 2 , the coupler via the tubular member 16 engages the elongate member 22 of the first blade means 18 which is drivenable to rotate in use.
[0032] As shown in FIGS. 1, 2 , 3 and 8 , the lid 6 of the container 2 is provided with a rotatable handle 38 having a spindle portion 40 extending vertically therethrough, a horizontally disposed arm portion 42 and a rotatable knob portion 44 . The lower end of the spindle portion 40 is provided with a cam means 46 engageable with and for rotating a second blade means 48 . The second blade means 48 has a cap member 50 on which a number of gear members 52 are provided. The cam means 46 is engageable with and is provided to drive the gear members 52 . Two ribs 54 , 56 are laterally extending from opposite sides of the cap member 50 , and two thin and elongate blade members 58 , 60 depend from opposite sides of the ribs 54 , 56 . A circular base member 62 having an outer ring 64 and an inner ring 66 is arranged at the bottom of the container 2 . The outer and inner rings 64 , 66 are connected together with a number of radially extending ribs 68 , 70 , 72 , 74 . The outer ring 64 of the base member 62 is connected to the lower end of the elongate members 58 , 60 . The elongate members 58 , 60 have a thinner side 76 and a thicker side 78 . When the removable second blade means 48 is assembled and installed in the container 2 , the elongate members 58 , 60 are arranged adjacent to the sidewall of the container 2 , with the thinner side 76 arranged very close to or abut the sidewall.
[0033] In use, when the various parts as shown in FIG. 8 are assembled together and become the container 2 as shown in FIGS. 1, 2 and 3 , the container 2 is ready to receive food for processing. It is envisaged that during operation the first blade means 18 is driven by the coupler and is caused to rotate in high speed. However, as food contained in the container 2 is being chopped into smaller pieces by the rotating blade members 30 , 32 , some foodstuff may be viscous or sticky and may be swung to adhere on the sidewall in the container. This is undesirable because this foodstuff may not yet be chopped by the blade members 30 , 32 , and in any case it may not have been evenly mixed with the rest of the food in the container 2 . In such circumstances, a user observing this can then rotate the rotatable handle 38 . This will cause the second blade means 48 to rotate and scrap off the foodstuff from the sidewall and direct it to the center in the container 2 for processing by the rotating blade members 30 , 32 .
[0034] After using the food processor, the first blade means 18 and the second blade means 48 are removable from the container 2 for cleaning. In this embodiment, both the first blade means 18 and the second blade means 48 are separate components and detachable from the container 2 . It is to be noted that the rotatable knob 44 of the handle 38 is movable between an upstanding configuration (see FIGS. 1 to 3 ) in which a user can rotate the second blade means 48 by holding onto the knob and move it in a circular path such that the thinner side of the elongate members 58 , 60 can scrap off the foodstuff as it rotates and a stowed configuration (see FIGS. 4 to 7 ) in which the knob is turned downward. The provision of such a handle 38 can reduce the height of the container 2 for ease of storage.
[0035] FIGS. 9 to 19 illustrate a second embodiment of a container 102 of a food processor in accordance with the present invention. Similar to the container 2 in the first embodiment, it likewise comprises a main body 104 with an upper opening 110 closable by a lid 106 , a pair of handles 112 , 114 adjacent to the opening 110 and arranged at opposite sides thereof, a first blade means 118 for chopping food therein and a second blade means 148 for scraping off foodstuff adhered on sidewall in the container 102 . One main difference from the container 2 of the first embodiment is that in the container 102 the second blade means 148 is operable by a different mechanism. FIG. 13 illustrates a cross section view of the container 102 taken at an off-center position and at line D-D′ in FIG. 12 a . As shown in FIG. 13 , the mechanism includes a relatively large turnable knob 144 to fit the grip of the palm of a user. This knob 144 basically replaces the rotatable knob portion 44 and the arm portion 42 . FIGS. 14 and 16 illustrate cross section views of the container 102 but taken at the center thereof (see FIGS. 12 a and 12 c ) (at lines E-E′ and G-G′). In FIG. 16 , it is shown that a pair of legs 178 with a hook 180 at the lower end thereof is downwardly extended from the underside of the knob 144 . This pair of legs 178 serves to retain the knob 144 in position. A spindle 140 similar to the spindle 40 is vertically arranged and runs through the center of the lid 106 . The upper end of the spindle 140 has a cross section which is non-circular in cross section, and it engages with a corresponding recess on the underside of the knob 144 such that as the knob 144 is turned the spindle 140 is also caused to turned accordingly. The lower end of the spindle 140 is provided with a cam means 146 engageable with and for rotating the second blade means 148 . A compression spring 182 is arranged between the knob 144 and the lid 106 and biases the knob 144 to an upper, or locked, position. When the knob 144 is disposed in the upper position (as in FIGS. 11 and 16 ), the knob 140 and also the second blade means 148 are locked in position and not movable. When the knob 144 is disposed to a lower position and is turned to rotate, the spindle 140 and thus the second blade means 148 are also caused to rotate, thus scrapping off any foodstuff adhered on the sidewall in the container 102 in a similar fashion as with the first embodiment. With the provision of the spring 182 , the knob 144 is biased to the upper locked position when not in use.
[0036] It should be understood that the above only illustrates examples whereby the present invention may be carried out, and that various modifications and/or verifications may be made thereto without departing from the sprit of the invention. For instance, the circular base 64 , 164 member may be provided with an upstanding circumferential flange in order to further discourage accidental access to the blade members 30 , 32 , 130 , 132 . The second blade means 48 , 148 may be modified to operate automatically to rotate periodically or simultaneously with the first blade means 18 , 118 . The container 2 , 102 may adopt an inverted-conical shape.
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A food mixing apparatus comprising a container defining a cavity and adapted to contain food to be treated, a first blade member rotatable to mix and/or cut food in said container, and a second blade member rotatable to remove food adhered on a sidewall of the container in the cavity in the container.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to the use of an Aspergillus oryzae protease preparation as an anti-inflammatory agent useful in the treatment of various diseases and conditions.
[0003] 2. Background of the Invention
[0004] Proteolytic enzymes have been used extensively as therapeutic agents for decades. The earliest studies used pancreatic enzymes in the treatment of cancer. Later, proteolytic enzymes from non-animal sources such as the plant enzymes bromelain and papain and proteases derived from fungi such as Aspergillus sp. were investigated.
[0005] Proteases from Aspergillus oryzae are commercially used in the production of sake and soy sauce as well as in flavoring of other food products. Clinically, these enzymes have been shown to have an anti-thrombolytic/anti-hypertensive effect (Frish, E., “Clinical Review on Brinase, a Protease from Aspergillus oryzae,” Folia Haematol., 101(1):63-82 (1974), Mizuno, S., et al., “Release of Short and Proline-Rich Hypertensive Peptides from Casein Hydrolysate with an Aspergillus oryzae Protease,” J. Dairy Sci., 87:3183-3188 (2004), Sano, J., et al., “Effect of Caesin Hydrolysate Prepared with Protease Derived from Aspergillus oryzae , on Subjects with High-Normal Blood Pressure or Mild Hypertension,” J. Medicinal Food, 8(4):423-430 (2005)), anti-cancer effect (Smyth, H., et. al., “The Effects of Protease I of Aspergillus oryzae (Brinase) on Membrane Permeability and Growth of Landshutz Ascites Tumour Cells,” Int. J. Cancer, 7:476-482 (1971), U.S. Pat. No. 5,562,900), and an anti-viral effect (Knight, C., “Immunogenic Properties of PR9 Influenza Virus After Treatment with Acid Protease,” Intervirology, 14:37-43(1980), Roth, R., et al., “Proteolytic Action of Aspergillus niger Extract on Influenza Virus,” Intervirology, 14:167-172 (1980), Singh, S., et al. “Isolation, Structure, and HIV-1 Integrase Inhibitory Activity of Structurally Diverse Fungal Metabolites,” J. Ind. Microbiol. Biotechnol., 30:721-731 (2003)). In addition, proteases from Aspergillus oryzae have been shown to be potent anti-inflammatory mediators (Kolodny, A., “Double Blind Evaluation of Asperkinase, a New Proteolytic Enzyme,” Am. J. Orthopedics, 234-235 (1963), U.S. Pat. No. 6,413,512 B1, U.S. Pat. No. 3,932,618, EP 1390 542).
[0006] In many diseases and injuries there is a marked increase in circulating proinflammatory cytokine levels. This increase in cytokine expression is hypothesized to contribute to the pathology of these conditions. Infection, cancer and tissue injury can all trigger the production of cytokines, which can then enter the blood stream to alter the physiology of distant tissues, or act locally as paracrine mediators. In some diseases and injury states cytokines are beneficial to the host, but in others, cytokines are detrimental to the host. Proteases and cytokines are intimately interrelated in that cytokines are involved in regulating the production of proteases and proteases are frequently involved in the liberation of soluble cytokines, as well as in their destruction. Diseases in which cytokines play a pathological role include multiple sclerosis, type I diabetes, rheumatoid arthritis, soft tissue injury, and solid tumor malignancies. It would be beneficial therefore in these disease states to decrease the levels of circulating cytokines. This has been accomplished by treating patients with antibodies to specific cytokines, i.e. TNFα, soluble receptor antagonists, and also proteases from plant and microbial sources.
[0007] Cytokines play a major role in the manifestation of inflammation, which is a predominant biological reaction to a myriad of injurious agents and events. It is well-known that host defensive and reparative processes in inflammation can be harmful to the body's welfare. Common characteristics of inflammation are fever, swelling, bruising and pain. The body's defensive mechanisms can bring about the release of products toxic to the host or lead to destruction of its host tissues.
[0008] Detrimental consequences of inflammation include fibrin deposition, and reduction in vascularity causing changes in tissue permeability creating additional morphologic barriers to the penetration of antibodies or pharmacological agents into the injured area. Some of the autolysis products released by tissue necrosis often constitute a good medium for microorganisms and can even antagonize the antimicrobial activity of many pharmaceutical agents, thereby exacerbating the injury or infection and prolonging the recovery process.
[0009] Cytokines released in the immune response to tumor antigens, such as IL-1β and IL-6 can upregulate angiogenic factors such as vascular endothelial growth factor (VEGF) which leads to new blood vessel formation providing nutrition to the growing malignancy, thereby helping the tumor to grow.
[0010] In addition, cytokines are pathogenic mediators in many autoimmune conditions such as rheumatoid arthritis (RA), multiple sclerosis (MS) and Crohn's disease. Current treatments in RA focus on inhibiting tumor necrosis factor alpha (TNF-α) production and signaling. In animal models of MS, inhibition of interferon-γ has shown promise.
[0011] The absorption of orally-administered proteases in mammals has been extensively studied. The prevailing finding of these studies is that proteases can be partially absorbed intact, with activity preserved, from the digestive tract and subsequently distributed systemically in the blood. Proteolytic enzymes from Aspergillus oryzae are often used as digestive aids, and as such stimulate bowel movements, often times leading to diarrhea in the host.
[0012] Early in the study of proteases, it was observed that the administration of animal-derived proteases could accelerate the healing of inflamed sites. Therefore, a large database exists of clinical results from orally-administered, animal derived proteases establishing the effectiveness of these proteases as therapeutic agents for inflammatory conditions. However, a clear mechanism of physiological action for animal-derived proteases is yet to be determined. Plant proteases have also been found to have a positive effect on inflammation The largest body of evidence supporting the use of proteases for inflammatory conditions studied the effects of a mixture of papain, bromelain, trypsin, chymotrypsin, pancreatin and rutin. In most cases, the mixture was in addition to standard medical care.
[0013] It has long been established that a number of chemical compounds typically referred to as vitamins and minerals provide significant health value and treat specific medical conditions, particularly when supplied in therapeutic doses. Over the years, a number of such vitamins and minerals have been identified. For example, vitamins include A, C, D, E, and the family of B vitamins and minerals include iron, zinc, calcium and chromium. The human body does not synthesize most of these vitamins and minerals which are essential to maintaining the health of the human body. Thus these necessary vitamins and minerals must be obtained from an external source. The two most common external sources are foods and nutritional supplements. Food is typically the primary source of obtaining the necessary nutrients for maintaining health, however many people do not eat foods that consistently provide the necessary daily requirements of vitamins and minerals. Thus, vitamin and mineral nutritional supplementation has become a recognized method of meeting these daily requirements.
[0014] While certain vitamins and minerals have been shown to be essential for the maintenance an individual's health, the use of vitamin and mineral nutritional supplementation has afforded the possibility to include micro-nutrients which, although not absolutely essential to maintaining health, provide significant benefit toward maintaining health.
[0015] U.S. Pat. No. 6,413,512 B1 describes treating patients suffering from a disease resulting from increased cytokine production with a pharmaceutical composition comprising 2 or more proteases from a microbial source in an amount of between 20,000 HUT and 550,000 HUT. The protease described this patent is made using rice and/or wheat bran as the carbohydrate source.
[0016] In light of the above, the present invention is based on the surprising result that proteases from Aspergillus oryzae made using potato dextrin as the carbohydrate source are better absorbed by the proximal small intestine than proteases using rice or when bran as the carbohydrate source and thus are exceptionally potent anti-inflammatory mediators. Proteases made using potato dextrin as the carbohydrate source, in contrast to those made from rice and or wheat bran, reduce gastrointestinal side effects such as diarrhea. In addition, administering more than 2,000,000 HUT/day of Aspergillus oryzae protease made from potato dextrin, along with a specific multi-vitamin formulation, provides an optimal and therapeutic anti-inflammatory effect.
BRIEF SUMMARY OF THE INVENTION
[0017] The present invention provides a method of treating mammalian diseases and conditions by administering a protease preparation derived from Aspergillus oryzae made using potato dextrin as the carbohydrate source in an amount of more than about 2,000,000 HUT per day. The protease preparation is preferably given on an empty stomach four times daily. The mammalian disease treated by the method of the instant invention is preferably selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohn's disease, viral infection, soft tissue injury, bacterial infection, solid tumor malignancy, osteoporosis, osteopenia, chronic obstructive pulmonary disease, and Alzheimer's disease.
[0018] Another embodiment of the invention provides a method of treating mammalian disease by adminstering a protease preparation derived from Aspergillus oryzae made using potato dextrin as the carbohydrate source at an amount of more than about 2,000,000 HUT per day, together with a nutritional supplement of vitamins and minerals. The nutritional supplement preferably contains vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, magnesium citrate, vitamin E, Vitamin D3, zinc citrate, manganese gluconate, copper gluconate, biotin, folate, chromium polynicotinate, citrus bioflavinoids, glucosamine sulfate, and boron sulfate. In the preferred embodiment, the dietary supplement is given 2-3 times per day with food while the protease preparation is given 4 times daily on an empty stomach.
[0019] In another embodiment an additional supplement of calcium is given. In the preferred embodiment calcium is given at a dose of 900 mg/day. It is preferred that the additional calcium supplement is given once daily in the evening.
DETAILED DESCRIPTION OF THE INVENTION
[0020] It is to be understood that this invention is not limited to the particular methods, compositions and materials disclosed herein as such methods, compositions and materials may vary. It is also understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.
[0021] It must also be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a protease” includes references to two or more of such proteases and “a vitamin” includes reference to one or more of such vitamins, unless otherwise specified.
[0022] In general the present invention is directed to a method of alleviating the manifestations of mammalian inflammatory disease or injury. The method of the present invention may be used to treat any type of inflammatory disease wherein pro-inflammatory cytokines are produced and exacerbate disease. Diseases that may be treated by the current invention include without limitation, rheumatoid arthritis, multiple sclerosis, Crohn's disease, viral infection, soft tissue injury, bacterial infection, solid tumor malignancy, osteoporosis, osteopenia, chronic obstructive pulmonary disease, and Alzheimer's disease.
[0023] The present invention offers improvements over prior proteolytic products in that, unlike other protease compositions, the primary benefit is obtained from the use of a protease from a particular microbial source in a defined dosing regimen. The invention does not contain animal-derived products, and thus is acceptable to patients who may object to the ingestion of animal products. The invention focuses specifically on protease preparations prepared using potato dextrin as the carbohydrate source instead of maltodextrin, wheat or rice bran. Surprisingly, protease preparations prepared using potato dextrin are more readily absorbed by the proximal small intestine and lead to less undesirable gastrointestinal side effects than those prepared with maltodextrin, wheat or rice bran. In addition, the invention does not contain gluten and may be safely ingested by persons who have an allergy to wheat gluten.
[0024] The preferred dietary supplement of the current invention comprises vitamin A, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin C, magnesium citrate, vitamin E, vitamin D3, zinc citrate, manganese gluconate, copper gluconate, biotin, folate, chromium polynicotinate, citrus bioflavinoids, glucosamine sulfate, and boron sulfate.
[0025] The preferred dietary supplement comprises vitamin A. Vitamin A functions as a regulatory hormone with effects on specific genes for differentiation and maintenance of epithelial tissue, and is important to reproduction, vision and immune function. Taken in excess vitamin A will cause birth defects, and in the active or athletically performing individual, can cause bone demineralization, loss of elasticity in connective tissue, muscle soreness and joint pain. The recommended daily allowance (RDA) for vitamin A is 5000 IU/day. In the preferred embodiment of the invention the dietary supplement contains 5000 IU/day of vitamin A in the form of retinyl palmitate.
[0026] The preferred dietary supplement comprises vitamin B1. Vitamin B1 is distributed widely in foods in low concentrations. Vitamin B1 is susceptible to destruction by refining processes, neutral and alkaline conditions, heat and oxidation. Vitamin B1 is important in energy production from food, especially carbohydrates, and plays a vital role in nerve function. Supplementation in large doses is safe and has shown some efficacy in the ability to control pain in connective tissue. The RDA for vitamin B1 is 1.5 mg/day. In the preferred embodiment the dietary supplement contains 100 mg/day in the form of thiamin mononitrate.
[0027] The preferred dietary supplement comprises vitamin B2. Vitamin B2 is essential to a large number of redox reactions, releasing energy from carbohydrates, fats and amino acids, and is thus important to the elderly, and the active or athletic individual. Vitamin B2 is highly water soluble and reactive to light. Strict vegetarians, pregnant and lactating women, and ill or trauma victims are also at risk for vitamin B2 deficiency. High oral doses of vitamin B2 are essentially non-toxic. The RDA for vitamin B2 is 1-1.5 mg/day. In the preferred embodiment the dietary supplement contains 50 mg/day vitamin B2.
[0028] The preferred dietary supplement comprises vitamin B3 (niacinamide, not niacin). Vitamin B3 plays an important role in energy production, cellular respiration, fat synthesis and joint pain and mobility. Vitamin B3 (niacinamide, not niacin) possesses no known side effects, and when supplemented several times during the day, demonstrates long-lasting objective improvements in joint mobility. The RDA for vitamin B3 (niacin) is 15-20 mg/day. In the preferred embodiment the dietary supplement contains 300 mg/day vitamin B3 (niacinamide).
[0029] The preferred dietary supplement comprises vitamin B5. Vitamin B5 plays a significant role in energy production from carbohydrates, fats and proteins. The toxicity of vitamin B5 is negligible. Active and elderly individuals in trauma or who suffer from rheumatoid arthritis have realized significant improvements in morning stiffness, disability and pain when supplemented with gram doses of vitamin B5. There is no RDA for vitamin B5, a provisional range of intake of 4-87 mg/day was established 1980. In the preferred embodiment the dietary supplement contains 1000 mg/day vitamin B5 in the form of panthothenic acid.
[0030] The preferred dietary supplement comprises vitamin B6. Vitamin B6 has recently been shown to be vital to bone health. However in high doses, vitamin B6 can be toxic. In low doses, vitamin B6 shows no efficacy. Pregnant and lactating women, oral contraceptive users and heavy drinkers are at risk for vitamin B6 deficiency. The RDA for vitamin B6 is 1.5-2 mg/day. In the preferred embodiment the dietary supplement contains 50 mg/day vitamin B6 in the form of pyridoxine hydrochloride.
[0031] The preferred dietary supplement comprises vitamin B12. Vitamin B12 deficiencies can interfere with normal cell division involving arrested synthesis of DNA causing cellular mutations leading to disease states, particularly in bone marrow and intestinal mucosa. Vitamin B12 has no appreciable toxicity, and is frequently deficient in strict vegetarians. The RDA for vitamin B12 is 2 μg/day. In the preferred embodiment the dietary supplement contains 100 μg/day vitamin B12.
[0032] The preferred dietary supplement comprises vitamin C. Most of the functions of vitamin C are directly applicable to the health of connective tissue and their response to injury. Vitamin C, however tends to change the valence of copper, rendering copper unavailable to the body. It is good nutritional practice to dose extra copper when using mega doses of vitamin C. The RDA for vitamin C is 50-60 mg/day. In the preferred embodiment the dietary supplement contains 500 mg/day vitamin C.
[0033] The preferred dietary supplement comprises magnesium. Magnesium is widely distributed in food. However, the refining and processing of foods tends to remove large amounts of magnesium. Magnesium fulfills so many essential functions that it is almost impossible to single out any one function as most critical. There is no established RDA for magnesium because it is ubiquitous in nature. Nonetheless, the food and nutrition board of the national academy of sciences has recommended intake based on age and gender of 40-400 mg/day as safe and adequate. In the preferred embodiment the dietary supplement contains 400 mg/day magnesium in the form of magnesium citrate.
[0034] The preferred dietary supplement comprises vitamin E. Vitamin E is synthesized only by plants, and therefore is found primarily in plant products, particularly in plant oils. Vitamin E affects almost every aspect of health to some degree in its role and function as a scavenger of free radicals. The RDA for vitamin E is 8-10 mg/day. In the preferred embodiment the dietary supplement contains 400 mg/day vitamin E.
[0035] The preferred dietary supplement comprises vitamin D3. Vitamin D3 is important in calcium, phosphate and magnesium absorption. Excess vitamin D causes hypercalcemia. Clinical signs are weakness, nausea, headaches, abdominal pain, cramps and diarrhea. Intake of vitamin D is not absolutely essential if adequate skin exposure to sunlight is available. The RDA for vitamin D3 is 400 IU/day. However, recent research has shown that the recommended dose of vitamin D3 should be 1000-2000 IU/day due to the newly discovered multiplicity of critical functions in metabolism other than simply bone health. In the preferred embodiment the dietary supplement contains 1000 IU/day vitamin D3.
[0036] The preferred dietary supplement comprises zinc. Zinc, in addition to cell growth and replication, has specific roles in sexual maturation, fertility, reproduction, night vision, immune function, taste and appetite. Zinc, with copper as a stabilizing influence, is vital to genetic stability and expression during cellular replication. Deficiencies or excesses of zinc can result in mutated cellular replication leading to disease states. Thus, zinc should be supplemented in balance with copper to protect the cellular reproductive function. The RDA for zinc is 12-15 mg/day. In the preferred embodiment the dietary supplement contains 25 mg/day of zinc in the form of zinc citrate.
[0037] The preferred dietary supplement comprises manganese. Manganese plays unique and vital roles in the synthesis of macromolecular components of connective tissues, especially for bone and cartilage. Since acute, severe deficiencies of manganese are rare, defects of manganese status appear to occur in active individuals during periods of stress, or from a life-long, chronic, intermittent, or marginal deficiency. Acute deficiency symptoms are not usually encountered but rather, as with copper and zinc, chronic or marginal deficiencies in manganese uptake results in decreased synthesis of connective tissues leading to loss of integrity for joints and bones. The RDA for manganese is 2.0 mg/day. In the preferred embodiment the dietary supplement contains 10 mg/day of manganese in the form of manganese gluconate.
[0038] The preferred dietary supplement comprises copper. Modest doses of copper as organic chelates are used to maintain physiologic levels of cuproenzymes important to connective tissue, particularly in the athletic or active individual. Copper has a long history of medicinal uses, including treatment of inflammatory conditions, osteoporosis, and arthritis. Copper functions primarily as a component of metalloenzymes with essential functions, and also activates other enzymes. There is no RDA for copper. Current research however, has established a beneficial, safe and adequate intake of 2-8 mg/day. In the preferred embodiment the dietary supplement contains 8 mg/day of copper in the form of copper gluconate.
[0039] The preferred dietary supplement comprises biotin. Biotin is important for energy production and fat metabolism. Biotin is rather widespread among foods and is synthesized by intestinal flora. Simple deficiencies of biotin in humans in the absence of other nutrient deficiencies are rare. However, those at risk for biotin deficiency include individuals on antibiotic therapy, alcoholics, pregnant and lactating women, surgical burn patients and the elderly. Relatively low levels of biotin have also been reported in physically active or athletic individuals. There is no RDA for biotin. However, the national academy of sciences food and nutrition board has published a nominal safe and adequate intake of 100-200 μg/day. In the preferred embodiment the dietary supplement contains 1000 μg/day of biotin.
[0040] The preferred dietary supplement comprises folate. Folate is important to blood cell formation as well as DNA and RNA synthesis. Deficiencies result in reduced cell division which is manifested as anemia, skin lesions and poor overall growth. Pregnant and lactating women, elderly persons and those taking certain folate antagonists such as aspirin, have an increased requirement for folate in the diet. The RDA for folate is 150-200 μg/day. In the preferred embodiment the dietary supplement contains 1000 μg/day of folate.
[0041] The preferred dietary supplement comprises chromium. Chromium is essential for optimal peripheral insulin action with respect to glucose intake. Studies of elderly and active adults with noninsulin-dependent diabetes mellitus showed improvement in glucose tolerance following a period of chromium supplementation. The RDA for chromium is 120 μg/day. In the preferred embodiment the dietary supplement contains 200 μg/day of chromium in the form of chromium polynicotinate.
[0042] The preferred dietary supplement comprises bioflavinoids. Bioflavinoids are a ubiquitous class of compounds found in plants. Most bioflavinoids exhibit antioxidant activity. Scavenging hydroxyl radicals, lipid peroxides, and reactive oxygen species has been repeatedly documented for many bioflavinoids. Bioflavinoids also reduce capillary fragility and/or permeability. This effect “spares” vitamin C, and is likely due to flavinoid chelation and antioxidant properties, particularly important to the physically active or elderly individual. Bioflavinoids appear to render other nutrients more effective as anti-inflammatory agents, especially vitamin C and proteolytic enzymes. There is no RDA for bioflavinoids. In the preferred embodiment the dietary supplement contains 1000 mg/day of bioflavinoids in the form of citrus bioflavinoids.
[0043] The preferred dietary supplement comprises glucosamine. Glucosamine is a naturally occurring amino sugar found in glycoproteins and glycosaminoglycans. Increased availability of glucosamine through supplements accelerates or enhances synthesis of hyaluronan, glycosaminoglycans and proteolysis There is no RDA for glucosamine. In the preferred embodiment the dietary supplement contains 1000 mg/day of glucosamine in the form of glucosamine sulfate.
[0044] The preferred dietary supplement comprises boron. Maintenance of boron intake by dietary manipulation and/or supplementation is recommended for bone loss conditions such as osteoporosis, fracture healing, arthritis and other degenerative joint diseases. There is no RDA for boron, however research has indicated that a boron intake of 3-6 mg/day is beneficial, safe and adequate. In the preferred embodiment the dietary supplement contains 3 mg/day of boron in the form of boron citrate.
[0045] In one embodiment, the dietary supplement is taken with an additional calcium supplement. Calcium should be given as a single dose, once per day in the evening. Calcium requirements should be provided by dietary means first. When increasing calcium intake through supplemental means to reach the recommended levels of 800-1200 mg/day, doses of 600 mg elemental calcium should be taken once daily with the evening meal. Supplementing calcium in the evening is preferred because calcium metabolizes differently in the early evening and is better absorbed at that time.
[0046] The present invention will be further illustrated by the following examples that are not limited.
EXAMPLES
[0047] A suitable Aspergillus oryzae protease preparation made with potato dextrin as the carbohydrate source is Protease A-DS, obtained from Amano Enzyme U.S.A. Co., Ltd., Elgin, Ill. This enzyme preparation contains not less than 300,000 HUT/gram. The protease extract can be given dissolved or suspended in water or in capsular form.
[0048] The dietary supplement employed in the following examples is comprised of the following vitamins in the indicated amounts:
[0000]
AMOUNT
PER SERVING
VITAMIN/MINERAL
(serving size 9 capsules)
Vitamin A (as retinyl palmitate)
5,000
IU
Vitamin B1 (as thiamin mononitrate)
100
mg
Vitamin B2 (as riboflavin)
50
mg
Vitamin B3 (as niaciniaminde)
300
mg
Vitamin B5 (as pantothenic acid)
1,000
mg
Vitamin B6 (as pyridoxine
50
mg
hydrochloride)
Vitamin B12 (as cyanocobalamin)
100
mcg
Vitamin C (as ascorbic acid)
500
mg
Magnesium citrate
400
mg
Vitamin E (as d-alpha-tocopherol)
400
IU
Vitamin D3 (as cholecalciferol)
1000
IU
Zinc Citrate
25
mg
Manganese Gluconate
10
mg
Copper Gluconate
8
mg
Biotin (as d-biotin FCC)
1
mg
Folate (as folic acid)
1
mg
Chromium polynicotinate
200
mcg
Citrus bioflavinoids
1,000
mg
Glucosamine Sulfate (13.2%
1,000
mg
potassium)
Boron Citrate
3
mg
Example 1
[0049] A 55-year-old female was admitted to the hospital for emergency bowel/appendix surgery. Three days later she underwent surgery to excise a short segment of bowel including two sites of abscess. Postoperatively, she had a prolonged course of bowel recovery. On post operative day 10, she continued to exhibit abdominal distension and nausea. She remained on clear liquids and it was suggested by the surgeon that a port be inserted into her upper chest for ease of treatment with fluids and antibiotics. On post operative day 11 in lieu of the port placement, the patient was placed on the enzyme therapy regimen of the present invention. The patient was immediately dosed with six grams (2,400,000 HUT) of the Aspergillus oryzae protease preparation described herein dissolved in water. This dose was repeated 3 more times throughout the day for a total daily dose of 9,600,000 HUT. At the end of post operative day 11, radiological reports illustrated that small bowel dilation may have been slightly less than was seen on the previous study. On post operative day 12, the patient again received 3 doses of 6 grams (2,400,000 HUT) of the Aspergillus oryzae protease preparation described herein dissolved in water for a total daily dose of 9,600,000 HUT. The scan taken on post operative day 12 illustrated that air was in the transverse and descending colons but not definitely seen in the rectum. The scan taken at post operative day 13, after the second full day of treatment illustrated that the dilation of small bowel loops had decreased and air was now observed in the region of the rectum in addition to the transverse and descending colons. According to the radiologist, these findings were consistent with a resolving partial small bowl (inflammatory) obstruction. The next morning, on post operative day 14, after 3 full days of treatment, the symptoms had resolved sufficiently as to allow the patient to be discharged.
Example 2
[0050] A 60-year-old female with relapsing-remitting multiple sclerosis (MS) began taking the protease preparation of the invention following a MS relapse involving numbness and weakness of her legs and hands. The patient received six grams of the claimed Aspergillus oryzae protease preparation dissolved in water on an empty stomach four times daily for a total daily dose of approximately 9,600,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food and two calcium capsules given once per day with the evening meal. The patient regained the strength and feeling she lost in her right leg. In addition, an unexplained stiffness and pain in her right hand also improved.
Example 3
[0051] A 79-year-old male sustained a back injury and was advised by doctors that the physical trauma of the injury would take approximately six months to heal. The patient, in hopes of a shortened healing time, began taking the Aspergillus oryzae protease preparation and nutritional supplement regimen of the present invention. The patient received six grams of Aspergillus oryzae protease preparation of the present invention dissolved in water four times daily on an empty stomach, for a total daily dose of approximately 9,600,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food. Within 1 month of beginning the protocol described herein, the patient was pain free and regained both flexibility and range of motion.
Example 4
[0052] An 84-year-old woman diagnosed as having severe Alzheimer's disease was unable to communicate with her family, was confined to a chair and necessitated the use of diapers. The patient was placed on the protease and dietary supplement protocol of the present invention. She received six grams of the claimed Aspergillus oryzae protease preparation dissolved in water four times daily on an empty stomach, for a total daily dose of approximately 9,600,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food. Within two weeks, the patient was able to walk, participate in conversations and recognized family members.
Example 5
[0053] A 54-year-old female patient was diagnosed with chronic obstructive pulmonary disease (COPD) based on a chest X-Ray, breathing test and physical exam by a pulmonologist. The patient was placed on a tiotropim bromide inhaler and a levalbuterol inhaler. In addition to these therapies, the patient also began taking six grams of the Aspergillus oryzae protease preparation of the present invention dissolved in water four times daily on an empty stomach, for a total daily dose of approximately 9,600,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food and two calcium capsules given once per day with the evening meal. After one week, her fatigue was drastically decreased and energy and concentration markedly increased. Approximately 1 month later, the patient increased her nutritional supplement dose to 4 capsules three times daily. Within days of increasing the dose, the patients energy and concentration further improved to the point where day-time naps were no longer necessary.
Example 6
[0054] A 55 year-old-female patient was diagnosed with osteopenia, a reduction in bone tissue and density. The patient was placed on the protease and dietary supplement protocol of the present invention. She received six grams of the claimed Aspergillus oryzae protease preparation dissolved in water four times daily on an empty stomach, for a total daily dose of approximately 9,600,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food and two calcium capsules given once per day with the evening meal. Since beginning the protease and nutritional supplement protocol claimed herein, the patient has exhibited complete reversal of bone and tissue loss associated with bone density loss.
Example 7
[0055] A 57 year-old-female patient was diagnosed with a sub-retinal hemorrhage. The patient was placed on the protease protocol of the present invention. She received six grams of the claimed Aspergillus oryzae protease preparation dissolved in water once daily on an empty stomach, for a total daily dose of approximately 2,400,000 HUT. Concurrently, the patient received three nutritional supplement capsules three times daily given with food and two calcium capsules given once per day with the evening meal. One week after beginning the protocol, an improvement of 25% was noted. Sixty days after onset of treatment, an improvement of 90% was noted.
Example 8
[0056] A 64 year-old-male patient accidentally scalded his left had with boiling water leading to blistering, edema, inflammation and swelling along with severe pain. After placing the scalded hand under cold water for approximately 14 minutes, the patient took 1,000 mg of Paracetamol tablets. The wound was bandaged with a Urgutol dressing. The patient then received six grams of the claimed Aspergillus oryzae protease preparation dissolved in water, on an empty stomach. Within 30 minutes, the severe pain was eliminated and within 30 minutes the swelling and inflammation had been considerably reduced. Approximately 7 hours after receiving the first dose of the claimed Aspergillus oryzae protease preparation, the patient was administered a second dose of 6 grams of the claimed preparation dissolved in water, for a total daily dose of 4,800,000 HUT. Within 35 minutes of receiving the second dose, the discomfort was completely eradicated and the areas of inflammation were noticeably disappearing. Two days later, when the dressings were removed, the hand appeared to be completely normal, with virtually no signs of the accident.
Example 9
[0057] A 3-year-old thoroughbred filly was treated with the Aspergillus oryzae protease preparation of the present invention after suffering with tying up syndrome. The horse received a single dose of the enzyme preparation claimed herein at a dose of 27 grams, 10,800,000 HUT, dissolved in water on an empty stomach. Within minutes the horse exhibited relaxed muscularity and walked out of the severe cramping discomfort.
Example 10
[0058] A mare suffering from a hematoma was administered the protease preparation of the present invention. The Aspergillus oryzae protease preparation was administered at a dose of 27 grams four times daily on an empty stomach for a total daily dose of 43,200,000 HUT per day. No other treatment was used in this case. Within four days of treatment the hematoma was no longer detectable.
Example 11
[0059] An adult male horse was diagnosed with a severely injured coffin joint in his right forelimb. According to the horse's veterinarian, there was no chance for recovery and it was suggested that the horse be euthanized. The horse went from lame to crippled to being forced to lay down only standing to urinate and sometimes eat. It was at this time that the horse was placed on the Aspergillus oryzae protease preparation of the present invention. The horse received 27 grams of Aspergillus oryzae protease preparation four times daily on an empty stomach for a total daily dose of approximately 43,200,000 HUT per day. In addition, the horse received the equivalent of 45 capsules of the nutritional supplement in powder form twice daily with feedings. Within six weeks he began standing for a significantly longer period of time putting all of his weight on his two back legs. Two months later, he began supporting himself on three limbs. Six weeks following that, he began slowly adding weight back to his injured right forelimb. Five months after beginning the protocol the grating and popping sound of bone on bone contact was almost totally gone. The horse soon regained the ability to walk on all four legs.
Example 12
[0060] An 8-year-old Jack Russell terrier was diagnosed with Lyme's Disease. Upon examination the dog was found to be suffering badly from renal failure. The veterinarian gave the dog a very poor prognosis stating that she had never seen a dog doing as badly as this dog recover from renal failure. The dog began receiving three grams of Aspergillus oryzae protease preparation of the present invention on an empty stomach three times daily (3,600,000 HUT). In addition, the dog received two nutritional capsules twice daily with meals. Within two months the dog made a complete recovery and was back to digging and hunting as she was before the illness.
Example 13
[0061] A 9-year-old Welsh Corgi was diagnosed with chondrosarcoma in his right nasal cavity. The veterinarians gave the dog between one week and one month to live. The dog also received pain relieving medications from the veterinarian. Soon after this, the dog began treatment with the protease and nutritional supplement protocol of the present invention. He received three grams of Aspergillus oryzae protease dissolved in water on an empty stomach four times daily for a total daily dose of approximately 4,800,000 HUT per day. In addition, the dog also received three nutritional capsules three times daily with meals. After only a few of days of taking the enzyme and nutritional supplement protocol the dog markedly improved so that he was taken off the pain relieving medication. After three-four weeks the dog was breathing through his nostrils freely again and regained both energy and appetite. After six months the enzyme dose was discontinued and reinstituted as a maintenance dose of 3 grams three times daily. One year later the dog exhibited no evidence of chondrosarcoma.
Example 14
[0062] A 7-year-old female Rottweiler was diagnosed with osteosarcoma. According to the veterinarian unless limb salvage procedures were to be undertaken, the most rapid and potentially curable option was partial or total limb amputation. The elective surgery was declined and the dog was placed on the enzyme protocol of the present invention. The dog received six grams of the Aspergillus oryzae protease preparation dissolved in water or in capsule form on an empty stomach four times daily, for a total daily dose of approximately 9,600,000 HUT per day. In addition, the dog received three nutritional supplement capsules three times daily with food. On day 50 after beginning the enzyme protocol a small fluid filled mass was found. On day 56 the small mass was drained. On day 63 post enzyme treatment, the dog was taken to another veterinarian. This veterinarian noticed that the primary tumor had become soft and ulcerated. A second mass was found to be totally necrotic. The dog was maintained on the enzyme protocol and was given Baytril for possible infection associated with the large amount of necrotic tissue sloughing-off from the tumor mass. On day 65 post enzyme treatment the dog was taken to the emergency room for massive bleeding from the tumor which could not be stopped after routine bandage change. The dog was given a sedative to lower blood pressure. The necrotic tissue was removed and the area was packed with sterile gauze and the pressure bandage was replaced. Surgery was scheduled for day 68 after the commencement of enzyme therapy. Surgery was performed to remove additional necrotic tissue. At this time laser surgery was also performed to cauterize the main feeder vein to the primary tumor in hopes of controlling the bleeding. During the surgery, the surgeon found that the second mass has also become totally necrotic as well as the surrounding tissue. The second mass was removed. The primary tumor was found to be full of pus and serous fluid.
Example 15
[0063] A 13-year-old Black Labrador Retriever developed a mass on his limb. Upon noticing the mass, the dog began treatment with the protease protocol of the present invention. He received six grams of Aspergillus oryzae protease dissolved in water on an empty stomach four times daily for a total daily dose of 9,600,000 HUT per day. After 4 weeks of treatment, the dog was scheduled for surgery to remove the mass. Upon removal of the mass, the, the pathologist that removed the mass noted that the tumor was >90% necrotic.
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A method for treating various diseases, conditions and injuries with a protease preparation derived from Aspergillus orzyze and made using potato dextrin as the carbohydrate source is described. The method comprises orally administering the Aspergillus oryzae protease preparation on an empty stomach and in an amount greater than about 2,000,000 HUT per day. Additionally, a method for treating various diseases, conditions and injuries with a protease derived from Aspergillus oryzae made using potato dextrin as the carbohydrate source along with a nutritional supplement of vitamins and minerals is also described. The method comprises orally administering the Aspergillus oryzae protease preparation on an empty stomach in an amount of greater than 2,000,000 HUT per day and administering the dietary supplement of vitamins and minerals orally with food.
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TECHNICAL FIELD
[0001] The present invention relates to a wash arm arrangement for a dishwasher, and more particularly to a wash arm arrangement comprising a satellite arm arranged on a central arm.
BACKGROUND OF THE INVENTION
[0002] Most conventional dishwashers are arranged having single wash arm arrangements comprising a central arm which is provided with a plurality of spray nozzles. The spray nozzles are typically arranged along the extension of the central arm for sufficient covering of the washing area of the treatment chamber with cleaning liquid and optionally for driving the central arm. The central arm is rotatably connected with a supply shaft for supply of the cleaning liquid, e.g. water, about which supply shaft the central arm revolves while water is spread within the treatment chamber of the dishwasher.
[0003] Further, wash arm arrangements with an additional second arm, herein after referred to as a satellite arm, arranged on one or both of the outer ends of the central arm are known. EP1 634 526 A discloses a wash arm arrangement for a dishwasher, having a central arm onto which a satellite arm is arranged. The central arm is attached at one end to a hollow central shaft which serves as a water and rinsing fluid supply duct. The central arm can be positioned either at the bottom or at the ceiling of the dishwasher treatment chamber. A spray arm is swivel mounted with its center to the outer end of the central arm thereby forming the satellite arm. The spray arm is provided with several nozzles at both ends. The nozzles are arranged having different spray angles for covering the different areas of the washing area of the treatment chamber with cleaning liquid and for driving the spray arm. When the cleaning liquid is released a thrust is created moving both arms in circles around their individual axis of rotation.
[0004] Both in single wash arm arrangements and wash arm arrangement with a satellite arm, the spray arms are typically provided with a plurality of nozzles which are spread out on the wash arm arrangement for providing cleaning liquid over the major part of the washing area of the treatment chamber, thereby achieving a high coverage of the washing area. The nozzles may in addition be utilized for making the spray arm and/or central arm rotate. These functionalities of the nozzles, alone and in combination, result in using large amounts of cleaning liquid during operation of the dishwasher which is negative from environmental and economic perspectives.
SUMMARY
[0005] In view of the above, an objective of the invention is to solve or at least reduce the problem discussed above. In particular, an objective is to provide a wash arm arrangement which provides a low cleaning liquid consumption combined with a good cleaning performance. The inventive concept is based on an understanding that by utilizing a collimated liquid jet with sufficient pressure and flow a good cleaning performance is achieved with a reduced water consumption.
[0006] According to a first aspect of the present invention, there is provided a wash arm arrangement for a dishwasher comprising a central arm adapted to be rotatably connected with a first shaft through which liquid under pressure is fed into the central arm during operation, and at least one satellite arm having a liquid inlet, which is rotatably connected with a second shaft arranged on the central arm for supplying liquid to the satellite arm during operation. The at least one satellite arm comprises a collimating nozzle with an exit arranged for providing a collimated jet for distributing liquid to a washing area of the dishwasher.
[0007] Thus, there is provided a wash arm arrangement for a dishwasher which has a collimating nozzle provided on the satellite arm, and which is arranged such that the washing area of the dishwasher is subjected to a collimated uniform liquid jet instead of sprinkled liquid. The collimated liquid jet provides an increased cleaning efficiency on the dishes, and is thus applicable for loosening soil from the dishes in the washing area. Further, the collimated liquid jet simultaneously supplies a sufficient flow of cleaning liquid onto the washing area. The liquid flow needs to be high enough to provide disposal of loosened soil from the washing area. By arranging the collimating nozzle on a satellite arm, a good covering of the washing area is achieved as the liquid jet provided by the rotating satellite arm, which in turn moves with the rotation of the central arm, rotates over the washing area.
[0008] According to an embodiment of the wash arm arrangement, the exit is arranged having a predetermined diameter selected for outputting a collimated jet of liquid with a substantially uniform cross-section. The diameter of the collimating nozzle is selected to be sufficiently large such that the liquid flow and pressure created in the hydraulic system formed by the liquid supply system which is connected to the first shaft for supplying the liquid under pressure during operation and the wash arm arrangement is balanced thereby providing a collimated jet from the exit.
[0009] According to an embodiment of the wash arm arrangement, the predetermined diameter is selected within a range of 3.5-7.5 mm.
[0010] According to an embodiment of the wash arm arrangement, the collimating nozzle is shaped like a hollow, truncated cone with rounded side wall, like a trumpet shape, of which the truncation is arranged for providing the exit for the collimated liquid jet. The cone or trumpet shape of the collimating nozzle is advantageous for collimating and speeding up the cleaning liquid jet before it exits the collimating nozzle. Further, these shapes may provide a smooth guiding of the liquid jet in a desired direction.
[0011] According to an embodiment of the wash arm arrangement, the satellite arm is arranged having at least two separate liquid supply channels arranged to provide fluid communication between the liquid inlet and the collimating nozzle, and converging at a collimation portion arranged at the collimating nozzle. During operation of the dishwasher, the resulting cleaning liquid jet out from the collimating nozzle is the converged contributions from the respective liquid supply channels. Each supply channel guides and speeds up the cleaning liquid from the second supply shaft to the collimating nozzle. At the collimation portion, the guided cleaning liquid from the respective liquid supply channels are converged to a collimated, homogenous liquid jet. The liquid jet is outputted from the collimating nozzle via the exit and subsequently subjects the washing area, and the dirty dishes, with a balanced ratio between the impact force of the jet and the liquid volume flow, which in turn provides a very good cleaning result.
[0012] According to an embodiment of the wash arm arrangement, the collimation portion comprises a control element for redirecting liquid supplied via each one of the liquid supply channels into a common direction. The control element may be integrated in the design of the collimation portion to support the converging of the individual contributions of cleaning liquid into one homogenous beam, by smoothly redirecting them towards the collimating nozzle which is favorable to create a converged, homogenous and accelerated common jet. The control element may alternatively be provided as a freestanding part arranged at or within the collimation portion.
[0013] According to an embodiment of the wash arm arrangement, the control element is further arranged for merging liquid supplied via each one of the liquid supply channels into a common jet. The common jet subsequently exits the collimating nozzle without breaking up into a spread sprinkle.
[0014] The supply channels, the trumpet shape of the nozzle and the control element cooperate to contribute to the collimation of the jet. When the water in the supply channels meet, the force vectors in the water are dampened, such that the water is easier to guide in the desired direction.
[0015] According to an embodiment of the wash arm arrangement, the collimating nozzle is arranged to provide a propulsion force for driving at least the rotation of the satellite arm around its axis of rotation during operation. This way the amount of liquid needed to drive the wash arm arrangement is minimized with a retained high enough liquid pressure and addition a high enough liquid flow to ensure a good cleaning result.
[0016] According to an embodiment of the wash arm arrangement, the collimating nozzle is skewed to provide the propulsion force, which is advantageous.
[0017] According to an embodiment of the wash arm arrangement, the collimating nozzle is skewed between 2-20° with respect to the vertical plane of the satellite arm.
[0018] According to an embodiment of the wash arm arrangement, the collimating nozzle is arranged at an outer end of the satellite arm.
[0019] According to an embodiment of the wash arm arrangement, the second shaft is arranged at an outer end of the central arm. According to an embodiment of the wash arm arrangement, the wash arm arrangement further comprises an additional collimating nozzle. The additional nozzle may be provided symmetrically on an opposite side of the satellite arm when the satellite arm is rotatably connected with a second shaft at its center, which is advantageous for balancing purposes. Alternatively the additional collimating nozzle may be arranged at a different radial distance with respect to the second shaft then the collimating nozzle for providing a more dense trace pattern of the liquid jets over the washing area.
[0020] According to a second aspect of the inventive concept there is provided a dishwasher comprising at least one wash arm arrangement according to the present inventive concept.
[0021] Generally, all terms used in the claims are to be interpreted according to their ordinary meaning in the technical field, unless explicitly defined otherwise herein. All references to “a/an/the [element, device, component, means, step, etc]” are to be interpreted openly as referring to at least one instance of said element, device, component, means, step, etc., unless explicitly stated otherwise.
[0022] Other objectives, features and advantages of the present invention will appear from the following detailed disclosure, from the attached dependent claims as well as from the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] The above, as well as additional objects, features and advantages of the present invention, will be better understood through the following illustrative and non-limiting detailed description of preferred embodiments of the present invention, with reference to the appended drawings, where the same reference numerals will be used for similar elements, wherein:
[0024] FIG. 1 is a perspective view of a dishwasher according to the invention;
[0025] FIG. 2 is a perspective cross-sectional view of an embodiment of a wash arm arrangement according to the present invention;
[0026] FIG. 3 a - 3 f are cross-sectional views illustrating a satellite arm of an embodiment of a wash arm arrangement according to the present invention; and
[0027] FIG. 4 a - 4 b illustrate cross-sectional side views of satellite arms of embodiments of wash arm arrangements according to the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0028] A dishwasher 10 according to the invention, as illustrated in FIG. 1 , comprises a housing 15 in which a treatment chamber 11 is arranged. The treatment chamber 11 has a lower and an upper basket, 12 and 13 , in which dish is inserted. Below and/or above each basket 12 and 13 , one or more wash arm arrangements 20 are arranged. The wash arm arrangements 20 , are adapted to rotate substantially horizontally during operation of the dishwasher 10 . Each wash arm arrangement is connected to a respective vertically arranged liquid supply duct, via which liquid supply duct a circulation pump distributes liquid under pressure during operation of the dishwasher (not visible in FIG. 1 ). Further, a door 14 for sealing the treatment chamber 11 is arranged on the housing 15 .
[0029] An embodiment of a wash arm arrangement 20 according to the present invention is now described, with reference to FIG. 2 . The wash arm arrangement 20 comprises a hollow and elongated central arm 21 with an upper and lower side. At the lower side of the central arm 21 , a first shaft alley 23 functioning as a liquid inlet is arranged. The first shaft alley 23 is adapted for rotatable connection with a vertically arranged cleaning liquid supply duct arranged in the treatment chamber of the dishwasher (not shown). The cleaning liquid supply duct is typically connected to a water supply, a circulation pump and alternatively to a cleaning agent supply, and is further controlled by a control system of the dish washer. The axis of rotation of the central arm 21 is located at the center of the liquid inlet 23 . In this embodiment the liquid inlet 23 is arranged at a first end of the central arm 21 .
[0030] In an alternative embodiment of an elongated hollow central arm, the liquid inlet, i.e. the first shaft alley, is arranged at substantially the centre point of the central arm, or alternatively at the mass centre of the wash arm arrangement, to achieve balance during operation of the dishwasher. The latter is advantageous with respect for e.g. avoiding unwanted acoustic resonance, and for avoiding mechanical stress in the shaft alley thereby increasing the lifetime of the mechanical parts.
[0031] To continue, the central arm 21 is provided with a liquid outlet arranged at a second shaft alley 24 . The second shaft alley 24 is here arranged on the upper surface of the central arm 21 . However, the second shaft alley may alternatively be arranged on the same side as the first shaft alley. An elongated satellite arm 22 with an upper and lower surface is rotatably connected at a liquid inlet, arranged in its lower surface, with the second shaft alley 24 . The satellite arm 22 is at least partly hollow and receives cleaning liquid via the second shaft alley 24 during operation. The satellite arm 22 is extending symmetrically in two directions from the second shaft alley 24 , about which the satellite arm 22 is arranged to rotate. The axis of rotation of the satellite arm 22 is located at the center of the second shaft alley 24 . At an outer end of the satellite arm 22 a collimating nozzle 25 is arranged. The collimating nozzle 25 and the second shaft alley 24 are in fluid communication. During operation cleaning liquid under pressure is distributed to the wash arm arrangement 20 from the dishwasher feeding duct via the first shaft alley 23 and into the central arm 21 and further through the second shaft alley 24 into the satellite arm 22 . Cleaning liquid is subsequently outputted through the exit of the collimating nozzle 25 . The collimating nozzle 25 is circular and is 6 mm in diameter. The length of the collimating nozzle is 4 mm. The collimating nozzle 25 is the only active nozzle on the washing arm arrangement 20 . The definition of being active is here outputting cleaning liquid over the washing area during operation of the dishwasher.
[0032] In an alternative embodiment of the wash arm arrangement, the collimating nozzle is oval (not shown).
[0033] The diameter of the collimating nozzle 25 is selected so as to provide an unbroken, collimated jet of liquid out from the satellite arm 22 . A typical spray nozzle according to known wash arm arrangements has a smaller diameter, and is arranged such that a high speed, sprinkle jet of cleaning liquid is provided to the washing area. To cover a large portion of the washing area, the shape and/or rim of the known nozzle is often selected so as to provide the sprinkle jet in a wide angle, e.g. in a sun feather distribution. In comparison with such a typical spray nozzle, in the present inventive concept, the size of the liquid output area is selected for providing a substantially uniform, homogenous jet with relatively low velocity/pressure, a large diameter, an even cross-section of the outputted jet, and thereby a large liquid volume flow. The amount of water subjected to the hit area of the jet on the wash area per time unit is thus larger than for a sprinkle jet. Thereby a more efficient cleaning of the dirty dishes is reached. The relatively wide and powerful jet provides a large cleaning liquid flow which is applicable for loosening and removing the soil.
[0034] In an alternative embodiment of a wash arm arrangement according to the present invention, the satellite arm is an elongated hollow body which is rotatably connected with the second shaft alley at a first end portion.
[0035] In an embodiment of the wash arm arrangement, the collimating nozzle 25 is skewed 8° with respect to the vertical plane of the satellite arm and in a direction perpendicular to the extension of the satellite arm such that the collimated jet outputted from the collimating nozzle 25 is inclined providing a propulsion force such that the satellite arm 22 rotates during operation. To provide a propulsion force the collimating nozzle the range of 2-20° for the inclination of the collimating nozzle is applicable. However, in addition to, or alternatively to, providing a propulsion force, the collimating nozzle can be inclined to improve the cleaning performance, by providing a liquid jet with an inclined impact towards the dishes, or for controlling the liquid jet covering of the washing area during operation.
[0036] In an embodiment of the wash arm arrangement the satellite arm 22 , which is described herein after with reference to FIGS. 3 a - 3 f , the satellite arm is elongated and provided with a collimating nozzle 25 at an outer end. A liquid inlet is arranged at a second shaft alley 24 , from which two separate liquid supply channels 30 , 31 extend to the collimating nozzle 25 , thereby providing fluid communication with the second shaft alley 24 . The liquid supply channels 30 , 31 extend along the elongated satellite arm 22 , and are at an outer portion of the satellite arm 22 curved such that the two channels 30 , 31 face each other, in two opposite soft reverse J-shapes. That is, the liquid supply channels 30 , 31 converge at a collimation portion 33 which is arranged at the collimating nozzle 25 . Referring now to FIG. 3 f , the collimating nozzle 25 is trumpet shaped, with concave inner surfaces 26 which form an integrated part of the collimation portion 33 together with the opposite inner surface of the hollow satellite arm 22 . The concave inner surfaces 26 are arranged for facilitating guiding of the respective liquid flow from the converging liquid supply channels 30 , 31 , into a common direction and to merge the contributing liquid flows to form a homogenous jet as the liquid is guided out from the satellite arm via the collimating nozzle 25 . The trumpet shape of the collimating nozzle 25 contributes to collimating and speeding up the outputted liquid jet. The collimating nozzle 25 is inclined, or skewed, such that its exit here is inclined 5° with respect to the upper surface of the satellite arm 22 . At the collimating nozzle 25 , where the two liquid supply channels, 31 and 32 , meet, a separating plate 35 is arranged extending from the inner surface of the satellite arm 22 at the opposite side of the entrance to the collimating nozzle 25 into a subportion of the collimating nozzle 25 , such that the separating plate 35 redirects the liquid supplied from the respective liquid supply channel 31 , 32 towards the collimating nozzle 25 . To facilitate the redirection of the liquid flow into the skewed collimating nozzle, the separating plate 35 is inclined with respect to the normal of the upper surface of the satellite arm 22 such that the inclination of the separation plate 35 coincides with the normal of the exit of the collimating nozzle 25 . The separation plate 35 is provided with a wedge shaped upper edge. As the upper edge is inserted in the nozzle the wedge facilitates the merging of the liquid flow from the two liquid supply channels 31 , 32 .
[0037] In an alternative embodiment of the wash arm arrangement, concave inner surfaces may further be arranged on the inner surfaces of the collimation portion opposite to the collimating nozzle to facilitate the guiding of the liquid flow towards the collimating nozzle.
[0038] In a satellite arm 22 according to an embodiment of the wash arm arrangement, as illustrated in FIG. 4 a , the separating plate 35 is arranged basically as described above. However, the separating plate 35 is here integrated with the inner surface of the satellite arm 22 . The inner surfaces opposite to the collimating nozzle then meet to form the separating plate 35 . The inner surface may then be designed to further control the direction of the contributing liquid flow from the two liquid supply channels 31 , 32 towards the collimating nozzle 25 , e.g. a combination of the separating plate 35 and concave inner surfaces can be utilized. A further variant of the redirection element 35 is illustrated in FIG. 4 b , in which the redirection element is divided such that it is partly integrated with the inner surface opposite to the collimating nozzle 25 and partly a free standing part which is arranged inside (and partly attached to) the collimating nozzle 35 .
[0039] In an embodiment of the wash arm arrangement, the collimating nozzle is shaped like a hollow, truncated cone with its wider base arranged facing the collimation portion, and its truncated top portion arranged as an exit for the liquid jet formed in the collimation portion. The tapering of the collimating nozzle increases the speed of the liquid as it moves towards the exit. In an alternative embodiment, the collimating nozzle is funnel shaped (not shown).
[0040] In further alternative embodiments, the tapering of the cone shaped or trumpet shaped nozzle, is arranged in a plurality of steps.
[0041] In embodiments of the invention, the diameter of the collimating nozzle is preferably selected in a range between 3.5 to 7.5 mm to provide a high liquid flow over the washing area, such that loosened dirt on the dish is properly rinsed off and transported out from the treatment chamber drain (not shown).
[0042] In an alternative embodiment of the wash arm arrangement, an additional collimating nozzle is arranged on an opposite end of the satellite arm, to provide a balanced wash arm arrangement. In this embodiment (not shown), the liquid supply to the respective collimating nozzle, may be provided with a respective set of liquid supply channels as described with reference to FIG. 3 b . The “twin” collimating nozzles are each arranged to output a collimated liquid jet. The additional collimating nozzle may be arranged at a radial distance from the second shaft alley which differs from the corresponding radial distance of the collimating nozzle to provide a more dense tracing pattern during the rotation of the wash arm arrangement on the washing area.
[0043] Above, embodiments of the wash arm arrangement according to the present invention as defined in the appended claims have been described. These should be seen as merely non-limiting examples. As understood by a skilled person, many modifications and alternative embodiments are possible within the scope of the invention.
[0044] It is to be noted, that for the purposes of this application, and in particular with regard to the appended claims, the word “comprising” does not exclude other elements or steps, that the word “a” or “an”, does not exclude a plurality, which per se will be apparent to a person skilled in the art.
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A wash arm arrangement ( 20 ) for a dishwasher is disclosed. The wash arm arrangement comprises a central arm ( 21 ) adapted to be rotatably connected with a first shaft ( 23 ) through which liquid under pressure is fed into the central arm during operation. A second shaft ( 24 ) is arranged on the central arm to provide liquid to a satellite arm ( 22 ) which is rotatably connected with the second shaft. The satellite arm comprises a collimating nozzle ( 25 ) with an exit. The collimating nozzle is arranged for providing a collimated jet for distributing liquid to a washing area of the dishwasher. The inventive concept is based on an understanding that by utilizing a collimated liquid jet with sufficient pressure and flow a good cleaning performance is achieved with a reduced water consumption.
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CROSS-REFERENCE TO RELATED PATENT APPLICATION OR PRIORITY CLAIM
[0001] This application claims priority on U.S. Provisional Patent Application No. 60/846,468, filed Sep. 21, 2006, the content of which incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates generally to compositions and methods for improving the efficacy of cell based therapies through use of a composition that significantly mitigates migration of the cells from the site of delivery. More specifically, the present disclosure relates to cell delivery matrices that localize adipose derived endothelial cells and improve adherence of the endothelial cells to the target tissue, body cavity, or joint.
BACKGROUND OF THE INVENTION
[0003] In recent years, numerous therapies have been developed utilizing a variety of stem cells, presaging an emerging new specialty called regenerative medicine that promises to harness stem cells from embryonic and somatic sources to provide replacement cell therapies for genetic, malignant, and degenerative conditions. Adipose derived endothelial cells are pluripotent stem cells, having the ability to differentiate into smooth muscle or other types of cells, as described in Oliver Kocher and Joseph A. Madri, Modulation of Actin mRNAs in Cultured Vascular Cells By Matrix Components and TGF-β, In Vitro Cellular & Developmental Biology, Vol. 25, No. 5. May 1989, which is incorporated herein by reference in its entirety. As such, these cells are useful in retention or restoration of cardiac function in acute and chronic ischemia. Cells within adipose tissue can differentiate into cells expressing a cardiomyocytic or endothelial phenotype, as well as angiogenic and antiapoptotic growth factors.
[0004] Direct injection or transplantation of cells may effectively restore small areas of damage, but to reconstruct severe damage to injured tissue, resulting from major coronary artery blockage, for example, will require extensive therapy with numerous differentiated cells. Such therapy is enhanced by maintaining endothelial cells at a target site for a therapeutically effective period of time, which may be from hours to days. In some embodiments, a therapeutically effective period of time is weeks to months.
SUMMARY OF THE INVENTION
[0005] Cell delivery matrices are described that maintain local delivery of adipose derived endothelial cells and other therapeutic agents to a target tissue, body cavity, or joint. The cell delivery matrix may be a three-dimensional matrix scaffold comprising fibrin derived from the patient's own body. The cell delivery matrix used in the methods of the invention may be degradable, bioabsorbable or non-degradable. In an embodiment, the cell delivery matrix is an artificial, FDA-approved synthetic polymer. In an embodiment, the cell delivery matrix comprises expanded polytetrafluoroethylene (ePTFE). In another embodiment, the cell delivery matrix comprises polyethyleneterephthalate (PET). The cell delivery matrix may be biocompatible and semi-permeable. The surface of the cell delivery matrix may comprise an immobilized adhesion molecule.
[0006] The present disclosure provides regenerative therapies comprising implanting in the subject cell delivery matrices localizing adipose derived endothelial cells. The cell delivery matrices maintain the adipose derived endothelial cells at the target for a therapeutically effective amount of time. The adipose derived endothelial cells can be allogenic or syngenic to the subject. The endothelial cells may be delivered alone or in combination with other therapeutic agents.
[0007] A skilled artisan will appreciate that the subject of the present invention may be any animal, including amphibians, birds, fish, mammals, and marsupials, but is preferably a mammal (e.g., a human; a domestic animal, such as a cat, dog, monkey, mouse, and rat; or a commercial animal, such as a cow, horse or pig). Additionally, the subject of the present invention may be of any age, including a fetus, an embryo, a child, and an adult.
BRIEF DESCRIPTION OF THE FIGURES
[0008] FIG. 1 depicts a cell delivery matrix. Arrows indicate localized endothelial cells and the semi-porous biomaterial.
DETAILED DESCRIPTION
[0009] Those of ordinary skill in the art will realize that the following detailed description is illustrative only and is not intended to be in any way limiting. Other embodiments will readily suggest themselves to such skilled persons having the benefit of this disclosure.
[0010] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the content clearly dictates otherwise. All publication, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Additionally, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All references cited in this application are expressly incorporated by reference for any purpose.
[0011] U.S. Pat. No. 5,372,945, incorporated herein by reference in its entirety, discloses methods and devices that may be used for the ready isolation of large quantities of endothelial cells having the ability to differentiate into smooth muscle. According to an embodiment, subcutaneous fat is removed from a patient using modified liposuction techniques and transferred to a self-contained, closed device where the fat can be stored under sterile conditions until needed. The fat is sterilely transferred to a digestion device where it is initially washed to remove red blood cells and other debris, followed by a controlled collagenase digestion for about 20 minutes at about 37° C. The fat slurry is then transferred to an endothelial cell isolation device, again under sterile conditions, where endothelial cells sediment into an isolation device, allowing automatic retrieval of the isolated endothelial cells. The cell suspension is then sterilely transferred to a processing unit wherein the cells are rapidly filtered onto the graft surface under sterile conditions. The endothelial cell isolation and deposition process requires only about 40 minutes for completion. Following an incubation period, the graft is ready for implantation into the patient. The system yields endothelial cell product in numbers acceptable for subsequent high density seeding, e.g., in a range of about 5.14×10 6 to 4.24×10 7 cells from 50 cc of fat, and adherence to the graft surface. The apparatus deposits cells along the entire length and diameter of the graft consistently, with no significant difference in cell concentration as compared by analysis of variance.
[0012] As depicted in FIG. 1 , after isolation these cells may then be localized by a cellular matrix. The cell delivery matrix that localizes the endothelial cells may be a three-dimensional culture, which is liquid, gel, semi-solid, or solid at 25° C. The three-dimensional culture may be biodegradable or non-biodegradable.
[0013] The cell delivery matrix used in the methods of the invention may be comprised of any degradable, bioabsorbable or non-degradable, biocompatible polymer. Exemplary three-dimensional culture materials include polymers and hydrogels comprising collagen, fibrin, chitosan, MATRIGEL, polyethylene glycol, dextrans including chemically crosslinkable or photocrosslinkable dextrans, and the like. In an embodiment, the three-dimensional culture comprises allogeneic components, autologous components, or both allogeneic components and autologous components. In an embodiment, the three-dimensional culture comprises synthetic or semi-synthetic materials. In an embodiment, the three-dimensional culture comprises a framework or support, such as a fibrin-derived scaffold. The term scaffold is used herein to include a wide variety of three-dimensional frameworks, for example, but not limited to a mesh, grid, sponge, foam, or the like.
[0014] The term “polymer” is also used herein in the broad sense and is intended to include a wide range of biocompatible polymers, for example, but not limited to, homopolymers, copolymers, block polymers, cross-linkable or crosslinked polymers, photoinitiated polymers, chemically initiated polymers, biodegradable polymers, nonbiodegradable polymers, and the like. In other embodiments, the prevascularized construct comprises a polymer matrix that is nonpolymerized, to allow it to be combined with a tissue, organ, or engineered tissue in a liquid or semi-liquid state, for example, by injection. In certain embodiments, the prevascularized construct comprising liquid matrix may polymerize or substantially polymerize “in situ.” In certain embodiments, the prevascularized construct is polymerized or substantially polymerized prior to injection. Such injectable compositions are prepared using conventional materials and methods know in the art, including, but not limited to, Knapp et al., Plastic and Reconstr. Surg. 60:389 405, 1977; Fagien, Plastic and Reconstr. Surg. 105:362 73 and 2526 28, 2000; Klein et al., J. Dermatol. Surg. Oncol. 10:519 22, 1984; Klein, J. Amer. Acad. Dermatol. 9:224 28, 1983; Watson et al., Cutis 31:543 46, 1983; Klein, Dermatol. Clin. 19:491 508, 2001; Klein, Pedriat. Dent. 21:449 50, 1999; Skorman, J. Foot Surg. 26:511 5, 1987; Burgess, Facial Plast. Surg. 8:176 82, 1992; Laude et al., J. Biomech. Eng. 122:231 35, 2000; Frey et al., J. Urol. 154:812 15, 1995; Rosenblatt et al., Biomaterials 15:985 95, 1994; Griffey et al., J. Biomed. Mater. Res. 58:10 15, 2001; Stenburg et al., Scfand. J. Urol. Nephrol. 33:355 61,1999; Sclafani et al., Facial Plast. Surg. 16:29 34, 2000; Spira et al., Clin. Plast. Surg. 20:181 88, 1993; Ellis et al., Facila Plast. Surg. Clin. North Amer. 9:405 11, 2001; Alster et al., Plastic Reconstr. Surg. 105:2515 28, 2000; and U.S. Pat. Nos. 3,949,073 and 5,709,854.
[0015] A cell delivery matrix may comprise collagen, including contracted and non-contracted collagen gels, hydrogels comprising, for example, but not limited to, fibrin, alginate, agarose, gelatin, hyaluronate, polyethylene glycol (PEG), dextrans, including dextrans that are suitable for chemical crosslinking, photocrosslinking, or both, albumin, polyacrylamide, polyglycolyic acid, polyvinyl chloride, polyvinyl alcohol, poly(n-vinyl-2-pyrollidone), poly(2-hydroxy ethyl methacrylate), hydrophilic polyurethanes, acrylic derivatives, pluronics, such as polypropylene oxide and polyethylene oxide copolymer, or the like. The fibrin or collagen may be autologous or allogeneic with respect to the patient. The matrix may comprise non-degradable materials, for example, but not limited to, expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), polyethyleneterephthalate (PET), poly(butylenes terephthalate (PBT), polyurethane, polyethylene, polycabonate, polystyrene, silicone, and the like, or selectively degradable materials, such as poly (lactic-co-glycolic acid; PLGA), PLA, or PGA. (See also, Middleton et al., Biomaterials 21:2335 2346, 2000; Middleton et al., Medical Plastics and Biomaterials, March/April 1998, at pages 30 37; Handbook of Biodegradable Polymers, Domb, Kost, and Domb, eds., 1997, Harwood Academic Publishers, Australia; Rogalla, Minim. Invasive Surg. Nurs. 11:67 69, 1997; Klein, Facial Plast. Surg. Clin. North Amer. 9:205 18, 2001; Klein et al., J. Dermatol. Surg. Oncol. 11:337 39, 1985; Frey et al., J. Urol. 154:812 15, 1995; Peters et al., J. Biomed. Mater. Res. 43:422 27, 1998; and Kuijpers et al., J. Biomed. Mater. Res. 51:136 45, 2000).
[0016] The surface of the cell delivery matrix may comprise an immobilized adhesion molecule, as described in U.S. Pat. No. 5,744,515, incorporated herein by reference in its entirety. In certain embodiments the immobilized adhesion molecule is selected from the group consisting of fibronectin, laminin, and collagen. The adhesion molecules may be immobilized to the surface, including the pores of the surface, of the matrix by means of photochemistry.
[0017] The cell delivery matrix, in addition to localizing endothelial cells, may localize at least one cytokine, at least one chemokine, at least one antibiotic, such as an antimicrobial agent, at least one drug, at least one analgesic agent, at least one anti-inflammatory agent, at least one immunosuppressive agent, or various combinations thereof. The at least one cytokine, at least one antibiotic, at least one drug, at least one analgesic agent, at least one anti-inflammatory agent, at least one immunosuppressive agent, or various combinations thereof may comprise a controlled-release format, such as those generally known in the art, for example, but not limited to, Richardson et al., Nat. Biotechnol. 19:1029 34, 2001.
[0018] Exemplary cytokines include angiogenin, vascular endothelial growth factor (VEGF, including, but not limited to VEGF-165), interleukins, fibroblast growth factors, for example, but not limited to, FGF-1 and FGF-2, hepatocyte growth factor, (HGF), transforming growth factor beta (TGF-.beta.), endothelins (such as ET-1, ET-2, and ET-3), insulin-like growth factor (IGF-1), angiopoietins (such as Ang-1, Ang-2, Ang-3/4), angiopoietin-like proteins (such as ANGPTL1, ANGPTL-2, ANGPTL-3, and ANGPTL-4), platelet-derived growth factor (PDGF), including, but not limited to PDGF-AA, PDGF-BB and PDGF-AB, epidermal growth factor (EGF), endothelial cell growth factor (ECGF), including ECGS, platelet-derived endothelial cell growth factor (PD-ECGF), placenta growth factor (PLGF), and the like. Cytokines, including recombinant cytokines, and chemokines are typically commercially available from numerous sources, for example, R & D Systems (Minneapolis, Minn.); Endogen (Woburn, Wash.); and Sigma (St. Louis, Mo.). The skilled artisan will understand that the choice of chemokines and cytokines for incorporation into particular prevascularized constructs will depend, in part, on the target tissue or organ to be vascularized or revascularized.
[0019] In certain embodiments, the cell delivery matrix further localizes at least one genetically engineered cell. Descriptions of exemplary genetic engineering techniques can be found in, among other places, Ausubel et al., Current Protocols in Molecular Biology (including supplements through March 2002), John Wiley & Sons, New York, N.Y., 1989; Sambrook et al., Molecular Cloning: A Laboratory Manual, 2.sup.nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; Sambrook and Russell, Molecular Cloning: A Laboratory Manual, 3.sup.rd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001; Beaucage et al., Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, New York, N.Y., 2000 (including supplements through March 2002); Short Protocols in Molecular Biology, 4.sup.th Ed., Ausbel, Brent, and Moore, eds., John Wiley & Sons, New York, N.Y., 1999; Davis et al., Basic Methods in Molecular Biology, McGraw Hill Professional Publishing, 1995; Molecular Biology Protocols (see the highveld.com website), and Protocol Online (protocol-online.net). Exemplary gene products for genetically modifying the genetically engineered cells of the invention include, plasminogen activator, soluble CD4, Factor VIII, Factor IX, von Willebrand Factor, urokinase, hirudin, interferons, including alpha-, beta- and gamma-interferon, tumor necrosis factor, interleukins, hematopoietic growth factor, antibodies, glucocerebrosidase, adenosine deaminase, phenylalanine hydroxylase, human growth hormone, insulin, erythropoietin, VEGF, angiopoietin, hepatocyte growth factor, PLGF, and the like.
[0020] In certain embodiments, a cell delivery matrix further comprises appropriate stromal cells, stem cells, or combinations thereof. As used herein, the term “stem cells” includes traditional stem cells, progenitor cells, preprogenitor cells, reserve cells, and the like. Exemplary stem cells include embryonic stem cells, adult stem cells, pluripotent stem cells, neural stem cells, liver stem cells, muscle stem cells, muscle precursor stem cells, endothelial progenitor cells, bone marrow stem cells, chondrogenic stem cells, lymphoid stem cells, mesenchymal stem cells, hematopoietic stem cells, central nervous system stem cells, peripheral nervous system stem cells, and the like. Descriptions of stem cells, including method for isolating and culturing them, may be found in, among other places, Embryonic Stem Cells, Methods and Protocols, Turksen, ed., Humana Press, 2002; Weisman et al., Annu. Rev. Cell. Dev. Biol. 17:387 403; Pittinger et al., Science, 284:143 47, 1999; Animal Cell Culture, Masters, ed., Oxford University Press, 2000; Jackson et al., PNAS 96 (25):14482 86, 1999; Zuk et al., Tissue Engineering, 7:211 228, 2001 (“Zuk et al.”); Atala et al., particularly Chapters 33 41; and U.S. Pat. Nos. 5,559,022, 5,672,346 and 5,827,735. Descriptions of stromal cells, including methods for isolating them, may be found in, among other places, Prockop, Science, 276:71 74, 1997; Theise et al., Hepatology, 31:235 40, 2000; Current Protocols in Cell Biology, Bonifacino et al., eds., John Wiley & Sons, 2000 (including updates through March, 2002); and U.S. Pat. No. 4,963,489.
[0021] Therapeutic agents that can also be localized by the cell delivery matrix may include Transforming Growth Factor beta (TGFβ and TGF-β-related proteins for regulating stem cell renewal and differentiation.
[0022] Further therapeutic agents that may be used include anti-thrombogenic agents or other agents for suppressing stenosis or late restenosis such as heparin, streptokinase, urokinase, tissue plasminogen activator, anti-thromboxane B 2 agents, anti-B-thromboglobulin, prostaglandin E, aspirin, dipyridimol, anti-thromboxane A 2 agents, murine monoclonal antibody 7E3, triazolopyrimidine, ciprostene, hirudin, ticlopidine, nicorandil, and the like. Anti-platelet derived growth factor may be used as a therapeutic agent to suppress subintimal fibromuscular hyperplasia at an arterial stenosis site, or any other inhibitor of cell growth at the stenosis site may be used.
[0023] Other therapeutic agents that may be used in conjunction with endothelial cells may comprise a vasodilator to counteract vasospasm, for example an antispasmodic agent such as papaverine. The therapeutic agents may be vasoactive agents generally such as calcium antagonists, or alpha and beta adrenergic agonists or antagonists. Additionally, the therapeutic agent may be an anti-neoplastic agent such as 5-fluorouracil or any known anti-neoplastic agent, preferably mixed with a controlled release carrier for the agent, for the application of a persistent, controlled release anti-neoplastic agent to a tumor site.
[0024] The therapeutic agent may be an antibiotic, which may be applied to an infected stent or any other source of localized infection within the body. Similarly, the therapeutic agent may comprise steroids for the purpose of suppressing inflammation or for other reasons in a localized tissue site.
[0025] Additionally, glucocorticosteroids or omega-3 fatty acids may be localized by the cell delivery matrix, particularly for stenosis applications. Any of the therapeutic agents may include controlled release agents to prolong the persistence.
[0026] The therapeutic agent may constitute any desired mixture of individual pharmaceuticals of the like, for the application of combinations of active agents. The pharmaceutical agent may support the survival of the cell (e.g., a carbohydrate, a cytokine, a vitamin, etc.). The cell delivery matrix can be delivered to the target tissue, body cavity, or joint by any local delivery means known in the art. Applicant's provisional application 60/841,009, entitled “Catheter for Cell Delivery,” incorporated herein by reference in its entirety, discloses methods and apparatuses suitable for local delivery of the cell delivery matrices of the present disclosure. In an embodiment, the cell delivery system used to deliver the cells locally comprises a catheter. The catheter may comprise an inner bladder and an outer perforated bladder that permits localized delivery of stem cells. The inner bladder may be expanded through the use of a pressure conduit in order to deploy a stent. Cell matrices comprising endothelial cells may be introduced between the inner and outer bladder. The inner bladder may be further expanded in order to exert pressure on the outer perforated bladder to advance the cells though the apertures of the outer bladder. The inner bladder may remain pressurized to hold the outer bladder against the vessel wall, thereby directing the cells to specific target sites. In an embodiment, a three-dimensional matrix scaffold comprising fibrin is delivered locally without cells, in accordance with the methods disclosed in Application No. 60/841,009.
[0027] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as the presently preferred embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
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Cell delivery matrices and methods for facilitating local delivery of adipose derived endothelial cells to a target tissue, body cavity, or joint are described. The cell delivery matrix may be a three-dimensional matrix scaffold comprising fibrin derived from the patient's own body. The cell delivery matrix may be biocompatible and semi-permeable. The cell delivery matrix used in the methods of the invention may be comprised of any degradable, bioabsorbable or non-degradable, biocompatible polymer. Regenerative therapies comprising implanting in the subject cell delivery matrices localizing adipose derived endothelial cells are described. The cell delivery matrices maintain the adipose derived endothelial cells at the target for a therapeutically effective amount of time. The adipose derived endothelial cells can be allogenic or syngenic to the subject. The endothelial cells may be delivered alone or in combination with other therapeutic agents.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present invention is a divisional application of U.S. patent application Ser. No. 11/029,396, filed Jan. 6, 2005 now U.S. Pat. No. 7,588,940, which is a divisional of U.S. patent application Ser. No. 10/210,519, filed Aug. 1, 2002, now U.S. Pat. No. 6,863,406, issued Mar. 8, 2005, the disclosures of which are incorporated herein by reference in their entirety.
The portion of this invention relating to spatially resolved photochemistry using holographic optical traps was made with U.S. Government support provided by the National Science Foundation through Grant Number DMR-9730189 and by the MRSEC program of the NSF through Grant Number DMR-9880595. The portion of this invention relating to sorting nonabsorbing from absorbing particles using optical traps was made with U.S. Government support provided by the National Science Foundation through Grant Number DMR-9730189.
The present invention is related generally to a method and apparatus for manipulating and modifying small dielectric particles or other materials using the intense illumination and intensity gradients in strongly focused beams of light. In particular, the invention is related to a method and apparatus which uses focused laser light directed by a diffractive optical element, such as a hologram or diffraction grating, to create optical traps or traps and any one of a variety of selectable optical intensity patterns to assemble or direct particulate materials, or other affected materials, into a desired spatial pattern for any one of a myriad of uses. More particularly, the invention is related to methods for manipulating, effecting interaction of, photochemically transforming and/or sorting small dielectric particles or other materials.
It is known to construct an optical trap (i.e., trap) using optical gradient forces from a single beam of light to manipulate the position of a small dielectric particle immersed in a fluid medium whose refractive index is smaller than that of the particle. The optical trap technique has been generalized to enable manipulation of reflecting, absorbing and low dielectric constant particles as well. Likewise, U.S. Pat. No. 6,055,106, co-invented by the inventor named herein and incorporated herein by reference, discloses the manipulation of multiple particles with multiple traps. However, it was previously unknown to use optical traps for the various applications of this invention.
Optical traps, originally described by A. Ashkin et al., have become an established method for trapping, moving and otherwise manipulating mesoscopic volumes of matter. See A. Ashkin et al., “Observation of single-beam gradient force optical trap for dielectric particles,” Optics Letters 11, 288-290 (1986). Central to their operation is minimizing the absorption of trapping light to avoid damaging the trapped material. Optical scalpels operate on the opposite principle, using the energy in a tightly focused laser beam to cut through soft materials. This application discloses and claims a novel hybrid system in which focused beams of laser light operate as optical traps for some nonabsorbing particles in a heterogeneous sample and simultaneously as optical scalpels for others.
Another application of optical trap technology of the invention involves introducing foreign materials into living cells by breaching the cell membrane without causing it to fail entirely, and for moving the materials through the breach. Various methods for accomplishing this have been developed, including viral vectors for transfecting short lengths of DNA, the gene gun and its variants for transferring larger sections, and electroporation for inducing transmembrane diffusion. None appears to be appropriate for transferring physically large materials, particular if those materials are themselves fragile. The present methods and apparatus described herein solves this and other problems.
In addition, holographic optical traps can be used to effect spatially-resolved photochemistry having several advantages over competing techniques for chemically defining small structures. For example, spatially-resolved photochemistry implemented with optical traps facilitates the creation of three-dimensional structures with features ranging in size from a small fraction of the wavelength of light to macroscopic scales. While techniques such as dip-pen nanolithography and microcontact printing offer superior spatial resolution, they are not amenable to three-dimensional fabrication. A very wide variety of photochemical reactions are known, and any of these might be amenable to spatially-resolved photo-fabrication. Thus spatially-resolved photochemistry offers more flexibility than most micro- and nano-fabrication methodologies. Performing spatially-resolved photochemistry with holographic optical traps greatly enhances the utility of the basic approach by greatly improving its efficiency.
It is therefore an object of the invention to provide an improved method and system for simultaneously establishing a plurality of optical traps using a single and/or plurality of devices, such as, for example, multiple holographic optical trap implementations operating simultaneously on a single sample and multiple optical traps and multiple intensity regions operating simultaneously on a single sample.
It is an additional object of the invention to provide a novel method and apparatus for using holograms for generating an optical gradient field for controlling a plurality of particles or other optical media.
It is a further object of the invention to provide an improved method and system for establishing a plurality of optical traps for a variety of commercial applications relating to manipulation of small particles such as in photonic circuit manufacturing, nanocomposite material applications, fabrication of electronic components, opto-electronic devices, chemical and biological sensor arrays, assembly of holographic data storage matrices, facilitation of combinatorial chemistry applications, promotion of colloidal self-assembly, and the manipulation of biological materials.
It is a further object of the invention to provide an improved method and system for using optical traps to incorporate foreign matter into living cells.
It is yet another object of the invention to provided an improved method and system to sort optically nonabsorbing particles from optically absorbing particles.
It is yet another object of the invention to provide an improved method and system to implement the fabrication of heterogeneous structures using spatially resolved photochemistry.
It is still another object of the invention to provide an improved method and system for constructing a temporally and spatially varying configuration of optical gradient fields for various particle sorting applications.
It is also an object of the invention to provide a novel method and system for using one or more laser beams in conjunction with one or more diffractive optical elements for constructing a selectable time varying and/or particular spatial array of optical traps for manipulating a dielectric metallic materials and other materials.
It is yet a further object of the invention to provide an improved method and system using a single input laser beam, a diffractive optical element, and a converging lens to form a static or dynamic optical trap which, in conjunction with other so formed optical traps can be used to manipulate, effect interaction of, photochemically transform and/or sort small dielectric particles or other materials.
It is also a further object of the invention to provide an improved method and system employing a laser beam input to a diffractive optical element with a beam scanning system enabling scanning of an array of optical traps for various commercial applications.
It is in addition another object of the invention to provide a novel method and apparatus for constructing an optical trap configuration using a laser beam, a diffractive optical element and a converging optical system to form the trap configuration at a selectable location relative to an objective lens focal plane.
It is yet another object of the invention to provide a novel method and apparatus for using a laser beam input to a diffractive optical element to generate a three-dimensional arrangement of optical traps.
It is another object of the invention to provide a novel method for creating multiple independently steered optical traps using a time-dependent addressable phase-shifting medium (such as a liquid crystal phase shifting array or other phase medium) as a diffractive optical element.
It is a further object of the invention to provide a novel method for creating time-dependent optical gradient fields for the segregation of microscopic particles.
It is yet another object of the invention to provide a novel method for manipulating a plurality of biological objects including the crystallization of proteins or implementing other phase changes.
Other objects, features and advantages of the present invention will be readily apparent from the following description of the preferred embodiments thereof, taken in conjunction with the accompanying drawings described below wherein like elements have like numerals throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a prior art method and system for a single optical trap;
FIG. 2 illustrates a prior art method and system for a single, steerable optical trap;
FIG. 3 illustrates a method and system using a diffractive optical element;
FIG. 4 illustrates another method and system using a tilted optical element relative to an input light beam;
FIG. 5 illustrates a continuously translatable optical trap (trap) array using a diffractive optical element;
FIG. 6 illustrates a method and system for manipulating particles using an optical trap array while also forming an image for viewing the optical trap array;
FIG. 7A illustrates an image of a four by four array of optical (traps) using the optical system of FIG. 6 ; and FIG. 7B illustrates an image of one micrometer diameter silica spheres suspended in water by the optical traps of FIG. 7A immediately after the trapping illumination has been extinguished, but before the spheres have diffused away;
FIG. 8A illustrates a first step in transferring material into a cell with material encapsulated in a liposome being immobilized with optical traps; FIG. 8B illustrates a liposome being fused to a cell membrane; and FIG. 8C the material in the liposome is transferred through a breach in the liposome cell function; and
FIG. 9 is a functional block flow diagram illustrating separation of nonabsorbing from absorbing particles.
DETAILED DESCRIPTION OF THE INVENTION
This invention presents several uses for the “Apparatus for Applying Optical Gradient Forces” disclosed and claimed in U.S. Pat. No. 6,055,106 to Grier et al. That apparatus is encompassed by use of the terminology optical trap, optical trap and optical gradient force trap hereinafter. By way of introduction, FIGS. 1 and 2 illustrate several prior art methods and systems. These systems will first be reviewed, and then the methods of the present invention will be described in terms of the optical trap embodiment examples of FIGS. 3-7A and 7 B. In prior art optical trap system 10 of FIG. 1 , optical gradient forces arise from use of a single beam of light 12 to controllably manipulate a small dielectric particle 14 dispersed in a medium 16 whose index of refraction is smaller than that of the particle 14 . The nature of the optical gradient forces is well known, and also it is well understood that the principle has been generalized to allow manipulation of reflecting, absorbing and low dielectric constant particles as well.
The optical trap system 10 is applied by using a light beam 12 (such as a laser beam) capable of applying the necessary forces needed to carry out the optical trapping effect needed to manipulate a particle. The method used to create a conventional form of the optical trap 10 is to project one or more beams of light, each with a specified degree of collimation, through the center of a back aperture 24 of a converging optical element (such as an objective lens 20 ). As noted in FIG. 1 the light beam 12 has a width “w” and having an input angle, .PHI., relative to an optical axis 22 . The light beam 12 is input to a back aperture 24 of the objective lens 20 and output from a front aperture 26 substantially converging to a focal point 28 in focal plane 30 of imaging volume 32 with the focal point 28 coinciding with an optical trap 33 . In general, any beam of light brought to a diffraction-limited focus, and possessing sufficiently large axial intensity gradients to trap a particle stably against axial radiation pressure, can form the basis for the optical trap system 10 .
Creating such a focus requires a focusing element with sufficiently high numerical aperture and sufficiently well-corrected aberrations. Generally, the minimum numerical aperture to form a trap is about 0.9 to about 1.0.
In the case of the light beam 12 being a collimated laser beam and having its axis coincident with the optical axis 22 , the light beam 12 enters the back aperture 24 of the objective lens 20 and is brought to a focus in the imaging volume 32 at the center point c of the objective lens focal plane 30 . When the axis of the light beam 12 is displaced by the angle .PHI. with respect to the optical axis 22 , beam axis 31 and the optical axis 22 coincide at the center point B of the back aperture 12 . This displacement enables translation of the optical trap across the field of view by an amount that depends on the angular magnification of the objective lens 20 . The two variables, angular displacement .PHI. and varying convergence of the light beam 12 , can be used to form the optical trap at selected positions within the imaging volume 32 . A multiple number of the optical traps 33 can be arranged in different locations provided that multiple beams of light 12 are applied to the back aperture 24 at the different angles .PHI. and with differing degrees of collimation.
In order to carry out optical trapping in three dimensions, optical gradient forces exerted on the particle to be trapped must exceed other radiation pressures arising from light scattering and absorption. In general this necessitates the wave front of the light beam 12 to have an appropriate shape at the back aperture 24 . For example, for a Gaussian TEM 00 input laser beam, the beam diameter, w, should substantially coincide with the diameter of the entrance pupil 24 . For more general beam profiles (such as Laguerre-Gaussian modes) comparable conditions can be formulated.
In another prior art system in FIG. 2 , the optical trap system 10 can translate the optical trap 33 across the field of view of the objective lens 20 . A telescope 34 is constructed of lenses L 1 and L 2 which establishes a point A which is optically conjugate to the center point B in the prior art system of FIG. 1 . In the system of FIG. 2 the light beam 12 passing through the point A also passes through the point B and thus meets the basic requirements for performing as the optical trap system 10 . The degree of collimation is preserved by positioning the lenses L 1 and L 2 as shown in FIG. 2 , their focal lengths and other optical characteristics being selected to optimize the transfer properties of the telescope 34 . In particular, the magnification of the telescope 34 can be chosen to optimize angular displacement of the light beam 12 and its width w in the plane of the back aperture 24 of the objective lens 20 . As stated hereinbefore, in general several of the light beams 12 can be used to form several associated optical traps. Such multiple beams 12 can be created from multiple independent input beams or from a single beam manipulated by conventional reflective and/or refractive optical elements.
In one optical trap configuration, shown in FIG. 3 , arbitrary arrays of optical traps can be formed. A diffractive optical element 40 is disposed substantially in a plane 42 conjugate to back aperture 24 of the objective lens 20 . Note that only a single diffracted output beam 44 is shown for clarity, but it should be understood that a plurality of such beams 44 can be created by the diffractive optical element 40 . The input light beam 12 incident on the diffractive optical element 40 is split into a pattern of the output beam 44 characteristic of the nature of the diffractive optical element 40 , each of which emanates from the point A. Thus the output beams 44 also pass through the point B as a consequence of the downstream optical elements described hereinbefore. In some situations, where it is desired to create a plurality of objects in a specific spatial relationship to one another, with each object in a specific orientation, it will be necessary to create the plurality of objects on a timescale faster than that on which relevant motion of the objects occurs. This timescale will be a function of, among other factors, the viscosity of the medium. In such a situation, an apparatus which allows fabrication of the plurality of objects in parallel may provide an advantage over one which fabricates the objects sequentially.
The diffractive optical element 40 of FIG. 3 is shown as being normal to the input light beam 12 , but many other arrangements are possible. For example, in FIG. 4 the light beam 12 arrives at an oblique angle β relative to the optic axis 22 and not at a normal to the diffractive optical element 40 . In this embodiment, the diffracted beams 44 emanating from point A will form optical traps 50 in focal plane 52 of the imaging volume 32 (seen best in FIG. 1 ). In this arrangement of the optical trap system 10 an undiffracted portion 54 of the input light beam 12 can be removed from the optical trap system 10 . This configuration thus enables processing less background light and improves efficiency and effectiveness of forming optical traps.
The diffractive optical element 40 can include computer generated holograms which split the input light beam 12 into a preselected desired pattern. Combining such holograms with the remainder of the optical elements in FIGS. 3 and 4 enables creation of arbitrary arrays in which the diffractive optical element 40 is used to shape the wavefront of each diffracted beam independently. Therefore, the optical traps 50 can be disposed not only in the focal plane 52 of the objective lens 20 , but also out of the focal plane 52 to form a three-dimensional arrangement of the optical traps 50 .
In the optical trap system 10 of FIGS. 3 and 4 , also included is a focusing optical element, such as the objective lens 20 (or other like functionally equivalent optical device, such as a Fresnel lens) to converge the diffracted beam 44 to form the optical traps 50 . Further, the telescope 34 , or other equivalent transfer optics, creates a point A conjugate to the center point B of the previous back aperture 24 . The diffractive optical element 40 is placed in a plane containing point A.
In another embodiment, arbitrary arrays of the optical traps 50 can be created without use of the telescope 34 . In such an embodiment the diffractive optical element 40 can be placed directly in the plane containing point B. In another form of the invention, one of the lenses can be positioned in the hologram itself rather than in the telescope 34 .
In the optical trap system 10 either static or time dependent diffractive optical elements 40 can be used. For a dynamic, or time dependent version, one can create time changing arrays of the optical traps 50 which can be part of a system utilizing such a feature. In addition, these dynamic optical elements 40 can be used to actively move particles and other materials with diverse optical properties relative to one another. For example, the diffractive optical element 40 can be a liquid crystal spatial light modulator encoding computer-generated phase modulations onto the wavefront of an incident laser beam. In another embodiment, a spatial light modulator may also be used in conjunction with a phase ring in place of the diffractive optical element.
In another embodiment illustrated in FIG. 5 , a system can be constructed to carry out continuous translation of the optical trap 50 . A gimbal mounted mirror 60 is placed with its center of rotation at point A. The light beam 12 is incident on the surface of the mirror 60 and has its axis passing through point A and will be projected to the back aperture 24 . Tilting of the mirror 60 causes a change of the angle of incidence of the light beam 12 relative to the mirror 60 , and this feature can be used to translate the resulting optical trap 50 . A second telescope 62 is formed from lenses L 3 and L 4 which creates a point A′ which is conjugate to point A. The diffractive optical element 40 placed at point A′ now creates a pattern of diffracted beams 64 , each of which passes through point A to form one of the trap 50 in an array of the optical traps system 10 .
In operation of the embodiment of FIG. 5 , the mirror 60 translates the entire trap array as a unit. This methodology is useful for precisely aligning the optical trap array with a stationary substrate, for dynamically stiffening the optical trap 50 through small-amplitude rapid oscillatory displacements, as well as for any application requiring a general translation capability.
The array of the optical traps 50 also can be translated vertically relative to the sample stage (not shown) by moving the sample stage or by adjusting the telescope 34 . In addition, the optical trap array can also be translated laterally relative to the sample by moving the sample stage. This feature would be particularly useful for movement beyond the range of the objective lens' field of view.
In another embodiment shown in FIG. 6 the optical system is arranged to permit viewing images of particles trapped by the optical traps 10 . A dichroic beamsplitter 70 , or other equivalent optical beamsplitter, is inserted between the objective lens 20 and the optical train of the optical trap system 10 . In the illustrated embodiment the beamsplitter 70 selectively reflects the wavelength of light used to form the optical trap array and transmits other wavelengths. Thus, the light beam 12 used to form the optical traps 50 is transmitted to the back aperture 24 with high efficiency while light beam 66 used to form images can pass through to imaging optics (not shown).
In yet another embodiment of the invention a method for incorporating foreign matter into living cells is described. It has been determined recently that optical trap devices can be advantageously used to incorporate foreign matter such as an artificial chromosome, into living cells using a combination of optical trapping, optically induced membrane fusion and optical cutting. By way of nonlimiting example, the method includes the steps of encapsulating the material to be transferred in, for example, a liposome, fusing the liposome to the cell membrane, and puncturing the juncture to effect transfer. The first step takes advantage of any of a variety of known possible encapsulation techniques. Once encapsulation is complete, the liposome can be captured with optical traps and translated toward a target cell. Depending on the material's sensitivity to light, several separate optical traps might be preferable to one, in which case holographic optical traps offer advantages to other techniques, such as scanned optical traps.
Unlike scanned optical traps which address multiple trapping points in sequence, and thus are time-shared, holographic optical traps illuminate each of their traps continuously. For a scanned optical trap to achieve the same trapping force as a continuously illuminated trap, it must provide at least the same time-averaged intensity. This means that the scanned trap has to have a higher peak intensity by a factor proportional to at least the number of trapping regions. This higher peak intensity increases the opportunities for optically-induced damage in the trapped material. This damage can arise from at least three mechanisms: (1) single-photon absorption leading to local heating, (2) single-photon absorption leading to photochemical transformations, and (3) multiple-photon absorption leading to photochemical transformations. Events (1) and (2) can be mitigated by choosing a wavelength of light which is weakly absorbed by the trapping material and by the surrounding fluid medium. Event (3) is a more general problem and is mitigated in part by working with longer-wavelength light. Multiple-photon absorption, the central mechanism of the photopolymerization part of this disclosure, occurs at a rate proportional to the intensity raised to a power (i.e., I 2 for two-photon absorption). The rates for such processes are rapidly reduced to acceptable levels by reducing the peak intensity of the trapping beam. As a result, lower intensity, continuously-illuminated holographic optical traps are preferable to time-shared scanned traps. Furthermore, the holographic optical trap method lends itself to distributing more independent traps throughout the volume of an extended object than does any scanned trap technique. In particular, holographic optical traps can distribute traps across an object's three-dimensional contours, unlike scanned traps which are limited to a single plane.
Distributing the trapping force among multiple sites on an object further permits holographic optical traps to minimize the maximum intensity and maximum force applied to any one point of the object. This may be thought of as being analogous to a bed of nails, in which any one nail could cause damage, but distributing the loading among multiple nails reduces the local force below the threshold for damage.
Consequently, holographic optical traps offer substantial benefits over both scanned traps and individual conventional optical traps. If the cell itself is motile, it also may be held in place and oriented with holographic optical traps. For some applications, for example when material must be transferred to a particular part of a cell while bypassing others, optical trap manipulation offers advantages. A single set of holographic optical traps can be used to hold both the cell and the liposome simultaneously.
As shown in FIG. 8C a cell 200 has an impermeable wall 210 , as for example in a plant cell. An optical scalpel can be used to cut away enough of the wall 210 to expose a region of cell membrane 215 for subsequent liposome fusion. The laser used for this cutting or ablation most likely will operate at a shorter wavelength than that used for holding and moving a liposome 220 and the cell 200 . Unlike trapping, where material damage is usually undesirable, cutting requires strong interaction between the focused light and the material. Consequently, the conditions discussed above for minimizing damage also provide a guide to optimizing desired damage. In particular, shorter wavelength light carries more energy per photon than longer wavelength light. Each photon absorption therefore is more likely to deliver enough energy to disrupt chemical bonds and to rearrange macromolecules in the cell wall 210 and the cell membrane 215 . The rate of all such transformations is increased in shorter wavelength light.
Once an appropriate section of the cell membrane 215 has been exposed, the liposome 220 can be moved into proximity, again using optical traps forces (see FIG. 8A ). Fusion can be accomplished either chemically, through the action of proteins or other biochemical agents incorporated into the liposome's outer leaf, or optically through one or more pulses of light directed at the liposome-membrane interface (see FIG. 8B ).
Fusion can proceed to effect the transfer in one step, or else further chemical treatment or additional pulse of light may be required to breach the membrane-liposome interface. Once the interface is breached, the liposome's contents (material 240 ) can transfer into the cell 200 through diffusion, or else can be moved into the cell 200 with one or more of the optical traps. In addition, for artificial chromosomes, for example, the material 240 can be placed directly into cell nucleus 220 by using the optical traps to transfer the matter through the cell membrane 215 and cytoplasm and, thereafter, cutting the nuclear membrane to effect transfer into the nucleus 220 directly.
Once transfer is complete, the cell 200 can be held in place for further observation before being collected. Both holding and collection can be facilitated by optical trap manipulation, particularly if the entire process described above takes place in a closed microfluidic system.
The entire process, from sample selection to cell collection can be carried out using a conventional light microscope for observation. Indeed, the same optical train used to create the optical traps and scalpel for this process also can be used to monitor its progress. If, furthermore, all steps are carried out using holographic optical traps, or a related manipulation technique, then the entire process also can be automated, with digitally recorded microscope images being used to program the pattern of optical traps and their motions.
The substance or the material 240 to be introduced into the cell 200 can be any substance and will preferably not be endogenous to the cell 200 into which it is to be introduced. Preferably the substance is a substance not normally able to cross the cell membrane. It is preferred that the substance to be introduced into the cell 200 is a hydrophilic substance, however the substance may also be hydrophobic. Any biological molecule or any macromolecule, for example, a complex of molecules, can be introduced into the cell 200 . The material 240 generally has a molecular weight of 100 daltons or more. In a more preferred embodiment, the material 240 is a nucleic acid molecule such as DNA, RNA, PNA (e.g. cDNA, genomic DNA, a plasmid, a chromosome, an oligonucleotide, a nucleotide sequence, or a ribozyme) or a chimeric molecule or a fragment thereof, or an expression vector. Additionally, the material 240 may be any bio-active molecule such as a protein, a polypeptide, a peptide, an amino acid, a hormone, a polysaccharide, a dye, or a pharmaceutical agent such as drug.
Although this discussion has focused on methods for modifying a single cell using the contents of a single liposome, the same approach could be used to fuse multiple liposomes to a single cell, and to process multiple cells simultaneously.
In another form of the invention a system and method are provided for sorting nonabsorbing particles from absorbing particles 290 is constructed (see FIG. 9 ). It has been discovered that an optical trap or trap array 300 can be advantageously formed from focused beams of laser light which operate as optical traps for some nonabsorbing particles 310 in a sample and as optical scalpels for others. Rather than precisely cutting the absorbing particles 290 as traditionally done by an optical scalpel, however, absorption of light is used to obliterate the absorbing particles 290 nonspecifically so as to reduce them to very small pieces 330 . These small pieces then can be separated from the undamaged nonabsorbing particles left behind in optical traps 320 .
An example of the utility of this method is the problem of searching for cancerous cells in a sample of blood. Ordinarily, the vast number of red blood cells in the sample would have to be separated from the candidate cancer cells before testing can begin. Light from optical traps operating in the visible range of wavelengths, for example at a wavelength of 532 nm, would be absorbed strongly by red blood cells and consequently can be used to destroy them through local heating. Other unpigmented cells, however, can be trapped by the same visible traps and manipulated for further testing. Consider, for example, an array of visible optical traps arranged with their characteristic spacing considerably smaller than the size of a red blood cell. A mixture of cells driven through this array of optical traps by an externally mediated fluid flow would encounter these optical traps. The strongly-absorbing cells would be reduced to much smaller components, such as membrane fragments through their interaction with the light. These smaller components would have a comparatively weaker interaction with the light and a small portion might be trapped by some of the traps in the array. More likely, however, they would be washed away by the fluid flow. Rather than being damaged by the light, weakly absorbing cells would encounter one or more optical traps in the array and experience a trapping force.
The intact cells would have larger and more numerous regions susceptible to optical trapping than the fragments of the destroyed cells, and therefore would be preferentially trapped by the array of optical traps. Cells localized in the array of optical traps can be transported for collection by moving the optical traps themselves, for example taking advantage of the features of an earlier application of the assignee herein, (Grier et al., application Ser. No. 09/875,812 which is incorporated by reference herein.) by moving the sample container to transport the trapped cells to a collection region within the sample container, or by periodically turning off the traps and directing the cells through a flow of fluid to a collection area. In any of these ways, the cells which do not absorb light are collected separately from the cells that do.
This approach can be generalized from sorting cells to sorting any other material whose absorption coefficients differ substantially for at least one particular wavelength of light. The benefits of this manipulation include excellent fidelity for rejecting the undesired absorbing material, and the ability to perform other active sorting steps. The same benefits would accrue to other applications of this ablative particle sorting method.
In preferred embodiments of optically ablative particle sorting, separation of nonabsorbing particles can be effected with multiple optical traps created with the holographic optical trap technique. Separation of the trapped particles from the obliterated absorbing particles could be performed with the previously disclosed techniques of active trap manipulation, optical peristalsis, or passive lateral deflection in a flow. The separation could also be performed in a microfluidics device with one channel for flushing waste products from the obliteration of absorbing particles and other channels for collecting selected nonabsorbing particles.
In previous uses of optical traps, great care was required to select a wavelength of light which would not damage any of the material to be trapped. In the present invention the goal is to select a wavelength which is absorbed strongly by the unwanted subpopulation of a mixed sample, and very weakly by the other subpopulation to be retrieved. Retrieval of the weakly absorbing subpopulation proceeds through conventional methods, and the separation in this case being effected through the passive destruction of the unwanted fraction, rather than through active selection. This could also be a preprocessing step for other analytical methods such as flow cytometry.
By way of nonlimiting example, this method could be used for early detection of cancer through blood screening. To with, several kinds of cancers in their earliest stages do not form particularly well defined tumors but, instead, define regions of abnormal cells which tend to slough into the bloodstream. In practice, detection of those cells would provide an indication that the patient has an early stage cancer. Such detection would provide at least a tentative diagnosis long before other methods requiring detection of a complete tumor or its metabolic products. Thus, this method would provide for early and more effective treatment. This can be compared with conventional separation methods of centrifugation to separate the denser, hemoglobin-bearing red blood cells from other cells carried in the blood. However, centrifugation often entrains the lighter cells with the heavier ones, thus making detection very difficult.
Using the method of the present invention, blood samples can be made to flow through an array of optical traps having wavelength and intensity that will destroy the cellular structure of the red blood cells, leaving non-red cells, such as white blood cells and possible cancer cells, intact. In fact, the red blood cells will be reduced to fragments too small to trap. In contrast, the undamaged cells can be trapped by the optical traps and transported, for example, by sequentially updating the pattern of traps, to a collection point for subsequent analysis.
In yet another embodiment of the invention a method concerns implementing spatially resolved photochemistry. Light can provide the activation energy for photochemical reactions, and in cases where one photon does not carry enough energy to initiate a photochemical reaction. The photochemical reaction still can proceed if two or more photons are absorbed simultaneously, such that the combined energy of all absorbed photons exceeds the activation threshold for the reaction. The rate at which multi-photon processes proceed depends nonlinearly on the intensity of the available light, with two-photon absorption occurring at a rate proportional to l 2 , the square of the light's intensity. This nonlinear dependence on intensity can be used to initiate photochemical reactions only in selected volumes within a larger sample and to proceed in a spatially resolved manner. The reaction only takes place in regions which are illuminated sufficiently intensely, and not in others.
Optical traps are tightly focused beams of light and, therefore, offer an ideal method for producing spatially resolved structures through photochemistry. The focal point in an optical trap is the most intense region of the illumination field. Tuning the intensity of this focal region close to the threshold for an appreciable rate of photochemical transformation facilitates controlled photochemistry in a volume comparable to the diffraction-limited focal volume of the optical trap. Whereas optical traps generally are used to trap and manipulate small volumes of matter, here they are being used to transform matter in desirable ways. Single optical traps have been used in the art to create locally intense illumination for initiating and propagating two-photon photochemistry to create photopolymerized devices as small as 10 micrometers in diameter. Defining photochemical patterns in previous conventional methods required either translating a single optical trap through the fluid precursor, or translating the fluid past the single stationary trap. In either case, the process of creating a structure by spatially-resolved photochemistry involved sequentially illuminating target volumes.
Unlike prior methods the present invention uses multiple holographic optical traps to perform spatially resolved photochemistry at multiple locations simultaneously to create structures composed of either heterogeneous or homogeneous materials. For example, in previous methods, one can use the multiple beams to draw multiple copies of the same structure at once, thus allowing the fabrication of multiple identical structures simultaneously. Alternatively, one could use multiple beams of light to simultaneously create different aspects of a single structure, thus allowing it to be made much more rapidly. Finally, separate beams can be used to create the outside structure around an extended volume and to simultaneously created interior volume structures (i.e., structures inside the separately created shell around the volume). Common to all of those techniques is the creation of a structure constituted from a homogeneous material such as a gel. Here, unlike the prior art, the unique combination of the manipulation of the optical traps and the chemical transformations effected thereby, also permit the creation of single or multiple heterogeneous structures. For example, where certain objects are preformed, particular optical traps can be used to hold them in place while other similarly focused beams of light are used to create interconnections made of photochemically transformed materials, thereby creating heterogeneous structures.
Moreover, unlike conventional optical traps, holographic optical traps use computer-generated diffractive optical elements to define multiple optical traps in any user-specified pattern in three dimensions. Each focal point in such a trapping pattern can be used to induce photochemical transformations. Computer algorithms permit placement of one or more optical traps anywhere within a three-dimensional accessible volume, and also permit independent modification of the properties of each of those traps. Creating a new configuration with the traps at a location displaced from the old trap, or where the trap properties are slightly different, can be effected by calculating and projecting a new hologram. A fixed arrangement of traps therefore can be steered through a precursor solution to fabricate multiple copies of a photochemically-defined pattern, although a sequence of small steps might be required to effect large changes. Conversely, the individual traps in a holographic optical trap array can be moved independently by calculating and projecting a sequence of computer-generated diffraction patterns with each trap's position updated as required in each pattern. This would enable multiple traps to induce photochemical transformations in multiple regions simultaneously and would be useful for efficiently addressing multiple parts of one or more photochemically-defined structures. Benefits of the holographic optical trap technique in these applications include greatly improved throughput, and the opportunity to tailor initiation and growth propagation rates locally so as to optimize material properties in the finished product which might depend on such aspects of the formation process.
In the method of the invention the holographic optical traps are utilized by photopolymerizing Norland Type 73 UV-cured adhesive and Norland type 88 UV-cured adhesive using light of wavelength 532 nm obtained from a frequency-doubled Nd:YVO 4 laser. We also have used optical traps to photopolymerize polyacrylamide from a precursor solution containing a UV-excited photoinitiator and a free-radical inhibitor.
While preferred embodiments of the invention have been shown and described, it will be clear to those skilled in the art that various changes and modifications can be made without departing from the invention in its broader aspects as set forth in the claims provided hereinafter.
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A method of manufacturing a semiconductor device able to reduce the number of manufacturing steps and attain the rationalization of a manufacturing line is disclosed. The semiconductor device is a high-frequency module assembled by mounting chip parts ( 22 ) and semiconductor pellets ( 21 ) onto each of wiring substrates ( 2 ) formed on a matrix substrate ( 27 ) after inspection. A defect mark ( 2 e ) is affixed to a wiring substrate ( 2 ) as a block judged to be defective in the inspection of the matrix substrate ( 27 ), then in a series of subsequent assembling steps the defect mark (e) is recognized and the assembling work for the wiring substrate ( 2 ) with the defect mark ( 2 e ) thereon is omitted to attain the rationalization of a manufacturing line.
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The invention herein described is a continuation-in-part of prior copending application Ser. No. 969,984, filed Dec. 15, 1978.
BACKGROUND OF THE INVENTION
The present development relates generally to fire escape devices and, more particularly, to a mechanical contrivance for extending a life saving receptacle to the immediate vicinity of an imperilled person trapped on the upper level of a burning building.
Every year numerous people are burned to death because of their inability to escape from burning buildings. Fire departments have long recognized the need for a relatively inexpensive, easily transportable piece of equipment which could be used in evacuating trapped persons from the upper levels of flame-engulfed buildings.
In 1881, U.S. Pat. No. 236,348 was issued to S. T. Mickey for a telescoping fire-escape tower apparatus which contained a flexible ladder mounted therein. Two years later Mickey was issued U.S. Pat. No. 277,049 for a similar device disposed permanently in a vault beneath the windows of a building. Both of these devices had the disadvantage that the escapee had to walk or crawl from the window sill to the door of the fire-escape tower and then climb down a flexible ladder to the ground.
Another method, considered in the past for escaping from burning buildings, has been the enclosed chute which comprises, in essence, a simple sliding board. A typical fire escape slide is described in U.S. Pat. No. 3,016,975.
A rescue device combining a segmented chute with a ladder is described in U.S. Pat. No. 3,088,542. This device is motorized and mounted to an automotive vehicle. This device has the disadvantage of being quite complex compared to the instant invention and is thus much more expensive to manufacture. The subject invention does not relate to slide or chute methods for escaping from fire.
While fire departments in many larger cities do have aerial fire trucks with long extension ladders available for rescue work, such expensive equipment is not usually available in smaller towns with lesser fire protection budgets. There is, therefore, a very real need for a relatively simple and inexpensive rescue device which can be afforded by smaller community fire departments and even volunteer fire companies.
SUMMARY OF THE INVENTION
A principal object of the present invention is to provide a mechanical contrivance for extending a life-saving receptacle to the immediate vicinity of a person imperilled by fire in a burning building.
It is another object of the invention to provide a method of egress for persons trapped in burning buildings whereby said persons can be lowered gently and safely to the ground from an upper level of a multistoried building.
It is yet another object of the invention to provide a fire escape receptacle which can be introduced directly into the window of a building and whereby a trapped person can enter the receptacle directly from his room and whereby he does not have to crawl across a dangerous catwalk or climb down a slippery or swaying ladder to safety.
It is a still further object of the invention to provide a device for rescuing persons from burning buildings which can be manufactured relatively easily and inexpensively and which can be afforded by fire departments having comparatively modest budgets.
The invention, accordingly, comprises a portable supportive base structure having attached thereto a plurality of interconnected channel members, said channel members being manually extendable by means of a winch and a series of interacting cables, and having a receptacle adapted to fit a window ledge at the terminal end of the final extendable member, said receptacle being useful for removing a trapped person from a burning building and, further, having a winch-operated cable for lowering said receptacle with a person therein safely to the ground.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the device embodying the invention.
FIG. 2 is a top plan view of the subject invention.
FIG. 3 is a schematic side view of the channel members of the device showing how said members are interconnected by means of cables and the manner in which the members are manually extended by means of a winch.
FIG. 4 is a schematic side view showing the manner in which the channel members interlock within one another when the device is retracted.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIGS. 1 and 2, the subject invention comprises a portable supportive base structure 20 to which the various operating components of the invention are attached.
Portable base structure 20 provides a rectangular framework comprising a first and second side member 22, 22' fixedly mounted to a forward bracing member 24 and an end bracing member 26. It is obvious that additional braces may be utilized to provide for the special structural integrity required to achieve the purpose of the invention. As seen in the perspective view of FIG. 1, portable base structure 20 is of a shape, design and size adequate to support the device of the invention mounted thereon.
In the embodiment shown, there are three interconnected channel members comprising, a first base channel member 30 fixedly and firmly fastened to supportive base structure 20; a second central channel member 32 slidably engaged within base channel member 30; and a third end channel member 34 slidably attached to central channel member 32. Not shown in the drawings but included in the invention are supporting tracks within base channel member 30 and central channel member 32 for the support and smooth travel of the interconnected central channel member 32 and end channel member 34, respectively. Square, rectangular or ovate-shaped channel members such as are generally available commercially, and having grooved rails or tracks therein so as to be slidably interconnectable are suitable for the invention described herein.
Supportive base structure 20 is provided with a means to extend and retract the plurality of interconnected channel members 30, 32, 34, said means comprising: a smaller winch 36 attached to a pull-out cable 38 which, in turn, passes over pulley 40 attached to the forward end of base channel member 30 and thence to fastener stud 42 located at the inner end of central channel member 32; and a larger winch 44 attached to a pull-back cable 46 which passes from larger winch 44 to fastener stud 48 at the inner end of end channel member 34, thence over pulley 50 along the floor of central channel member 32 and base channel member 30 to fastener stud 52 at the lower end of said base channel member 30.
Having reference to FIG. 3 and FIG. 4, it is necessary for the operation of the invention for pull-out cable 38 and pull-back cable 46 to be wound onto opposite sides of smaller winch 36 and larger winch 44, respectively, whereby pull-out cable 38 and pull-back cable 46 always move in opposite directions. It is further required for the proper operation of the invention that winch 44 be two times the circumference of winch 36.
Referring still to FIG. 3 and FIG. 4, when larger winch 44 is turned by means of crank handle 53 in a counter clockwise manner, central channel member 32 and end channel member 34 are caused to be extended from base channel member 30. Stops 55, 55' on the rearward end of end channel member 34, and stops 57, 57' on the rearward end of central channel member 32 retain said members within central channel member 32 and base channel member 30, respectively.
Conversely, when smaller winch 36 is turned by means of crank handle 53 in a clockwise manner, cable 46 attached to fastener stud 48 is shortened thereby pulling end channel member 34 into central channel member 32 to the point at which stops 54, 54' engage the forward end of central channel member 32 whereupon central channel member 32 is drawn into base channel member 30. Similarly, stops 56, 56' prevent central channel member 32 from penetrating base channel member 30 any further than necessary.
It is important to an understanding of the invention to know that the lengths of cables wound onto winches 36, 44 is limited and critical. There is only as much pull-back cable 46 as is shown in FIG. 3 and only as much pull-out cable 38 as is shown in FIG. 4. Excess or insufficient cable is detrimental to the operation of the channel members.
To illustrate: as pull-out cable 38 is wound counter clockwise onto winch 44, and central channel member 32 is moved forward, it is necessary for the movement of end channel member 34, that pull-back cable 46 not be of unlimited length. As seen in FIG. 3 and FIG. 4, the turning of winch 36, in a counter clockwise direction, will cause pull-back cable 46 to be released. However, prior to the full extension of the channel members there is no remaining cable on winch 36 to be released. At this point a positive force is exerted on cable 46 from the direction of the fastener stud 52 over pulley 50 to fastener stud 48, in a manner similar to that exerted on fastener stud 42 by pull-out cable 38, whereby both channel members 32, 34 are fully extended.
Ratchet wheel 58 having toothed notches therearound and controlled by winch crank 53, is located outside of supportive base structure 20 on the same axle to which winches 36, 44 are mounted whereby pull-out cable 38 and pull-back cable 46 can be locked firmly in place when said ratchet wheel 58 is engaged by pawl 60.
The final components of the invention comprise a life-saving receptacle 62 adapted for entry by at least one person and means for lowering said receptacle to the ground. As seen in FIG. 1 and FIG. 2, the life-saving receptacle 62 is attached to cable 64 which passes over pulley 66 thence down channel members 34, 32, 32 to winch 68 operated by crank handle 70 and having a brake 72 operable against drum 74 to control the descent of receptacle 62.
In actual operation, the subject fire-escape device is carried by two men to a point on the ground beneath the window to which the escape device is to be extended. After extending the channel members to the window or other opening where a person is trapped by fire or other hazard, it is only necessary for the person to get into the life-saving receptacle to be quickly and easily lowered to the ground. Alternatively, the device can be mounted on a self-propelled vehicle, or in another embodiment, can be towed into place on a mobile platform.
It will be understood that the described device is not limited to extending a receptacle to a trapped person. The life-saving device could just as easily be used to extend a rope ladder or rope to a trapped person whereby said person could descend swiftly to safety.
A preferred embodiment of this invention has been set forth in the description and drawings. These descriptions are used in the generic sense only and not for purposes of limitation. Various changes may, therefore, be made therein without departing from the spirit and scope of the invention.
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A device is described which provides egress for persons trapped in burning buildings. The invention comprises a portable supportive base structure having attached thereto a plurality of interconnected channel members which are manually extended to reach the upper levels of multi-storied buildings wherein trapped victims of fire may be located. Winches attached to the device enable an operator to position the extendable members in front of an upper level window whereupon the person being removed enters a personnel receptacle attached to the terminal end of the final extendable member and is thereupon lowered safely to the ground.
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BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a radiation therapy device comprising a radiation source and an aperture plate arrangement located between the radiation source and its object and defining a field of radiation.
2. Description of the Prior Art
U.S. Pat. No. 4,121,109 discloses a radiation therapy device having a aperture plate arrangement in which at least one aperture plate is movable. It has also been proposed to move the plates by a control device during irradiation in such a manner that it is possible to obtain an effective dose distribution that decreases in the open direction of the aperture plates.
From an article "Wedge-Shaped Dose Distribution by Computer-Controlled Collimator Motion" in Medical Physics (5), Sept./Oct. 1978, pages 426 to 429 it is known to use a defined plate motion to obtain a wedge-shaped isodose during irradiation. Such a wedge shaped isodose is frequently desired in radiation therapy in order to adjust to the anatomical conditions of the treatment subject. The wedge-shaped isodose results from the fact that different areas of the radiation field are exposed to irradiation for varying lengths of time. The requisite motion of the plate is caused by an iterative process.
The movable aperture plate can be regarded as a substitute for conventional wedge-shaped filters. It is also possible to obtain a wedge-shaped isodose curve by introducing a wedge-shaped filter between the radiation source and its object; however, in this case the filter has to be changed in accordance with each desired isodose curve.
On the other hand, the movable aperture plates have the disadvantage that the dose always increases in a predetermined direction, namely the one opposite to the opening direction of the plates.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a radiation therapy device which has greater flexibility with respect to the achieved isodose curves that are to be employed.
According to the invention, this object is accomplished by introducing in the radiation path a non-movable filter body, in addition to the movable plate arrangement, which filter body has a decreasing absorbability in the opening direction of the plate.
By this means, it is possible to obtain an isodose curve which, for example, increases in the area to be irradiated and then decreases again. Unlike arrangements which have only an exchangeable filter body and no plate with a control device, a wide variation in the isodose curves can be obtained with this arrangement, using a single filter body.
Additional objects and features of the invention will be more readily appreciated and better understood by reference to the following detailed description which should be considered in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts the schematic construction of a radiation therapy device with an electron accelerator, incorporating the principles of the invention;
FIG. 2 illustrates various isodose curves that are obtained with the arrangement according to the invention; and
FIG. 3 is a schematic arrangement of a plate, a filter body and the body of a treatment subject.
DETAILED DESCRIPTION
The basic construction of a treatment head for a radiation therapy device is shown schematically in FIG. 1. An electron beam 1 generated in an electron accelerator 2a is guided by a guide magnet 2b onto a circular path and directed through a window 3 along an axis 4. The electron beam 1 then encounters a first scattering foil 6, goes through a passage way 7 of a shield block 8 and encounters a second scattering foil 9. Next, it is sent through a measuring chamber 11, in which the radiation dose is ascertained. If the first scattering foil 6 is replaced by a target, the electron beam may also be converted into an X-ray beam. Finally, an aperture plate arrangement 12 is provided in the path of the beam, with which the irradiated field of the subject of investigation is determined. The aperture plate arrangement 12 consists of four individual plates 12a to 12d; plate 12d cannot be seen in FIG. 1, because it is covered by plate 12c. Plates 12a to 12d produce a rectangular irradiation field.
The individual plates 12a to 12d can be adjusted by hand or with a motor. In FIG. 1 this is indicated with respect to plate 12a by a drive unit 13 which is controlled by a control unit 14. In the methods described below for determining the local dose distribution, it is assumed that at least one of plates 12a to 12d can be adjusted by means of a motor.
Finally, a wedge-shaped filter 15 is provided underneath the aperture plate arrangement 12.
The construction of a treatment head for a radiation therapy device with an electron accelerator is well known to those skilled in the art and is described, for example, in greater detail in U.S. Pat. No. 4,121,109.
It is frequently desirable in radiation therapy to have a wedge-shaped isodose curve--that is, one that has a specified angle--in which case this curve has up to now been obtained by using a wedge-shaped filter. There have, however, already been proposals to adjust the isodose curve by means of a moving plate. In the known proposals, the motion of the plate is achieved by an iterative process. The requisite motion of the plate for an angle α of the isodose curve can, however, also be determined analytically by means of the following equation: ##EQU1## where v(x) is the speed of the plate 12a, I 0 and k are the dose and the dose power, respectively, in open air at the depth O, B is the field width, x is the plate position, μ the effective linear attenuation coefficient and α the desired isodose angle. This analytic approach is possible only because in this case no scattering effects of the partial fields--that is, the fields in the individual plate positions--are taken into account.
Surprisingly enough, however, it has turned out that this leads only to negligible errors. This results from the fact that the completely opened field is weighted considerably higher in time than the growing partial fields that are opened with the moved plates. In the usual isodose curves, the largest weighing factor for a partial field is only 4% of the weighing factor for the completely open field. The analytic determination of the plate motion can be performed much more rapidly by computation than an iterative process.
Various isodose curves are shown in FIG. 2. If it is assumed that the plate 12a moves from the closed position (x=0) to the opened position (x=B), then only isodoses of the types marked I or II in FIG. 2 can be generated, that is, isodoses with tanα>0. Specifically, we have:
I(x)=I.sub.O exp (-μx tanα),
since I (x)<I O and x,μ>0 the result is that tanα≧0 and 0°≦α≦90°.
This implies a limitation on the available isodose curves, which limitation can be overcome with the following arrangement described with the aid of FIG. 3. In this case, the effect of a real wedge-shaped filter 15 with a fixed angle α K and an attenuation coefficient μ K is superimposed on the system including the irradiation object and the aperture plate arrangement 12. In this case, α can also be negative. In principle, the filter can have any desired shape; the only condition that must be fulfilled is that the beam absorption decreases as the value of x increases (i.e., in the open direction of the plate 12a).
Below, we consider the configuration for a wedge-shaped filter with an angle α K . For the dose value I(x), we have:
I(x)=I.sub.S exp{μ.sub.G [d+(B-X) tanα.sub.G ]·exp[μ.sub.K (B-X) Tanα.sub.K ]}
where I S is the value of the isodose which is to travel at the depth d within the angle α G . Here the index G stands for tissue.
For the open-air dose I O at the level of the body surface (without the effect of the plate 12a and the filter 15), we have:
I.sub.O =I.sub.S exp[μ.sub.G (d+B tanα.sub.G)+μ.sub.K B tanα.sub.K)]
From which we obtain:
I(x)=I.sub.o exp[-x (μ.sub.G tanα.sub.G +μ.sub.K tanα.sub.K)]
By analogy with the considerations set forth above, the following relationship must apply:
μ.sub.G tanα.sub.G +μ.sub.K tanα.sub.K ≧0
As a result, we have: ##EQU2##
This defines the range of the possible isodose angle α G , and it is evident that both positive and negative values are possible.
For the situation in which the isodose is to have only the constant angle α G , we can derive the following motion equation: ##EQU3##
The motion equation given for an isodose with a constant angle α G can also be generalized for the situation in which the isodose has a number of different angle segments α i for the coordinates x. For the range i, the following motion equation applies: ##EQU4## For the case in which it is desired to generate isodoses that increase only in the x-direction, the real wedge-shaped filter 15 can be dispensed with, and the above equation is simplified, with tanα K =0 and μ K =0.
The use, described above, of a computer-controlled plate with the simultaneous introduction of a real wedge-shaped filter 3 permits a wide variation in the specification of the isodose curve, with the option of obtaining increasing doses in the opening direction of the plate. There is no way in which a dose curve of this kind can be obtained with movable plates alone. In principle it would be possible to establish more complex isodose curves by means of filters alone but in view of the great number of special filter shapes required, this is not practical. However, with the combination of a movable plate and real wedge-shaped filter as presented here, a wide range of variation in the determination of isodoses is obtainable, even with a single wedge-shaped filter and even for several different angle segments.
Even for complicated isodose curves, the motion equation for the plate can be obtained by purely analytic methods; in other words, time-consuming iterative computation processes are not required.
There has thus been shown and described a novel radiation therapy device which fulfills all the objects and advantages sought for. Many changes, modifications, variations and other uses and applications of the subject invention will, however, become apparent to those skilled in the art after considering the specification and the accompanying drawings which disclose an embodiment thereof. All such changes, modifications, variations and other uses and applications which do not depart from the spirit and scope of the invention are deemed to be covered by the invention which is limited only by the claims which follow.
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In a radiation therapy device isodose curves are adjusted both by a movable plate that is controlled during the irradiation and by a non-movable filter body in the radiation path. The filter body is located in such a manner that it has decreasing absorbability in the opening direction of the plate. On the other hand, the plate produces a decreasing effective dose in its opening direction. by superimposing the two effects, it is possible to have the isodose curve in the object of irradiation rise or fall in the opening direction, so that a wide range of variation in the possible isodose curves is obtained, without having to change the fixed filter body.
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BACKGROUND OF THE INVENTION
[0001] The present invention relates to lawn and garden equipment, in particular, the present invention relates to a lawn apparatus known as an aerator. Aerators are generally used to punch holes in soil or to remove cores from soil of approximately one half inch in diameter and three inches long to allow air and moisture and nutrients to enter the soil.
[0002] Several problems are present in existing aerators. The most common form of aerator has a reel or a tine assembly equipped with coring tubes or tines that are positioned on the reel or the tine assembly so they extend radially outwardly from the central shaft of the reel. The tines or coring tubes, in addition to providing aeration, provide propulsion for the aerator. As the assembly rotates, the tines rotate and punch into the ground to remove a core from the ground and also push the aerator forward. This arrangement provides excellent traction to propel the aerator along the lawn. However, it presents a substantial impediment to turning the device in a sharp turn, or to making a turn of sufficiently small radius to allow the operator of the aerator to make a second pass across the lawn immediately laterally adjacent to the previous pass. Typically, to accomplish a small radius turn, the user must expend substantial effort to force the aerator into position by lifting the front wheels or rear wheels of the aerator with the handle to remove the tines from the ground and to allow pivoting on one of the aerator wheels. Alternatively, if the tines are left in contact with the ground and allowed to propel the aerator, a turn having a large radius—on the order of eight to ten feet-only can be accomplished. As aerators typically weigh between two and three hundred pounds, the repetitive lifting of the device by the operator can be exhausting to the operator. This can present a serious problem during the operation of a reasonably dangerous piece of equipment.
[0003] Yet another problem that exists with current aerators is the assembly of the plugging or coring tines on the reel or tine assembly of the aerator. Typically, aerators have coring tines which are sandwiched between parallel mounting plates. The tines are held in place by bolts passing through the mounting plates and through the tines. The mounting plates are then, typically, welded onto a shaft or a tube which is then mounted onto a shaft to comprise the coring tube reel. It is very difficult, if not impossible, for a user of the device to replace individual components of such a welded tine wheel assembly. In addition, the connection of the tine wheel assembly to the frame of the aerator makes it difficult for a user to remove the tine wheel assembly if it is possible to replace any parts of the tine wheel assembly.
[0004] Therefore, it would be an advantage, and is an object of the present invention to provide an aerator which allows the user to change the direction of travel of the aerator while reducing the need to manually lift the aerator tines out of contact with the ground.
[0005] Yet another object of the present invention is to provide an aerator that offers a much smaller turning radius and allows the user to re-position the aerator on the reverse line of travel adjacent to the previous line of travel with greatly reduced effort by the operator and without the need to lift and pivot the aerator to achieve pivoting on the front support or wheel of the aerator.
[0006] Another object of the present invention is to provide a tine assembly which is easily removable from the aerator and which allows the operator of the aerator to easily change the type of tine which is mounted on the aerator and the number of tines and the spacing between individual tine wheels to allow near complete user selection of the type of aeration process being achieved. It would be a great benefit to users and the small equipment rental industry if an aerator was provided with a easily removable tine wheel assembly which allowed the user to replace any damaged part of the tine wheel assembly.
[0007] Yet another object of the present invention is to provide an aerator having a differential in the front axis of the device to allow great maneuverability of the aerator as it is operated.
[0008] Another object of the present invention is to provide a front axle having a differential in combination with castered rear wheels to further improve the maneuverability of the aerator.
SUMMARY OF THE INVENTION
[0009] The present invention provides an aerator having a tine wheel assembly which is easily removable by an operator. Further, the present invention provides a tine wheel assembly which allows the operator to change the spacing between tine wheels and to change the number and type of tines included in each tine wheel and to individually replace tines which have become damaged. A differential is provided in the front axle to increase maneuverability and to allow the user to reduce the need for manually lifting the aerator by its handle in order to and to reduce the need to remove the tine wheels from contact with the ground during the maneuvering of the aerator. The present invention also provides a combination of a front axle differential with castered rear wheels to assist in maneuverability of the device. Further, the present invention allows the tine wheel assembly to be raised from contact with the earth while power is supplied to the differential of the front axle to assist in maneuverability of the present invention. Another feature of the present is a non-welded, easily removable tine wheel assembly which permits the user to easily replace components of the assembly.
[0010] The foregoing and other objects are intended to be illustrative of the invention and are not meant in a limiting sense. Many possible embodiments of the invention may be made and will be readily evident upon a study of the following specification and accompanying drawings comprising a part thereof. Various features and subcombinations of invention may be employed without reference to other features and subcombinations. Other objects and advantages of this invention will become apparent from the following description taken in connection with the accompanying drawings, wherein is set forth by way of illustration and example, an embodiment of this invention.
DESCRIPTION OF THE DRAWINGS
[0011] [0011]FIG. 1 is the right side and top perspective view of the aerator of the present invention;
[0012] [0012]FIG. 2 is an enlarged fragmentary view of the tine wheel assembly of FIG. 8 and which is shown in FIG. 2 from a direction which is the reverse of that shown in FIG. 8;
[0013] [0013]FIG. 3 is a front and right side perspective view of a tine wheel;
[0014] [0014]FIG. 4 is an exploded view of the tine wheel shown in FIG. 3.
[0015] [0015]FIG. 5 shows the lift handle of the present invention when not engaged;
[0016] [0016]FIG. 6 shows the lift handle of the present invention engaged to assist in lifting the present invention;
[0017] [0017]FIG. 7 is a front and top perspective view of the engine and power transfer assembly of the present invention;
[0018] [0018]FIG. 8 is a front and bottom perspective view of the present invention showing the differential on the front axle of the present invention and showing the tine wheel assembly in position on the front frame of the present invention; and
[0019] [0019]FIG. 9 is an exploded view of the engine and drive train of the present invention and showing the idler pulley and the connection of the drive chains to the differential and to the tine wheel assembly.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0020] Referring now to FIG. 1, the preferred embodiment of the present invention is shown as aerator 10 . In its general configuration, aerator 10 is comprised of handle 12 which is attached to front frame 14 which contains the operational components of aerator 10 . Attached to front frame 14 is rear frame 16 which is pivotally connected to front frame 14 by bolts 18 . Castered wheels 20 are connected to rear frame 16 and allow the rear of aerator 10 to be easily moved any direction while relying on one of non-castered wheels 22 to act as a pivot for the move of castered wheels 20 . Front frame 14 also holds engine 24 which provides the power for forward movement of aerator 10 and which provides the power for rotation of tine wheel assembly 26 . Also mounted on front frame 14 is weight 28 which is fitted onto weight pins 30 . Weight 28 provides additional downward force on tine wheel assembly 26 to assist in forcing tines 32 of tine wheel assembly 26 into the ground as aerator 10 is operated.
[0021] Still referring to FIG. 1, aerator 10 is guided along its path by an operator grasping handle 12 . Within reach of handle 12 , the operator also can control rear frame lift bar 34 which is connected to rods 36 and which are attached to lift flange 38 . Lift flange 38 is pivotally mounted onto front frame 14 and is movable between a first position and a second position to raise or lower rear frame 16 with respect to front frame 14 . A user will wish to raise front frame 14 with respect to rear frame 16 when it is desired to disengage tine wheel assembly 26 from contact with the ground. Conversely, when the user wishes to engage tine wheel assembly with the ground, the user will pull rear frame lift bar toward handle 12 to raise rear frame 16 with respect to front frame 14 and thereby lower tine wheel assembly 26 into contact with the ground. Another component available to the user and which is mounted on handle 12 is engine throttle 40 which permits the user to advance the engine speed. Also mounted on handle 12 is power engagement bar 42 to which is attached cable 44 . As will be later described, cable 44 is connected to an idler pulley which compresses and releases a belt to transfer power between engine 24 and drive shaft 86 (FIG. 7).
[0022] Referring now to FIG. 2, tine wheel assembly 26 will be described in greater detail. Tine wheel assembly 26 is attached to front frame 14 by pillow bearings 46 . Use of pillow bearings 46 provides the advantage that when maintenance work must be performed upon tine wheel assembly 26 , the entire tine wheel assembly 26 may be removed conveniently and easily by simply unbolting pillow bearings 46 from front frame 14 and removing wheel assembly 26 from beneath aerator 10 . This easy removal of tine wheel assembly 26 and is an important feature of the present invention which, among its other benefits, allows the user to replace individual tines 32 or other component of tine wheel assembly 26 which have become damaged during use of aerator 10 . In addition tine wheel assembly 26 is assembled or constructed without any parts being welded together. Each part of the tine wheel assembly of the present invention can be disassembled thereby allowing the user to replace any part of the tine wheel assembly as desired.
[0023] Referring now to FIGS. 2, 3, and 4 , the construction of tine wheel assembly 26 will be described in detail. Assembly 26 , in general, is comprised of a number of tine wheels 48 mounted on a shaft 50 . Tine wheels 48 are separated by spacers 52 which may be of whatever length the user believes to be appropriate for the work at hand. Each of tine wheels 48 is comprised of a pair of tine lock plates 54 a , 54 b which have secured therebetween a number of tines 32 . Tine lock plates 54 a , 54 b are spaced apart by plate spacer 53 . Plate spacer 53 protects shaft 50 and maintains tine lock plates 54 a , 54 b at the appropriate distance apart for the particular tine size which is mounted on tine wheel 48 . Each of tines 32 is held in place between the opposed tine lock plates 54 by a single mounting bolt 56 . The mounted tine 32 is further supported during operation by support bolt 58 which resists the force placed against tine 32 as tine 32 meets the ground during operation.
[0024] Referring now to FIGS. 3 and 4, the assembly of tine wheels 48 and tine wheel assembly 26 will be described. In FIG. 3, a tine wheel 48 is shown with five tines extending therefrom. It should be appreciated that a greater number or a fewer number than five tines can be assembled onto tine wheel 48 . This is accomplished through the use of either providing additional mounting holes or providing alternate tine lock plates 54 which are prepared to hold a greater or lesser number of tines. It will also be appreciated that in any of such tine lock plates which are used in tine wheel 48 that the diameter of the tines can be varied depending on the type of operation being performed. For example, in some cases, the operator may simply wish to use a narrow spike to poke holes into the ground and not actually remove a core of ground as will the tines 32 shown in FIG. 4. In such a case the operator will simply change the length of spacers 52 and 53 to take-up any extra space along shaft 50 .
[0025] Referring now to FIG. 4, each tine wheel 48 is assembled by securing each of tines 32 between tine lock plates 54 a , 54 b with mounting bolts 56 which pass through mounting void 60 of tine 32 and through the opposed tine lock plate 54 where the mounting bolt 56 is secured by a nut 62 . When the tines have been mounted between lock plates 54 , support bolts 58 are introduced to pass through tine lock plates 54 and also are secured with a nut 62 . When the assembled tine wheel is to be mounted on shaft 50 , shaft 50 is passed through drive engagement voids 66 of tine lock plates 54 a , 54 b . It will be appreciated that drive engagement void 66 shown in the present embodiment is rectangular in shape to match shaft 50 which also is rectangular. This shaping of shaft 50 provides a power transferring means which communicates the rotational power of the shaft from to shaft to at least one of tine wheels 48 while avoiding the use of welded connections between the shaft 50 and the tine wheels 48 . It will be appreciated that such welded or permanent connections between the shaft and the tine wheels or other device mounted on shaft 50 would prevent a user from being able to dismantle the tine wheels from the shaft to replace damages parts or to reconfigure the tine wheels on shaft 50 . Alternate shapes can such a hexagonal or pentagonal cross-section and which are effective for transferring power also could be used for shaft 50 and drive engagement void 66 . Those skilled in the art will appreciate that a round shaft cross-section and a round engagement void 66 would not accomplish a transfer of power from shaft 50 to the tine wheel 48 which is slidably mounted thereon.
[0026] Referring now to FIGS. 5 and 6, a lift handle and lockout means will be described which permits the user to conveniently lift aerator 10 which is both a bulky and heavy object. Also the lift handle, simultaneously prevents rear frame 16 from collapsing against front frame 14 during the manual movement of aerator 10 .
[0027] Referring now to FIG. 5, lift handle 70 is shown in its unused position in which it is pivoted against rear frame 16 of aerator 10 . When the operator wishes to lift aerator 10 to place aerator 10 in the back of a vehicle or to lift aerator 10 over an obstacle such as a low wall or other obstruction, the user, after shutting down engine 24 , pulls rearwardly on rear frame lift bar 34 . This draws lift flange 38 into the position which lowers rear frame 16 , thus effectively raising front frame 14 and tine wheel assembly 26 off the ground. The user then grasps lift handle 70 and pulls outwardly causing lift handle 70 to rotate around pivot 72 and place lockout flange 74 underneath lift flange 38 . This prevents inadvertent shifting of lift flange 38 into the position which would raise rear frame 16 and which could result in the pinching of the fingers of the user's other hand or the fingers of another person who has placed their hands about rear frame 16 to assist in lifting aerator 10 . Once aerator 10 has been moved into its new position, user simply releases lift handle 70 which pivots back into its at rest position shown in FIG. 5 and restores lift flange 38 to an operable mode.
[0028] Referring now to FIGS. 7 and 8, the power train of the present invention will be described. As previously mentioned, the use of a front axle differential in combination with castered rear wheels assists in the maneuverability of aerator 10 and reduces the amount of effort required by the user to turn aerator 10 into a reverse path. This combination also reduces the turning radius required by the present invention as compared to other aerator devices. In FIG. 7, engine power takeoff pulley 80 is shown attached to engine 24 . Belt 82 passes around engine power takeoff pulley 80 and transfers the power to drive shaft pulley 84 which is part of power shaft 86 . Also mounted on power shaft 86 by means of gears are differential chain drive 88 and tine wheel assembly chain drive 90 .
[0029] Referring to FIGS. 8 and 9, the connection of differential chain drive 88 is shown on differential 92 and the connection of tine wheel chain drive 90 is shown connecting to a gear which is a part of tine wheel assembly 26 . It will be appreciated that engine power takeoff pulley 80 (FIG. 9) is always rotating when engine 24 is operating although use of engine throttle 40 may reduce or increase the amount of torque being applied to engine power takeoff pulley 80 . Therefore, as shown in FIG. 9, to engage and disengage the transfer of power from engine power takeoff pulley 80 to drive pulley 84 an idler pulley 98 is used to compress belt 82 sufficiently to cause rotation of drive pulley 84 or to release tension on belt 82 and to provide enough slack that drive pulley 84 does not rotate. Referring to FIG. 7, the tensioning and release of idler pulley 98 is accomplished by the user compressing power engagement bar 42 (FIG. 1) against handle 12 which causes tension on cable 44 which is passed to spring 94 which pulls on idler pulley flange 96 and compresses idler pulley 98 against belt 82 to transfer power from engine power transfer pulley 80 to drive pulley 84 .
[0030] It will be appreciated by those skilled in the art that at all times when drive pulley 84 is engaged, power is transferred to both tine wheel assembly 26 and to differential 92 . This allows the user to better manipulate the path of travel of aerator 10 when tine wheel assembly is engaged in the ground and especially when the tine wheel assembly has been disengaged from the ground as previously described. The combination of differential 92 on front axle 100 of aerator 10 and the castered wheels at the rear of aerator 10 and the ability to mechanically raise the tine wheel assembly while having power to the front axle, provides the user with far greater maneuverability of aerator 10 than is available in other conventional aerators which either do not have a front axle having a differential or instead of a front axle have a large hollow drum, usually filled with water, to add weight to the aerator. In a typical circumstance, the prior art type of aerator using a weighted drum as a front axle or an axle not containing a differential will require a turning radius of 10 to 15 feet to reverse the direction of the aerator. The present invention reduces this turning radius to a distance of 2 to 5 feet depending upon the slope of the ground being worked.
[0031] In the foregoing description, certain terms have been used for brevity, clearness and understanding; but no unnecessary limitations are to be implied therefrom beyond the requirements of the prior art, because such terms are used for descriptive purposes and are intended to be broadly construed. Moreover, the description and illustration of the inventions is by way of example, and the scope of the inventions is not limited to the exact details shown or described. Certain changes may be made in embodying the above invention, and in the construction thereof, without departing from the spirit and scope of the invention. It is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not meant in a limiting sense.
[0032] Having now described the features, discoveries and principles of the invention, the manner in which the inventive aerator is constructed and used, the characteristics of the construction, and advantageous, new and useful results obtained; the new and useful structures, devices, elements, arrangements, parts and combinations, are set forth in the appended claims. It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
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An aerator is provided having a front axle, including a differential and a tine wheel assembly which may be raised from the ground during maneuvers of the aerator while power continues to be supplied to the front axle, and a tine wheel assembly is provided which allows the operator to repair and change the configuration of the tines of the tine wheel assembly.
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TECHNICAL FIELD
The present invention relates to devices for diffusing gas into liquid, and more particularly to a system to be submerged in a liquid for the efficient contacting of air or other gas to a liquid in the aeration treatment of water, fluids, industrial wastes, processed liquids, or the like.
BACKGROUND ART
Gas diffusion devices and systems have long been used to control the distribution of gas in processes which require aeration treatment. In such processes, the gas diffusion system is located below the liquid surface and is connected to a source of gas supply.
One type of gas diffusion device known in the art is constructed of a porous medium. Numerous small openings in the porous medium break the gas into small bubbles thereby increasing the gas/liquid contact. A drawback of the prior art porous device is that the porous medium has a tendency to clog, thereby reducing or completely stopping the aeration process.
Another type of gas diffusion device known in the art is the hollow-body diffuser, such as that shown in U.S. Pat. No. 4,421,696 to Graue, et al. The Graue et al diffuser is a hollow body having a plurality of slot-shaped ports disposed in a vertical distribution tube through which gas is released. Immediately above the distribution tube is a frustro-conical directional distribution surface upon which the gas streams exiting the ports impinge. The directional distribution surface evenly distributes the gas streams as they rise. The frustro-conical directional distribution surface terminates at a shear edge upon which gas bubbles are dispersed to the liquid. A plurality of drift control vanes are provided to equalize the spread of gas streams exiting each part. While the Graue, et al diffuser has been highly successful in many applications, it has been found that the prior diffuser alone is less than optimum as regards energy use and aeration efficiency in certain applications, such as those requiring deep aeration.
SUMMARY OF THE INVENTION
The present invention provides an improved system for diffusing gas into a liquid which substantially improves or eliminates the aforesaid deficiencies in prior art diffusion systems. In preferred form, the system of the present invention includes a lower gas diffuser constructed in accordance with the Graue, et al patent described above. The lower gas diffuser is gas-tightly connected to a conduit extending out of the liquid to a source of gas supply. Mounted above the lower gas diffuser on the conduit is an upper gas diffuser which includes a gas distribution surface having a larger maximum dimension than a lower gas distribution surface on the lower gas diffuser. Bubbles released from the lower gas diffuser impinge upon the upper gas distribution surface for further distribution and mixing. Preferably, a draft conduit extends between a location adjacent the upper gas diffuser to a location in proximity to the tank bottom. The lower gas diffuser is enclosed by the draft conduit, such that liquid is pumped up through the draft conduit by the action of bubbles, thereby maintaining a homogeneous mixture of tank contents.
BRIEF DESCRIPTION OF THE DRAWINGS
A more complete understanding of the invention and its advantages will be apparent from the Detailed Description taken in conjunction with the accompanying Drawings in which:
FIG. 1 is a partially broken-away side view of a gas diffusion system constructed in accordance with the invention;
FIG. 2 is a sectional view taken along lines 2--2 of FIG. 1;
FIG. 3 is a sectional view taken along lines 3--3 of FIG. 1;
FIG. 4 is a perspective view of the upper gas diffuser illustrated in FIGS. 1, 2 and 3; and
FIG. 5 is a side view of an alternate embodiment of an upper gas diffuser usable in accordance with the present invention.
DETAILED DESCRIPTION
Referring initially to FIGS. 1, 2 and 3, gas diffusion system 10 is intended for use in connection with a liquid-filled tank having a liquid top surface 12 and a tank bottom surface 14. System 10 includes a gas conduit 16 extending downwardly into the liquid 17. Gas conduit 16 is a tubular member having a vertical central axis with a cylindrical exterior surface 18 and a cylindrical inner surface 20 (FIG. 3). Gas conduit 16 includes an upper means for coupling (not shown) the interior surface 20 to a source of gas supply (not shown).
Conduit 16 terminates at a lower means for coupling 30, where a lower gas diffuser 32 is gas-tightly connected to conduit 18. In the preferred embodiment of the invention, lower gas diffuser 32 is a gas diffuser constructed in accordance with the Graue, et al patent identified above. The disclosure of the Graue, et al patent, U.S. Pat. No. 4,421,696 issued Dec. 20, 1983, is hereby expressly incorporated herein by reference. Lower gas diffuser 32 includes a lower gas distribution surface 34, a lower shear edge 36, and a plurality of gas outlets 38. Lower gas distribution surface 34 has a maximum dimension defined by shear edge 36. In other words, the maximum dimension of lower gas distribution surface 34 is defined herein as the length of shear edge 36, that is, the circumference of shear edge 36. In the event an equivalent but non-circular cross-sectioned shear edge is utilized, the total perimeter of the shear edge would define the maximum dimension of lower gas distribution surface 34.
Referring now to FIG. 4 in addition to FIGS. 1, 2 and 3, an upper gas diffuser 50 is fixed with respect to the exterior surface 18 of gas conduit 16 at a pre-determined distance above lower gas diffuser 32. Upper gas diffuser 50 includes an upper gas distribution surface 52 terminating at an upper shear edge 54. As shown in FIG. 1, upper gas distribution surface 52 is vertically spaced apart from lower gas distribution surface 34 on lower gas diffuser 32.
Upper gas diffuser 50 is supported by the exterior surface 18 of gas conduit 16 by way of collars 60 and 62. Collars 60 and 62 include clamping screws 64 for engagement with exterior surface 18 of gas conduit 18 in conventional fashion.
Upper gas diffuser 50 includes interior walls 66 and 68 defining a passageway therethrough and enclosing a portion 70 of gas conduit 16. Upper gas diffuser 50 also includes upper and lower portions 72 and 74 formed by cylindrical walls being sized slightly more largely than exterior wall 18 of gas conduit 16. As shown in FIG. 2, collars 60 and 62 vertically fix upper gas diffuser with respect to gas conduit 18, but no portion of upper gas diffuser 50 is in communication with the interior wall 20 of gas conduit 16.
Upper gas distribution surface 52 is bell-shaped and coaxial with the vertical central axis of the lower distribution surface 34 and gas conduit 18. Upper gas distribution surface 52 diverges in an upward direction and is concave outwardly and downwardly, as best shown in FIGS. 2 and 4. Upper gas distribution surface 52 terminates at a sharp circular upper shear edge 54, and upper gas distribution surface 52 extends from lower portion 74.
A plurality of drift control vanes 80 extend from the lower portion 74 to shear edge 54. The drift control vanes are equally spaced radially from the vertical central axis of upper gas diffuser 50. Each drift control vane 80 includes a linear outer edge 82 and a curved inner edge 84 coextensive with upper gas distribution surface 52. Each drift control vane 80 is planar and extends outwardly in a radial direction from the vertical central axis of gas diffuser 50.
In preferred form, system 10 includes a draft conduit 100 comprising a tubular member coaxially fixed with respect to upper and lower gas diffusers 50 and 32 and gas conduit 16. Draft conduit 100 has a circular lower opening 104 located adjacent to but spaced apart from tank bottom surface 14 to allow ingress of liquid therethrough. Cylindrical interior walls 106 enclose lower gas diffuser 32, portion 108 of gas conduit 16, and at least a portion of upper gas diffuser 52 as shown in FIGS. 1 and 3. Draft conduit 100 has a circular upper opening 110 located in proximity to but spaced apart from upper gas distribution surface 52 and edges 82 of drift control vanes 80.
Upper gas distribution surface 50 has a maximum dimension defined by the perimeter of upper shear edge 54, in the same fashion as the maximum dimension of lower gas distribution surface 34 is defined as described above. In preferred form, as shown in FIG. 1, upper shear edge 54 has a larger perimeter than lower shear edge 36, such that upper gas distribution 52 has a larger maximum dimension than lower gas distribution surface 34.
Referring now to FIG. 5, upper gas diffuser 200 is an alternate embodiment of upper gas diffuser 50 shown in FIGS. 1, 2, 3 and 4. Upper gas diffuser 200 can be utilized when an increased diameter upper gas diffuser is preferred. In this alternate embodiment, a bell-shaped upper gas distribution surface 202 extends between a lower opening 204 and an upper shear edge 206. In this embodiment, however, drift control vanes 208 do not extend to lower portion 204 but terminate at an intermediate location defined by dotted line 210.
In operation, the preferred embodiment includes a gas conduit 16 having a one inch diameter with a draft conduit 100 having a 12 inch diameter. Draft tube 100 could be as long as 15 to 20 feet long in a tank having a liquid depth of 30 feet. Lower opening 104 is typically located 1 to 2 feet above tank bottom 14 and is supported independently of gas conduit 18, lower gas diffuser 32 and upper gas diffuser 50. Preferably, lower diffuser 32 is located at least one-third the distance from the upper opening 110 of draft conduit 100.
Upper and lower gas diffusers 50 and 34 are manufactured from ABS plastic and have high impact characteristics, as well as the ability to retain their original mechanical properties. Aerobic digesters, anaerobic digesters, and the like can be completely aerated in an energy efficient manner, because as bubbles are released from lower gas diffuser 34 they rise through draft tube 100 causing a pumping action of liquid. The air and water mixture resulting from the pumping action is directed in a horizontal direction by upper gas distribution surface 52. Drift control vanes 80 prevent coalescence while directing and equally separating the air/water mixture. Because of the strong pumping action, many air bubbles remain entrapped in the system. Greater energy efficiency is achieved because the vertical elevation of the gas outlet ports may be submerged at a location having less depth than with other aeration methods. One skilled in the art will readily appreciate that energy use is directly related to the depth of the gas outlet location.
While particular embodiments of the present invention have been described in detail herein and illustrated in the accompanying drawings, it will be evident that various further modifications are possible without departing from the scope of the invention.
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A gas diffusion system for use in aeration treatment of water, sewage, industrial waste and the like is provided. Gas is released from a lower gas diffuser and rises under the influence of buoyancy and impinges upon an upper gas diffuser having a larger maximum dimension than the lower gas diffuser. In preferred form, a draft conduit is utilized to cause pumping of liquid from the bottom of the liquid tank.
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CLAIM OF PRIORITY
This application makes reference to, incorporates the same herein, and claims all benefits accruing under 35 U.S.C. §119 arising from an application for Device For Switching Paper Passage in Multi-Functional Image Producing Apparatus earlier filed in the Korean Industrial Property Office on Feb. 13, 1996 and there duly assigned Ser. No. 3417/1996.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates, in general, to a device for controlling the paper passage in an image producing apparatus and, more particularly, to a device for switching the paper passage between an original document passage and a copy paper passage in a multi-functional image producing apparatus selectively used as a facsimile, a copying machine and a printer.
2. Description of the Prior Art
The use of electromagnetic sheet diverters is not new in the art. For example, U.S. Pat. No. 4,518,161 for a Sheet Sorting Apparatus to Nakamura discloses an electromagnetically operated sheet sorting apparatus. Sheets originate from a common path and are diverted by the magnetically controlled sheet diverter to one of the two paths.
U.S. Pat. No. 2,076,700 for a Sorting Machine to Bryce discloses an electromagnetic sheet diverter controlled by a solenoid. Sheet diverters and are used to discharge sheets of paper from an image forming apparatus. A magnet serves to trigger a sheet deflector.
Finally, U.S. Pat. No. 5,394,992 for a Document Sorter to Winkler discloses a document sorter which is magnetically operated. Once again, a magnet triggers the sheet diverter which determines which direction and path a sheet will be discharged from the image forming apparatus.
What is needed is a compact sheet diverter designed to operate in a compact desktop image forming apparatus. The compact sheet diverter has a compact electromagnet and a compact rotating member which serves to divert a piece of paper between one of two paths. The sheet diverter is operated automatically by a control unit so that original documents are diverted automatically down one path and copy paper is automatically diverted down another path.
SUMMARY OF THE INVENTION
It is, therefore, an object to provide a sheet diverter for an image forming apparatus that can select between one of two paths in which a sheet of recording medium is to be discharged from the machine.
It is also an object to provide a compact electromagnetic sheet diverter that can be used on desktop image forming equipment.
In order to accomplish the above object, the present invention provides a device for switching the path of discharge so that originals fed into one input tray emerge at one output tray, and recording sheets that originate from a separate input tray are discharged onto a separate tray. The sheet diverter is made up of a holding bracket fixedly arranged on a position just after the distributing roller. An electromagnet is mounted to the holding bracket. A paper diverting member is rotatably mounted to a housing of the apparatus by a hinge shaft and is biased by a tension coil spring. The paper diverting member is selectively attracted by and brought into contact with the electromagnet only when the magnet is activated. A longitudinal shaft is tightly held by the paper diverting member and is selectively rotated along with the paper diverting member when the magnet is activated. The longitudinal shaft has a plurality of fitting grooves, which are spaced out at regular intervals and have a D-shaped cutting configuration. A plurality of passage switching members are fixed to the respective fitting grooves of the longitudinal shaft and are selectively rotated along with the longitudinal shaft, thus switching the paper passage between the original document passage and the copy paper passage.
BRIEF DESCRIPTION OF THE DRAWINGS
A more complete appreciation of this invention, and many of the attendant advantages thereof, will be readily apparent as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings in which like reference symbols indicate the same or similar components, wherein:
FIG. 1 is a view showing the construction of a facsimile which is an example of an image producing apparatus provided with a paper passage switching device according to the present invention;
FIG. 2 is a partially-exploded perspective view showing the construction of a paper passage switching device in accordance with the preferred embodiment of the present invention; and
FIGS. 3A and 3B are side views showing the operation of the paper passage switching device of FIG. 2.
DESCRIPTION OF THE INVENTION
FIG. 1 is a view of a facsimile which is an example of an image producing apparatus provided with a paper passage switching device according to the present invention. As shown in FIG. 1, the facsimile 100 has an image transmitting part which is integrated with the image receiving part. In the image transmitting part, a document feed tray 40 is mounted to one side (the right-hand side in the drawing) of the facsimile 100 and holds original documents 50 thereon. During image transmission, the frictional force between each document 50 and a motor-driven document feed roller 32 is larger than either the frictional force between the documents 50 or the frictional force between each document 50 and the rubber pad of the document feed roller 32. Therefore, each document 50 passes by the document feed roller 32 and return roller 33 and in turn is fed to a contact image sensor 42. The contact image sensor 42 reads and transmits the image data written on the document 50.
In the above state, a scanning white roller 34, which is arranged under the contact image sensor 42, checks the reference data prior to reading the data of the document 50 and frictionally feeds the document 50 to the roller 35 while reading the data of the document 50. Prior to feeding the document 50, an LED of the contact image sensor 42 emits light and senses the return light, which is reflected by the white roller 34, by an optical sensor thereby checking the reference data. Thereafter, the data is coded and compressed prior to being transmitted through a telephone line. The document 50 from the roller 35 passes by a photosensitive drum 36 and is fed to the fixing part or the nip between the heating roller 37a and the pressure roller 37b, and is fed to a distributing roller 38. The document 50 is, thereafter, fed to the document discharge roller 39 thus finishing the image transmitting operation.
In the above image transmitting operation, the photosensitive drum 36, heating roller 37a and pressure roller 37b do not perform their intrinsic operational functions, but are only used as document feeding rollers.
In operation of the image receiving part integrated with the image transmitting part, the outer surface of the photosensitive drum 36 is uniformly charged with electricity due to corona discharge of a charged body (not shown) installed in the facsimile 100. The photosensitive drum 36 in the above state is rotated, so that the charged surface of the drum 36 is exposed to the electric image signals from a light exposing unit (not shown) thereby forming an electro-static latent image on the charged surface of the drum 36. The electro-static latent image of the photosensitive drum 36 in tum is developed by toner thus forming a visible image on the drum 36 while the rotated drum 36 passes by the developing unit (not shown), which is arranged at a position in the vicinity of the photosensitive drum 36. A sheet of copy paper 30, which is contained in the paper cassette 43, is fed by the motor-driven copy paper feed roller 31. The visible image of the photosensitive drum 36 is thus transcribed onto the copy paper 30 due to the high voltage operation of a transcriber (not shown) The copy paper 30 is, thereafter, fed to the nip between the heating roller 37a and the pressure roller 37b, so that heat and pressure are applied to the paper 30 thereby fixing the image on the paper 30. The copy paper 30 with the image in turn is fed to the distributing roller 38 and is discharged onto a copy paper tray 41, thus finishing the image receiving operation. In the above image receiving operation, toner and latent image remain on the outer surface of the photosensitive drum 36 after the visible image is transcribed onto the copy paper 30. The toner remaining on the drum 36 is removed by a cleaner (not shown), while the latent image remaining on the drum 36 is removed by a latent image erasing lamp (not shown).
The facsimile 100 also has a copying part. In the facsimile 100, the document feed tray 40, which is mounted to the rear portion of the facsimile 100, holds documents 50. In operation of the copying part, the frictional force generated between each document 50 and the motor-driven document feed roller 32 is larger than either the frictional force between the documents 50 or the frictional force between each document 50 and the rubber pad of the document feed roller 32. Therefore, each document 50 passes by the document feed roller 32 and return roller 33 and is fed to the contact image sensor 42. The contact image sensor 42 reads and transmits the image data written on the document 50.
In the above state, the scanning white roller 34, which is arranged under the contact image sensor 42, checks the reference data prior to reading the data of the document 50 and frictionally feeds the document 50 to the roller 35 while reading the data of the document 50. Prior to feeding the document 50, the LED of the contact image sensor 42 emits light and senses the return light, which is reflected by the white roller 34, by the optical sensor thereby checking the reference data. Thereafter, the document 50 is fed to the nip between the heating roller 37a and the pressure roller 37b by way of the photosensitive drum 36 and in turn is fed to the distributing roller 38. In the above operation, the photosensitive drum 36, heating roller 37a and pressure roller 37b do not perform their intrinsic operational functions, but are only used as document feeding rollers. At the same time, the outer surface of the photosensitive drum 36 is uniformly charged with electricity due to corona discharge of the charged body installed in the facsimile 100. The photosensitive drum 36 in the above state is rotated, so that the charged surface of the drum 36 is exposed to the electric image signals from the light exposing unit thereby forming an electro-static latent image on the charged surface of the drum 36. The electro-static latent image of the photosensitive drum 36 in tum is developed by toner thus forming a visible image on the drum 36 while the rotated drum 36 passes by the developing unit, which is arranged at the position in the vicinity of the photosensitive drum 36. Thereafter, the copy paper 30, which is contained in the paper cassette 43, is fed by the motor-driven paper feed roller 31. The visible image of the photosensitive drum 36 is thus transcribed onto the copy paper 30 due to the high voltage operation of the transcriber. The copy paper 30 is, thereafter, fed to the nip between the heating roller 37a and the pressure roller 37b, so that heat and pressure are applied to the paper 30 thereby fixing the image on the paper 30. The copy paper 30 with the image in turn is fed to the distributing roller 38 and is discharged onto the copy paper tray 41, thus finishing the copying operation. In the above copying operation, toner and latent image remain on the outer surface of the photosensitive drum 36 after the visible image is transcribed onto the copy paper 30. The toner remaining on the drum 36 is removed by the cleaner, while the latent image remaining on the drum 36 is removed by the latent image erasing lamp.
In the above facsimile 100 having the image transmitting part integrated with the image receiving pat the passage of the documents 50 of the document feed tray 40 and the passage of the copy papers 30 of the paper cassette 43 are partially identified with each other. That is, each document 50 and each copy paper 30 commonly passes through the passage, which includes the return roller 33, contact image sensor 42, scanning white roller 34, roller 35, photosensitive drum 36, heating roller 37a, pressure roller 37b and distributing roller 38. However, the documents 50 from the distributing roller 38 are fed to the document discharge roller 39, while the copy papers 30 from the roller 38 are fed to the copy paper tray 41. Therefore, in accordance with a selected operation of the facsimile 100, the paper passage inside the facsimile 100 must be appropriately switched between the document passage and the copy paper passage at a position just after the distributing roller 38. In order to achieve the above object, a paper passage switching device of this invention is installed on a position just after the distributing roller 38. At this position, the document passage extending to the roller 39 is branched from the copy paper passage extending to the tray 41.
FIG. 2 is a partially-exploded perspective view showing the construction of the paper passage switching device in accordance with the preferred embodiment of the present invention. The copy paper tray 41 is installed on the other side (the left-hand side in the drawing) of the facsimile 100. The paper passage switching device includes a holding bracket 27 which is stably arranged on the paper passage at a position just after the distributing roller 38. An electromagnet 26 is mounted to the holding bracket 27. A paper diverting member 23 is rotatably mounted to the housing of the facsimile 100 by a hinge shaft and is biased by a tension coil spring 25, so that the paper diverting member 23 is selectively attracted by and brought into contact with the electromagnet 26 when the magnet 26 is turned on and activated. Meanwhile, the magnet 26 releases the paper diverting member 23 when the magnet 26 is turned off. Tightly fitted into the other end of the paper diverting member 23 is a longitudinal shaft 22 which is provided with a plurality of fitting grooves 22a and 22b. The above grooves 22a and 22b are spaced apart from each other at regular intervals and have a D-shaped cutting configuration.
One end of the paper diverting member 23 has a drive plate 23d, while the other end of the member 23 has both a fitting hole 23a and a pin hole 23b in order to hold the shaft 22. The drive plate 23d has a spring hook 23c which connects one end of the tension coil spring 25 to the drive plate 23d.
When fitting the shaft 22 into the paper diverting member 23, one end of the shaft 22 is fitted into the fitting hole 23a of the paper diverting member 23. Thereafter, a pin 24 is inserted into the pin hole 23b of the paper diverting member 23 and into a pin hole 22c of the shaft 22 thereby fixing the shaft 22 to the paper diverting member 23.
A plurality of paper passage switching members 21 are fixed to the fitting grooves 22a and 22b of the shaft 22. One end of each member 21 has a flat surface 21d. A guide surface 21a is formed on the middle portion of each member 21, while a fixing part 21b is formed on the other end of each member 21. A fitting slit 21c, which has a configuration corresponding to the cross-section of each fitting groove 22a, 22b of the shaft 22, is formed on the tip of the fixing part 21b.
The paper passage switching members 21 are tightly fitted over the fitting grooves 22a and 22b of the shaft 22. The paper diverting angle of the shaft 22 is predetermined by the paper diverting motion of the paper diverting member 23. The paper diverting member 23 is rotatable about the hinge shaft in opposite directions by the attraction force of the electromagnet 26 and the restoring force of the tension coil spring 25.
The above facsimile 100 has the document feed tray 40 on its paper outlet side. In operation of the image transmitting part of the facsimile 100, the frictional force between each document 50 and the motor-driven document feed roller 32 is larger than either the frictional force between the documents 50 or the frictional force between each document 50 and the rubber pad of the document feed roller 32. Therefore, each document 50 is fed to the contact image sensor 42 by both the document feed roller 32 and return roller 33. The contact image sensor 42 reads and transmits the image data written on the document 50.
In the above state, the scanning white roller 34, which is arranged under the contact image sensor 42, checks the reference data prior to reading the data of the document 50 and frictionally feeds the document 50 to the roller 35 while reading the data of the document 50. Prior to feeding the document 50, the LED of the contact image sensor 42 emits light and senses the return light, which is reflected by the white roller 34, by the optical sensor thereby checking the reference data. Thereafter, the data is coded and compressed prior to being transmitted through a telephone line. The document 50 is fed to the nip between the heating roller 37a and the pressure roller 37b by way of the photosensitive drum 36 and in turn is fed to the distributing roller 38. The document 50 is, thereafter, fed to the document discharge roller 39 thus finishing the image transmitting operation.
In the above image transmitting operation, the photosensitive drum 36, heating roller 37a and pressure roller 37b do not perform their intrinsic operational functions, but are only used as document feeding rollers. In the above operation, electric power is applied to the electromagnet 26 of the paper passage switching device under the control of both the control unit 60 (FIG. 3A) and the drive unit 62 electrically connected to the magnet 26, thus activating the magnet 26. The drive plate 23d of the paper diverting member 23 is thus attracted by and brought into contact with the magnet 26 thereby being maintained in its vertical position as shown in FIG. 3A. Therefore, each document 50 from the distributing rollers 38 is fed to the document discharge rollers 39 under the guide of the guide surface 21a of the paper passage switching member 21.
In the printing operation of the facsimile 100, the outer surface of the photosensitive drum 36 is uniformly charged with electricity due to corona discharge of the charged body installed in the facsimile 100. The photosensitive drum 36 in the above state is rotated, so that the charged surface of the drum 36 is exposed to the electric image signals from the light exposing unit thereby forming an electrostatic latent image on the charged surface of the drum 36. The electro-static latent image of the photosensitive drum 36 in turn is developed by toner thus forming a visible image on the drum 36 while the rotated drum 36 passes by the developing unit, which is arranged at the position in the vicinity of the photosensitive drum 36. In the above state, the copy paper 30, which is contained in the paper cassette 43, is fed by the motor-driven paper feed roller 31. The visible image of the photosensitive drum 36 is thus transcribed onto the copy paper 30 due to the high voltage operation of the transcriber.
The copy paper 30 is, thereafter, fed to the nip between the heating roller 37a and the pressure roller 37b, so that heat and pressure are applied to the paper 30 thereby fixing the image on the paper 30. In the above state, the electromagnet 26 of the paper passage switching device is turned off, so that the magnet 26 does not attract the drive plate 23d of the paper diverting member 23 thereby releasing the drive plate 23d. The paper diverting member 23 in the above state is pulled by the restoring form of the tension coil spring 25 thereby being rotated counterclockwise as shown in FIG. 3B. Therefore, the paper passage toward the copy paper tray 41 is opened thereby guiding the copy paper 30 to the copy paper tray 41. In the above facsimile printing operation, toner and latent image remain on the outer surface of the photosensitive drum 36 after the visible image is transcribed onto the copy paper 30. The toner remaining on the drum 36 is removed by the cleaner, while the latent image remaining on the drum 36 is removed by the latent image erasing lamp.
As described above, the present invention provides a device for switching the paper passage between an original document passage and a copy paper passage in a multi-functional image producing apparatus. The paper passage switching device of this invention effectively and automatically switches the paper passage in accordance with a selected operation of the multi-functional image producing apparatus, thus being convenient to users.
Although the preferred embodiment of the present invention has been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims. That is, the paper passage switching device according to the preferred embodiment is installed on a position in vicinity to the paper outlet side of the apparatus and uses a tension coil spring and an electromagnet as a means for generating the power which is used for moving the passage switching member. However, it should be understood that the device may be effectively installed on another position where the paper passage is branched. In addition, the device of this invention may use two electromagnets which are alternately activated when it is necessary to switch the paper passage. That is, any type of means, which can generate the power for moving the passage switching member, can be used in place of the above-mentioned tension coil spring and electromagnet without affecting the functioning of this invention.
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An electromagnetically operated sheet diverter for an image forming apparatus. The sheet diverter diverts a sheet from a common path to one of two possible paths upon discharge from the image forming apparatus. The sheet diverter is small and compact, making the sheet diverter suitable for desktop image forming devices. A main controller operates the sheet diverter to divert sheets depending on the tray of origin. The sheet diverter has a holding bracket. An electromagnet is mounted to the holding bracket. A spring-biased paper diverting member is selectively attracted by and brought into contact with the electromagnet only when the magnet is activated. A longitudinal shaft is tightly held by the paper diverting member and is selectively rotated along with the paper diverting member. The longitudinal shaft has a plurality of fitting grooves, which are spaced out at regular intervals and have a D-shaped cutting configuration. A passage switching member is fixed to each fitting groove of the longitudinal shaft and is selectively rotated by the magnet thereby switching the paper passage between the document passage and the copy paper passage.
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This is a continuation of application Ser. No. 08/308,213, filed on Sep. 19, 1994, abandoned upon the filing hereof, which is a continuation of 08/015,131 filed Feb. 9, 1993 now abandoned which is a continuation of 07/770,152 filed Oct. 3, 1991 now abandoned, which is a cont. of 07/452,833 filed Dec. 21, 1989 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an anti-AIDS viral agent and anticancer agent comprising polysaccharides which are extracted from nuts, mainly nutshells of deciduous tall trees belonging to the genus Juglans or the genus Cayra of angiosperm Juglandaceae.
2. Description of the Prior Art
At present, various compounds have been proposed as anti-AIDS viral agents and anticancer agents and developed as drugs. However, it is the actual situation that any decisive drug has not yet been obtained in view of effects, side effects, etc.
The present inventors found that substances having an extremely high physiological activity were contained in the extract from nutshells of a pine.
It was positively confirmed by vitro tests and the like that in particular, polysaccharides contained in the extract could activate granulocytes in leucocytes contained in blood and were protective against infectious diseases with E. coli and various viruses including herpes virus and against cancer.
Therefore, the present inventors have further attempted to extract the effective compound from various natural nutshells. As a result, it has been revealed that polysaccharides similar to the substances extracted from the pine nutshells described above are also contained in the extract from shells of nuts belonging to the genus Juglans or the genus Carya of angiosperm Juglandaceae. It has then been confirmed that the polysaccharides have inhibitory effect to viral infections, that is, an effect of preventing proliferation or virus and further have a carcinostatic activity against cancer.
SUMMARY OF THE INVENTION
The present invention aims at providing an anti-AIDS viral agent and anticancer agent comprising polysaccharides as an effective ingredient extracted from nutshells of nuts belonging to the genus Juglans or the genus Carya of angiosperm Juglandaceae.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1(a)-(c) are graphs showing the results on the cell growth prevention effect and the cytotoxicity of the extract according to the present invention as an anti-AIDS viral agent.
FIGS. 2(a)-(c) are graphs showing the results on the cell growth prevention effect and the cytotoxicity of the extract according to the present invention as an anti-AIDS viral agent.
FIG. 3 shows the results obtained by the test on carcinostatic activity.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As a means for attaining the object described above, nutshells (dry shells) belonging to the genus Juglans or the genus Carya of angiosperm Juglandaceae are finely ground with a grinder, etc. Then, the ground shells are immersed in an alkali aqueous solution and extracted with an alkali water.
Next, an appropriate acid such as acetic acid, etc. is added to the extracted liquid to neutralize. Thereafter, salts are removed by dialysis, membrane separation, etc. and at the same time, the mixture is centrifuged by a centrifuging machine, etc. and the extracted substances are precipitated. The precipitates are filtered and the filtrate is concentrated. The resulting solid is freeze dried to recover the powdery extract.
Example of extraction treatment:
In the example, shells of nuts belonging to the genus Carya were ground with a grinder and 10 l of 0.85% ammonia water was added to 1 kg of the ground shells. The mixture was stirred at 40° C. for 5 hours.
Next, the liquid was filtered and acetic acid was added to he filtrate (9.5 l ) to neutralize to pH of 6.5. After dialyzing through a dialysis membrane, the recovered substance was freeze dried. As the result, the powdery extract showing light brown color could be obtained. The yield was 40 g based on 1 kg of the ground shells.
1. Anti-AIDS viral test with the extract
Using MT-4 cell, a HTLV-I carrying cell line, anti-HIV tests (proliferation of cells or viable cells, viability rate of cells, HIV antigen positive rate by IF) of the extract described above in the cell free viral infection system and cytotoxicity test of HIV-uninfected MT-4 cells described above were performed as described below.
Notes: HIV . . . AIDS virus
IF . . . immunofluorescence
(1) Cells used for the tests
Cells for the test were produced as follows. MT-4 cells were cultured in RPMI-1640 (RPMI stands for Rosewell Park Memorial Institute) medium plus 10% fetal calf serum. After the cell density was adjusted to 60×10 4 counts/ml, the cells were centrifuged and a fresh medium was added thereto to divide into two equal portions. One was provided for the viral infection test and another was provided for the cytotoxicity test.
(2) Virus used in the tests
HIV (human immunodeficiency viruses) having a cell density of 3.4×10 5 PFU/ml
(3) Method
(a) Method for virus infection
The cells for the tests prepared in (1) described above were infected with HIV sample of (2) in m.o.i=0.002. After maintaining at 37° C. for an hour to adsorb, centrifugation was again performed. RPMI-1640 medium plus 10% fetal calf serum (culture medium) was added to adjust the respective cell densities of the infected cells and the intact cells to 60×10 4 (finally 30×10 4 ) counts/ml, respectively.
(b) Distribution of cells
Into each well of a 24-well microplate, 0.5 ml of the infected and unifected cells prepared as in (a) were charged.
(c) Dilution and addition of the extract (drug)
The extract solution (drug) of the present invention obtained by dissolving the extract in PBS (phosphate buffered saline) in a concentration of 5 mg/ml was sterilized by filtering through a filter having a pore size of 0.22 μm. However, the extract was not fully dissolved but some residue actually remained. Thus, filtration was performed in order using filters having pore sizes of 0.8, 0.45 and 0.22 μm sequentially. The respective solutions collected from the thus filtered extract solutions (drug) were adjusted with RPMI-1640 medium to show concentrations within parentheses.
2048 (1020 after the adjustment), 1024 (512), 512 (256), 256 (128), 128 (64), 64 (32), 32 (16), 16 (8), 8 (4), 4 (2), 2 (1), 0 (test standard)
From these solutions having these concentrations, 0.5 ml each was taken and added to the 24 wells of microplate, in which the cells had been distributed and the infected and uninfected MT-4 cells had already been charged by the method in (a), to make the minimum cell density 30×10 4 /ml.
2. Test on HIV-induced cytotoxicity and on cytotoxicity induced by the extract of the present invention
Vital cells were counted and the viability rate was visually observed on Day 3 and Day 6. Furthermore a test to find HIV-specific antigen was performed on Day 3 and Day 6, using indirect immunofluorescence.
The results are shown in Tables 1 and 2 below.
TABLE 1______________________________________ Extract (Drug)Concentration HIV (+) HIV (-)of Drug Day 3 Day 6 Day 3 Day 6______________________________________1024 cell n 9 + 56 14 + 52 6 + 39 15 + 26 % viab. 86 79 87 63 % IF p. <0.2 <0.2 <0.2 <0.2512 cell n 6 + 47 8 + 140 5 + 56 12 + 167 % viab. 89 95 92 93 % IF p. <0.2 <0.2 <0.2 <0.2256 cell n 5 + 65 13 + 146 5 + 62 15 + 167 % viab. 93 92 93 92 % IF p. <0.2 <0.2 <0.2 <0.2128 cell n 6 + 53 11 + 146 3 + 65 15 + 170 % viab. 90 93 90 92 % IF p. <0.2 <0.2 <0.2 <0.264 cell n 7 + 70 13 + 93 5 + 71 14 + 177 % viab. 91 88 93 93 % IF p. <0.2 37 <0.2 <0.232 cell n 7 + 65 40 + 6 4 + 75 18 + 205 % viab. 90 13 95 92 % IF p. 1.7 71 <0.2 <0.2______________________________________
TABLE 2______________________________________ Extract (Drug)Concentration HIV (+) HIV (-)of Drug Day 3 Day 6 Day 3 Day 6______________________________________1024 cell n 3 + 60 36 + 2 7 + 80 13 + 185 % viab. 94 5.3 92 93 % IF p. 3.12 8.3 <0.2 <0.2512 cell n 5 + 58 31 + 3 4 + 78 19 + 208 % viab. 92 8.8 95 92 % IF p. 4.5 8.72 <0.2 <0.2256 cell n 6 + 69 32 + 2 5 + 81 10 + 219 % viab. 92 5.9 94 96 % IF p. 7.7 82 <0.2 <0.2128 cell n 5 + 60 30 + 4 4 + 62 16 + 205 % viab. 92 12 94 93 % IF p. 9.6 91 <0.2 <0.264 cell n 4 + 52 21 + 2 6 + 67 17 + 198 % viab. 93 8.7 92 92 % IF p. 11.5 92 <0.2 <0.232 cell n 10 + 47 29 + 3 4 + 72 6 + 178 % viab. 82 9.4 95 97 % IF p. 12.9 91 <0.2 <0.2______________________________________
Notes: cell n . . . The number of cells counted; when it is shown by 4+60, this indicates 4 dead cells and 60 vital cells.
(3) Results of test of HIV
Cell proliferation in the group added with the extract (drug) of the present invention (1 to 256 μg/ml) was almost equal to that in the intact group without drug (cf. FIG. 1 A).
From the results, it is believed that the cytotoxicity of the extract (drug) of the present invention would be extremely low. On Day 6 after the incubation, HIV-infected cells without drug were almost killed but most cells were alive (60 to 90% of the non-infected cells were alive) in the group added with the extract (drug) of the present invention (64 to 512 μg/ml) (cf. FIGS. 2 A and B). Furthermore, on Day 6 after the incubation, the frequency of HIV antigen-positive cells was 90% in the drug-free control group but in the group added with the extract (drug) of the present invention (128 μg/ml or more), the viral antigen-positive cells were almost negative (0.2% or less) (cf. FIG. 2 C). From the foregoing experimental results, it has been proven that the use of the extract according to the present invention as a drug in a concentration of 64 to 512 μg/ml after diluting with PBS showed anti-HIV effect.
2. Test for carcinostatic activity
Next, the powdery extract obtained by the example was examined as described below, with respect to its carcinostatic activity as a drug.
(a) Preparation of cancer-bearing mice
Sarcoma 180 cells were intraperitoneally administered to ICR (Institute of Cancer Research) mice of 5 week age weighing about 25 g in a dose of 1×10 6 to prepare cancer-bearing mice.
(b) Preparation of injection from the extract
In 5 ml of physiological saline 5 mg of the powdery extract was dissolved. The solution was filtered through a millipore filter for sterilization to make injection A. Injection A was diluted to 10-fold with physiological saline to make injection B.
(c) Method for evaluation of carcinostatic effect
Injection A or B described above and physiological saline as a control were intraperitoneally administered to the cancer-bearing mice prepared in (a) above, respectively, in a dose of 0.2 ml. The number of days the mice survived and the number of the alive mice were counted.
(d) Results of the carcinostatic activity
The number of the alive mice and the number of days the mice survived are taken on the ordinate and on the abscissa, respectively. The results are shown in FIG. 3.
From the figure, the total number of the survival days is counted as follows, respectively, in the group administered with physiological saline, the group administered with injection A and the group administered with injection B.
Group administered with physiological saline=(1×15)+(1×16)+(1×17)+(3×18)+(3×19)+(1×120)=179
Group administered with injection A=(1×17)+(2×19)+(2×20)+(1×25)+(1×30)+(3.times.60)=330
Group administered with injection B=(1×19)+(2×20)+(1×22)+(1×25)+(1×33)+(4.times.66)=379
As described above, the survival day number was 17.9 days in the group administrated with physiological saline, 33.0 days in the group administered with injection A and 37.9 days in the group administered with injection B. The results reveal that the extract (drug) according to the present invention exhibits an effective carcinostatic activity.
While the invention has been described in detail and with reference to specific embodiments thereof, it is apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and the scope of the invention.
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An anti-AIDS viral agent and anticancer agent comprising as an effective ingredient in the extract containing polysaccharides from nutshells of nuts belonging to the genus Juglans or the genus Carya of angiosperm Juglandaceae with an alkali aqueous solution is disclosed. The extract has anti-HIV effect at the concentration ranging from 64 to 512 μg/ml and exhibits an increased life span in animal.
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BACKGROUND OF THE INVENTION
The present invention relates to apparatus for forming cleat edges on sheet metal workpieces and more specifically to such apparatus in which the cleat edge is formed by a pair of wiping arms aft of and below a bending blade. The present invention is particularly addressed to the problem of forming cleat edges on one of the two panels of L-shaped duct sections previous to forming to the L shape, as well as to the problem of forming cleat edges on the side edges of duct pieces of greater length than the wiping arms.
Heretofore, complicated roll forming machines, such as the one shown in U.S. Pat. No. 3,815,398 to McClain, were utilized to perform these operations. With such apparatus, cleat edges could be formed on duct pieces of any desired length, and alternate portions of the workpiece edges could be cleated, leaving intermediate portions uncleated.
U.S. Pat. No. 2,973,796 to C. F. Engel, et al. discloses an apparatus for forming cleat edges on sheet metal workpieces by the use of a pair of wiping arms, one aft of and one beneath a bending blade. The wiping arms, their drive mechanism, and a rocker-arm type clamp for clamping the sheet metal workpiece relative to the bending blade are supported by vertical end plates at both sides of the bending blade. The clamp is driven by a tilt lever mechanism which extends forward at each side of the bending blade to circular tracks on heavy steel discs driven by the drive mechanism. Starting at a gaging position, against which the edge of the workpiece is first presented, the upper wiper arm turns to a clearance position, by which the cleated workpiece may be removed by an aft movement to free it from the bending blade, followed by upward and forward movement to remove the workpiece entirely. The wiper arm is then rotated the remainder of the 360° revolution, returning it to the gaging position. Since the vertical end plates, drive mechanism and tilt lever lie at the ends of the bending blade, no clearance is provided for sideward projection of a workpiece from the wiping mechanism; a flat workpiece of greater length than the distance between the end plates cannot be cleated, nor may a cleat edge be formed on only one portion of a side edge of a workpiece except by first bending it upward at 90° to fit in a space between clamping fingers. Thus, such prior apparatus does not permit insulating the interior surfaces of an L-shaped duct workpiece while flat. U.S. Pat. No. 3,994,152 to Wolters, though in most respects similar to the patent to Engel, discloses a slightly different way of both gaging and providing for removal of cleated workpieces. The cleat is formed during an unhalted 360° revolution of the wiping arm; as it rotates from an initial position an expanding radius wiper arm portion directs the workpiece to be cleated to a gaging position. The cleat edge is then formed by continued rotation to the initial position, which now provides clearance, permitting the cleated workpiece to be removed by the same movements as in the patent to Engel.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a simple cleat former, of the type in which the cleat edge is formed by a pair of wiping arms aft of and below a bending blade, which will form continuous cleats on duct pieces of greater length than the length of the wiping arm mechanism. A further object is to provide such apparatus which will form cleat edges on one panel of two-panel flat workpieces, whereby insulation may be affixed after cleating and before forming into a duct. Still another object is to provide such apparatus which would permit insertion and removal of the workpiece sideward. Still another object is to provide such side access cleat forming apparatus which will optimally perform the cleat-forming operation in a single unhalted 360° revolution of the wiping arm mechanism. Other objects will be apparent from the disclosure which follows.
Briefly summarizing, in the present invention there is provided a work table and a bending blade supported at the level of the work table by an angle connecting a pair of generally L-shaped side plates. Each L-shaped side plate has a lower portion, which supports the bending blade in its upper edge, the upper edge having a cutout of sufficient size outward of the bending blade bending edge to permit removal of a cleat edge sideward. The L-shaped side plates each have an aft portion continuing upward from the lower portion. Between them the side plates support an upper wiping arm aft of and at the level of the bending blade and a lower wiping arm beneath the edge of the bending blade. Outward of one of the side plates, below the upper edge of its lower portion and aft of the forward edge of its aft portion, a powered gear train serves to rotate the upper and lower wiper arms in the same sense at the same speed. A rocker-arm type clamp, supported rotatably on a shaft between the upper aft portions of the side plates, clamps the sheet metal workpiece fixed relative to the bending blade. A generally circular cam having a segment removed, driven by the gear train means, serves to rotate a lever arm fixed to the outer end of the rocker-arm clamp, driving the clamp down to hold the workpiece. The lever arm is so mounted that it is driven off of the aft side of the circular cam and is aft of the cutout at the level of the cutout.
Such apparatus may be utilized in the manufacture of L-shaped duct pieces to form 180° cleats on the opposite edges of one panel only of a flat workpiece previously notched to define two panels. By aligning the notch with one edge of the wiper arm mechanism, clamping the workpiece so aligned, and then performing the steps required to cleat the edge, an edge of one panel only of the two-panel workpiece may be cleated. To cleat the edge on the opposite side of the same panel, the workpiece is reversed, the notch aligned with the other side edge of the wiper arm mechanism, and the cleat forming steps repeated.
By providing a plurality of slits in the edge of a workpiece of greater length than the length of the wiping arm mechanism to divide its edge into edge portions of no greater length than the wiping arm mechanism, such apparatus may be utilized to form a continuous cleat along the entire length of the sheet metal workpiece. The endmost workpiece portion is cleated, by first aligning its slit with one side edge of the wiping arm mechanism such that the remaining portions extend sideward from the apparatus, and then forming the cleat by the conventional steps. To continue cleating the entire workpiece edge, the workpiece is slided sideward, the nonadjacent end of the next separate edge portion is aligned with the same side edge of the wiping arm mechanism, and the cleat edge is formed by the conventional steps. This is repeated until the entire cleat edge desired to be formed is completed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front elevation of a cleat former embodying the present invention, with the work table and clamping fingers partially broken away to reveal the wiping arm mechanism.
FIG. 2 is an enlarged fragmentary view, partly as seen along line 2--2 at the right side of FIG. 1, immediately after clamping and prior to initial wiping.
FIG. 3 is a similarly enlarged sectional view taken along line 3--3 of FIG. 1, shown after the edge of the sheet metal workpiece has been wiped downward to 90°.
FIG. 4 is a left elevation, otherwise corresponding to FIG. 2, showing the mechanism in the clearance position after forming a cleat, which may be removed either conventionally or endwise.
FIG. 5 is a left elevation similar to FIG. 4, showing the mechanism fully rotated back to gaging position, which permits endwise removal. A second microswitch, forming part of a bypass circuit, is shown in phantom lines.
FIG. 6 is an enlarged sectional view taken from above of the left side of the present invention as seen along line 6--6 of FIG. 5. A sheet metal workpiece notched to permit cleating of a portion of the edge, is shown with the cleat formed over the bending blade.
FIG. 7 is a wiring diagram for the present invention with an optional bypass circuit shown in phantom lines.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In the preferred embodiment of the present cleat-forming machine, a conventional work table a is provided into which the cleat-forming mechanism may be installed, as shown in FIGS. 1 and 2. The work table a has a table top b formed of heavy gauge sheet metal, which establishes a working level and which extends fore and aft between front legs c and intermediate legs d, constructed of metal angles. An upper fore-to-aft tie plate e, one on each side of the work table a, extends from the front legs c to the intermediate legs d, supporting the table top b. Below these upper tie plates e are intermediate fore-to-aft tie plates f extending from the front legs c rearward beyond the intermediate legs d to aft legs g, formed of angles which extend no higher than the intermediate tie plates f. An upper aft cross member h, formed of a metal angle, links the aft legs g at their upper ends, while a lower aft cross tie plate j links them at a lower level. An intermediate upper cross member k, formed of an angle, links the intermediate legs d at the same level as the upper aft cross member h. The frame of the work table a is completed by a lower intermediate cross tie plate m linking the intermediate legs d and lower fore-to-aft tie plate n extending from the front legs c rearward to the aft legs g.
As shown in FIG. 1, mounted on the right side of the work table a between the intermediate and aft legs d, g is an upper speed reducer mount q upon which is mounted a speed reducer r with an outward pulley s. A motor mount t is provided below the speed reducer mount q. An electric motor u is bolted thereto with its pulley v extending outward and aligned with the speed reducer pulley s. The pulleys s, v are linked by a V-belt w. The motor u and speed reducer r serve as the cleat former's power source.
In the preferred embodiment of the present invention, the basic machine structure mounting the elements which perform wiping and clamping operations is a pair of parallel right and left generally L-shaped side plates 10, 11. Each has a forward lower side plate portion 12 whose upper edge 13 is slightly below the level of the table top b, and has a rectangular cutout 14 in sideward registration with the aft edge of a bending blade, to be described below. The cutouts 14 are of sufficient length from front to back and of sufficient depth vertically to provide clearance at both ends of the bending blade for removal of a cleat edge therefrom.
Each L-shaped side plate 10, 11 has an aft side plate portion 16 which continues rearward and upward from the lower side plate portion 12, its edge slanting upward and rearward from the cutout 14 in the lower side plate portion upper edge 13 to the upper edge of the aft portion 16.
Referring to FIG. 2, joining the right and left side plates 10, 11 at their forward ends is a blade support angle 20. One leg of the angle 20 links the forward edges and the other leg links the upper edges of the side plate lower portions 12. That side of the angle which links the side plate upper edges 13 tapers therebeneath along a curve which provides clearance for the lower wiper arm mechanism, to be described below. Stud bolts 22 through the side plates 10, 11 into the ends of the blade support angle 20 hold it in place.
Supported at the working level on the blade support angle 20 is a forming or bending blade 30, shown in FIGS. 2-5, extending rearward from the work table b to a straight rear edge 31. To provide adequate clearance forward of the forward edge of the aft side plate portion 16 for the unformed edges of long sheet metal workpieces, the bending blade rear edge 31 is located forward of the forward edge of the aft side plate portion 16 by a distance measured at the level of the blade 30 greater than twice the width of a cleat edge to be formed. The bending blade 30 is fixed in position on the blade support angle 20 by screws 32.
The right and left side plates 10, 11 are joined by a forward support angle 40 at the lower ends of their forward edges and by an aft support angle 41 at the lower end of their aft edges. On assembly to the work table a, the support angles 40, 41 rest on its cross members h, k.
Aligned bushings 45 are provided in the lower portions 12 of the L-shaped side plates 10, 11 below the cutouts 14 beneath the bending blade rear edge 31. The bushings 45 support between them on an axis parallel to the bending blade rear edge 31 the shaft ends 49 of a lower rotatable wiper arm assembly, generally designated 50, which includes an inner wiper arm 51 having, along its circumference, a full-radius wiping portion 52 and a reduced-radius portion 53. The inner wiper arm 51 terminates in wiper arm side edges 54 inward of the side plates 10, 11, shown in FIGS. 1 and 6. That shaft end 49 which extends rightward has a lower wiper sprocket 56 fixed thereto outward of the side plate 10.
In the aft side plate portions 16 are provided aligned bushings 46, having their centers substantially at the level of the bending blade 30, and serving to mount the shaft ends 59 of an upper or aft rotatable wiper arm assembly, generally designated 60, on an axis parallel to the bending blade rear edge 31. Inward of the side plates 10, 11, the upper wiper arm assembly 60 has an inner wiper arm 61 whose side edges 62 align with the side edges 54 of the lower wiper arm 51, as shown in FIGS. 1 and 6. The inner wiper arm 61 has successively along its circumference a gaging surface portion 64 of constant radius measured from the wiper arm axis of rotation, a wiping portion 63, and a reduced-radius clearance portion 65, best shown in FIG. 3. The wiping and gaging portion 63, 64, have a plurality of spaces of notches 66 spaced along the length of the wiper arm 61, shown in FIGS. 1 and 6, whose use is explained hereafter. Fixed on that shaft end 59 which extends rightward is an upper wiper sprocket 68.
An idler shaft 70 is fixed to the right side plate 10 and extends outward beneath the upper wiper arm shaft 67 slightly below the level of the lower wiper arm shaft 49. Rotatably supported on the bushing 71 on the idler shaft 70 is an idler sprocket 72, engaging the lower wiper sprocket 56 and the upper wiper sprocket 68. The lower wiper sprocket 56, upper wiper sprocket 68 and idler sprocket 72, which make up a gear train, are all of equal diameters, as shown in FIG. 2. Therefore, the lower and upper wiper arms 50, 60 rotate in the same sense at the same speed.
The right and left side plates 10, 11 have bearings 47 aft of the idler shaft 70, slightly below the level of the lower wiper arm shaft 49 and slightly above the level of the idler shaft 70, through which extends a cam shaft 80 perpendicular to the side plates 10, 11. Outward of the right side plate 10 a cam shaft sprocket 81, identical to the above-described sprockets, is fixed on the shaft 80, engaging the gear drive train idler sprocket 72 and, being of the same size as the other sprockets, to be rotated at the same speed as the rotatable wiper arms 50, 60. Outward of the cam shaft sprocket 81 a generally circular cam 82 is keyed to the cam shaft 80 and outward of the cam 82 the shaft 80 is driven by the speed reducer r. The cam 82 has a noncircular portion 84 made by removal of a generally segment-shaped piece, shown in FIG. 2. At one end, the noncircular portion 84 curves outward to meet the remaining circular outer portion of the cam 80, hereinafter referred to as the full-radius portion 85.
Outward of the left side plate 11, fixed on the cam shaft 80, is another cam 87, similar to the right side circular cam 82 and correspondingly numbered. The left side cam 87 has, bolted on its outer surface, a switch block 88 which extends outward to actuate a roller on the lever arm of a limit switch, described below.
Aligned bushings 48 mounted in the aft side plate portion 16 above the level of the uper wiper arm 60 mount, on an axis parallel to the bending blade rear edge 31 in and between the side plate aft portion 6, a rocker-arm type clamp shaft assembly, generally designated 90 which is made up of a clamping mechanism 91 and a pair of tilt levers 100, described below. A clamping mechanism 91 has, inward of the side plates 10, 11, a rectangular bar 92 from which shafts 93 extend outward through the aligned bushings 48. Extending forwardly and down from the rectangular bar 92 are clamp portions comprising L-shaped clamping fingers 94 which project above the bending blade 30. The clamping fingers 94 have spaces 95 therebetween which correspond to and are aligned with the notches 66 in the wiping and gaging portion 63, 64 of the upper wiper arm 60, as shown in FIGS. 1 and 6. These are conventionally used to accommodate an upward-bent sheet metal edge.
The rocker-arm clamp shaft assembly 90 is completed by a pair of tilt levers 100, one mounted on the end of each clamping mechanism shaft 93 outward of the side plates 10, 11. The tilt lever 100 is a rectangular bar having an upper bore 101 at one of its ends engaged on the clamping mechanism shaft 93. A slot 102 extends from the bore 101 to the end of the tilt lever 100, dividing the end into two portions which are pulled together by a stud bolt 103, to clamp the tilt lever 100 tightly to the clamping mechanism shaft 93. The tilt lever 100 is so positioned as to be aft of the side plate cutout 14 at the level of the bending blade 30. At its opposite end, the tilt lever 100 has a lower bore 104, similarly having a slot 105 extending to that end from the bore 104. The lower bore 104 receives a short axle 106, similarly clamped by a stud bolt 107. Each axle 106 supports a roller 108 thereon, aligned with the right and left circular cams 82, 87 and operative from their aft sides. An L-shaped bracket 109, mounted to the side of the tilt lever 100 by a mounting bolt 110, extends outward and downward to the end of the axle 106, retaining the roller 108 thereon.
A tension spring 113, shown in FIG. 2, is connected between the lower end of the right tile lever 100 and an eye bolt 114 in the speed reducer mount q.
On the outer side of the left side plate 11, at its lower edge, is a mounting channel 115, shown in FIG. 1, extending outwardly nearly to the outer side of the left circular cam 87. As shown in FIGS. 4 and 5, mounted to the outer side of the channel 115 is a first limit switch 120, of the double-pole, single-throw type, having a set of normally open contacts 121 and a set of normally closed contacts 122.
Referring to the wiring diagram of FIG. 7, the cleat former electrical control circuit comprises an A.C. power supply 123 in series connection with the parallel shunt electric motor u. A first foot switch 124 is in series with the normally open contact 121, while a second foot switch 125 is in series with the normally closed contact 122. These two series combinations, formed control means to start and stop rotation of the mechanism, are both in parallel with the series combination of the electric motor u and the power supply 123.
Construction of the present invention may be apparent to persons skilled in the art from the above description of its structure. Briefly, first the various bearings and bushings are installed in the right and left side plates 10, 11 and the lower wiper arm 50, the upper wiper arm 60 and the cam shaft 80 are put into position therethrough. The blade support angle 20, forward support angle 40 and aft support angle 41 are attached as by bolting to the side plates 10, 11, fixing them in position and the bending blade 30 is screwed to the blade support angle 20. Next the sprockets, 56, 68, 72, 81 are positioned on the shafts 49, 59, 71, 80 and aligned with each other, with care taken that the wiping arms 50, 60 are in proper angular position with respect to one another. The right and left circular cams 82, 87 are next positioned and keyed to their shaft 80 in such angular positions as to properly interact with the tilt levers 100, next to be installed, to produce clamping at the desired position of the wiping arm mechanism. Last, the tilt levers 100 are clamped to the clamping mechanism shaft 93 and the coil spring 113 is installed.
Using the wiring circuitry in solid lines in FIG. 7, operation of the present cleat former proceeds as follows: in its initial gaging position, the wiping arm mechanism is so rotated that the upper wiper arm gaging portion 64 is adjacent to and aligned with the bending blade straight rear edge 31; the clamping fingers 94 are up, shown in FIG. 5. A sheet metal workpiece upon which a cleat edge is to be formed is pushed into position with that edge abutting the gaging portion 64. The cleat former operator first actuates the mechanism by pressing the second foot switch 125; since the switch block 88 has previously been rotated to a position slightly clockwise from the first limit switch 120, its normally closed contacts 122 are closed and the electric motor u begins to run. The cams 82, 87 rotate; when the full-radius portion 85 reaches the roller 108 on the tilt lever 100, it causes the tilt lever to rock upward so far as to drive the clamping fingers 94 clamping onto the sheet metal workpiece to the bending blade 30, as shown in FIG. 2. As rotation continues, the upper wiper arm wiping portion 63 first wipes the edge of the workpiece downward to approximately 90°, as shown in FIG. 3, and then the lower wiper arm 50 wipes the edge to 180°, about the bending blade 30. When the switch block 88 on the left circular cam 87 next engages the first limit switch 120, its normally closed contacts 125 open, turning off the electric motor u, leaving the upper wiper reduced-radius clearance portion 65 aligned with and adjacent to the bending blade straight rear edge 31 and the tilt lever rollers 108 on the noncircular portions 84 of the circular cams 82, 87, as shown in FIG. 4 and referred to as the clearance position. Thus, the workpiece is no longer clamped and may be removed. After removal, the operator presses the first foot switch 124, referred to as the second actuation, and the upper wiper arm 60 returns to its gaging position.
Removal of the workpiece may be by either of two ways. First, the conventional manner of sliding the workpiece aft until the 180° cleat clears the straight rear edge 31 and then moving the workpiece upward and forward may be utilized. Second, sideward removal is possible by sliding the workpiece sideward until the cleat edge is free of the bending blade 30. The present invention makes possible this method of removal by use of the L-shaped side plates 10, 11 with cutouts 14, the aft placement of the tilt levers 100 to operate from the aft side of the circular cams 82, 87, and placement of the gear train aft of the forward edge of the side plates.
The above embodiment and its equivalents lend themselves to a new method of manufacturing L-shaped duct pieces, in which it is necessary to form cleats on the opposite edges of the panel to be cleated of a flat workpiece notched to define two panels, as shown in FIG. 6, but not yet bent along the line indicated by such notches. First, the workpiece is positioned with one of the panel edges to be cleated extending over the end of the bending blade 30 a distance substantially equal to the depth of the cleat to be formed plus a bend allowance, which distance may be measured simply by pushing the workpiece against the adjacent gaging portion 64 of the upper wiper arm 60. The notch on the panel edge is aligned with one side edge of the wiper arm so that the panel not to be cleated projects outward from the side edge. This is followed by the steps of clamping the workpiece, so positioned and so aligned, to the bending blade, wiping the edge extending over the bending blade 30 downward to 90° angle by rotation of the first wiper arm, wiping the edge to a 180° angle by rotation of the second wiper arm, and unclamping the workpiece. Thereafter, the workpiece is removed and positioned with the other of such panel opposite edges extending over the bending blade straight rear edge 31 a distance substantially equal to the depth of the cleat to be formed plus a bend allowance, which, in use of the above-described embodiment, may be measured by pressing against the upper wiper arm gaging portion 64. The notch which defines the junction of the two panels is so aligned with the other side edge 62 of the upper wiper arm 60 that the panel not to be cleated projects outward from the side edge 62. Last, the steps of clamping, wiping to 90°, wiping to 180° and unclamping are performed. Thus, a cleat is formed without previously forming a 90° bend between the panel to be cleated and the panel not to be cleated.
The present cleat former and equivalents may also be utilized in a new method of forming on a sheet metal workpiece a 180° cleat edge longer than the length of the wiping arm mechanism. First, the workpiece edge is divided in separate edge portions by providing a plurality of spaced-apart slits in its edge to be cleated to a depth substantially equal to the depth of the cleat plus a bend allowance, similar to the notches shown in FIG. 6. Thus, the end of each separate portion comprises either an end of the workpiece or a slit; the length of each of the separate portions is no greater than the length of the wiping arm mechanism. Next, the workpiece is inserted into the cleat former with a portion commencing with one end of the workpiece positioned on the bending blade, extending over its straight rear edge 31 a distance substantially equal to the depth of the cleat to be formed plus a bend allowance, measured in the above embodiment by the upper wiper arm gaging portion 64. The slit which forms the inserted endmost workpiece separate portion is aligned with one side edge 62 of the wiper arm 60 such that the endmost portion is adjacent to the wiping arm mechanism. A cleat edge is formed on that portion by the conventional steps of clamping the workpiece, so positioned and aligned, relative to the bending blade, wiping the edge extending over the bending blade downward to substantially a 90° angle by rotation of the upper arm, wiping that same edge to a 180° angle by rotation of a lower wiper arm, and unclamping the workpiece. Next, the workpiece is slided sideward so that its advancing end projects through the side plate cutout 14 and a nonadjacent end of the next separate edge portion is aligned with the same side edge of the wiping arm mechanism. Again, a cleat edge is formed on this next separate edge portion by the above-described steps. The steps of moving sideward, aligning and forming a cleat edge are repeated thereafter until any successive separate edge portions are cleated.
If, after the cleat edge has been formed about the bending blade 30, the sheet metal workpiece is to be removed sideward by sliding over the open end of the blade 30, through either of the cutouts 14, halting the wiping arm mechanism in the clearance position is not necessary. The sheet metal workpiece may be removed sideward, even though the wiping arm mechanism has been rotated directly to the gaging position. This is accomplished by the phantom line circuitry of FIG. 7, which adds a bypass circuit including a second limit switch 130, normally closed, mounted on the mounting channel 115 aft of the first limit switch 120 by a distance substantially equal to the circumferential length of the switch block 88, as shown in phantom lines in FIG. 5. The second limit switch 130 is in series combination with a manual switch 131, which series combination is in parallel with the series combination of the electric motor u and A.C. power supply 123.
Closing of the manual switch 131 serves to bring this optional bypass circuit into operation. In its use, the manual switch 131 is closed while the wiping arm mechanism is at its gaging position, at which point the normally closed contacts of the second limit switch 130 are open while the normally closed contacts 122 of the first limit switch 120 are closed, as shown in FIG. 5. To actuate the mechanism, the second foot switch 125 is pressed momentarily until the second limit switch 130 is no longer actuated by the switch block 88 and closes. The mechanism then continues to rotate without either foot switch 124, 125 being pressed until the second limit switch 130 is again actuated by the switch block 88, at which time the second limit switch 130 opens and the electric motor u stops. The mechanism has returned to the gaging position, as shown in FIG. 5.
Other modifications of the present preferred embodiment will be apparent. For example, a single circular cam mounted on either side, with a corresponding single tilt lever, could be utilized to operate the rocker-arm clamp shaft assembly. Any releasable means to clamp the sheet metal workpiece fixed relative to the bending blade may be utilized. Means, operative between the power gear train and a clamping means, aft of the clearance portion provided sideward of the bending blade, which operates the releasable clamp in timed sequence with the rotation of the wiping mechanism, will perform the desired function. Other forms of switching mechanisms to achieve the timed sequence might be substituted. These and other modifications, from the above disclosure, will suggest themselves to those skilled in the art.
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A cleat-former machine, of the type which utilizes two rotating wipers, permits removal of formed cleats sideward from either end of the bending blade, and can be used with workpieces whose length exceeds that of the wipers. L-shaped side plates, which support between them a bending blade and a wiper arm mechanism adjacent the aft bending edge of the bending blade, have cutouts provided in their upper edges in registration with the ends of the bending edge. A rocker-arm clamping assembly, rotatably mounted on a shaft above and aft of the bending blade, is rotated to clamp and unclamp a sheet metal workpiece relative to the blade by a tilt lever outward of the side plate, aft of the cutout, at their level, and operated off the aft side of a circular cam supported outward of said side plate and rotated by the gear train. Side access to the ends of the blade bending edge is thereby provided. In the method of the present invention, especially useful in fabricating L-shaped duct workpieces, 180° cleats may be formed on the opposite edges of one panel only of a flat workpiece notched to define two panels by aligning the notch with the side edge of the wiper arm mechanism, with the panel not to be cleated projecting outward. A 180° cleat longer than the length of the wiping arm mechanism may be formed by making slits to divide the workpiece edge into separate portions of no greater length than the wiper arm mechanism length and cleating successive portions individually while the yet uncleated portions project outward.
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[0001] This application is a continuation of application Ser. No. 09/999,537, filed Nov. 15, 2001, which is a continuation of application Ser. No. 29/101,631 filed Mar. 8, 1999, which in turn is a continuation of application Ser. No. 08/984,893 filed Dec. 4, 1997, now U.S. Pat. No. 6,027,644 issued Feb. 22, 2000, which in turn is a division of application Ser. No. 08/695,134 filed Aug. 8, 1996, now U.S. Pat. No. 5,753,107 issued May 19, 1998.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to water purification and filtration systems and, in particular, to a disposable cartridge system having a manifold which cooperates with the cartridge to interrupt the supply and return lines during cartridge changes to prevent drainage from the supply system.
[0003] A particular problem experienced with the changing of single appliance water purification/filtration cartridges is the necessity of dealing with drainage released from the supply and return lines with the release of the cartridge from a system manifold. Unless shutoff valves are provided in the system supply lines that mate to the manifold, water typically drains from one or both of the conduits with the removal of the cartridge from the manifold. The sporadic frequency of the cartridge changes and attendant operator forgetfulness to the problem typically results in drainage. That is, the maintenance personnel forget to mount a catch pan or other spill prevention appliance beneath the manifold and it becomes necessary to clean up the spill.
[0004] A number of cartridge systems which are subject to the foregoing problem are disclosed at U.S. Pat. Nos. 3,746,171; 4,515,692; 4,915,831; 4,877,521; and 5,354,464. The cartridges of the disclosed systems variously provide projecting bayonet return ports which mate with recessed outflow cavities at the manifold. Twist lock mountings to the manifold are also provided at some of the cartridges. Cartridge interlock retainers are also disclosed. However, flow control valving is not provided at either the manifold or cartridge for any of the foregoing systems. Nor do any of the cartridges include surfaces which cooperate with associated valving.
[0005] In appreciation of the foregoing problem and inconvenience, the present manifold and cartridge system was developed. In contrast to conventional cartridges, the manifold of the invention provides a bayonet fitting at a center out flow port which couples to a recess at the cartridge. Seals displaced along the fitting and internal to the cartridge contain viral contaminants to the cartridge. A spring biased stem valve at the manifold inlet port cooperates with a raised, tapered surface at the cartridge to permit flow only upon the rotational seating and locking of the cartridge to the manifold. A one-way check valve at the outlet port to prevents back flow. In an alternative construction, a slotted or split stem, check valve provides noise free operation. The system finds particular advantage with cartridge based appliance systems, such as ice makers and chilled water dispensers at a refrigerator or water cooler, and for under cabinet cartridge mountings, such as at sinks.
SUMMARY OF THE INVENTION
[0006] It is therefore a primary object of the invention to provide a cartridge based water purification and filtration system that prevents drainage from the supply and return lines upon removing a treatment cartridge.
[0007] It is a further object of the invention to provide a supply manifold containing shut off valves at one or both of provided supply and return ports.
[0008] It is a further object of the invention to provide a manifold having a stem valve at a supply port which cooperates with a surface at the treatment cartridge, such that with cartridge mounting and rotation or removal the valve retracts and extends to control supply flow.
[0009] It is a further object of the invention to provide a manifold having a projecting surface or bayonet fitting which contains a number of O-ring seals and which fitting mounts to a mating outlet recess at the cartridge which is backed by additional seals at the cartridge to prevent bypass migration of contaminants.
[0010] It is a further object of the invention to provide a manifold having channel ways which interlock to flanged shoulders at the cartridge, upon rotation of the flanges into the channelways.
[0011] It is a further object of the invention to provide a cartridge container having an infeed flow cavity defined between a sealed external housing and internal liner whereby flow is directed to the bottom of the cartridge and thence through filtration and purification treatment media supported in the liner and to the outlet port.
[0012] Various of the foregoing objects, advantages and distinctions of the invention are obtained in a presently preferred system which provides a manifold having integral flow control valves at inlet and outlet ports. The valves cooperate with a treatment cartridge to prevent drainage of liquid from the manifold supply lines during the changing of a treatment cartridge. Extraneous shut-offs are thereby avoided at the primary supply system.
[0013] The manifold is molded to provide a central tubular out flow or “bayonet” fitting. O-ring seals are fitted to the fitting to mate with a recessed port at the treatment cartridge to seal out flow from the cartridge. Radially displaced from the bayonet fitting are a number of channelways which interlock with shoulders of a mounted cartridge.
[0014] Depending from the manifold is a stem valve which controls flow from the inlet port. Raised surfaces at the cartridge contact the valve with the seating and rotation of the cartridge to the channelways. Supply flow is thereby enabled and disabled with a corresponding extension and retraction of the valve.
[0015] The treatment cartridge provides an open ended housing which supports a concentrically mounted internal liner. Radial flanges at the liner displace the liner from the housing and form an infeed channel. Flow is re-directed from a cartridge end cap. Successive stages of filtration and purification media treat the water prior to directing the water through a central recess which mates to the bayonet fitting.
[0016] A one-way check valve at the manifold outlet port permits liquid out flow but prevents back flow. A tapered valve stem is normally biased to a closed condition at the manifold to mate with a seat surface and opens upon liquid outflow being directed against the valve stem. In another construction, the valve includes a split, cylindrical stem and is constructed to provide surfaces that promote non-symmetrical flow to prevent valve oscillation and nuisance audible sounds.
[0017] Also disclosed is a dual cartridge manifold. Interconnected, manifolds support a filter cartridge and a purification cartridge.
[0018] Still other objects, advantages and distinctions of the invention are discussed below in relation to the appended drawings. To the extent various modifications and improvements have been considered, they are described as appropriate. The description should not be literally construed in limitation of the scope of the invention, which rather should be interpreted to include all those equivalent embodiments within the scope of the further appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a perspective drawing to the manifold and treatment cartridge of the invention.
[0020] FIG. 2 is a partial cross-section view through the manifold taken along section lines 2 - 2 at the longitudinal center of the manifold and cartridge;
[0021] FIG. 3 is a longitudinal cross-section view through the center of a treatment cartridge;
[0022] FIG. 4 is a cross-section view through the center of an alternative treatment cartridge;
[0023] FIG. 5 is a plan view to a slotted stem check valve;
[0024] FIG. 6 is a perspective view of the valve stem of FIG. 5 ; and
[0025] FIG. 7 is a longitudinal cross-section view through a dual cartridge manifold assembly.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] With attention to FIG. 1 , an exploded assembly drawing is shown to the improved purification and filtration treatment system of the invention. The system 2 includes a supply manifold 4 having a sealed bayonet fitting 6 which mounts to a two stage recess 8 at a treatment cartridge 10 . Radially displaced from the recess 8 are a pair of shoulder flanges 12 , 14 , which have tapered leading edges 16 , that mate with a pair of interlocking flanges 18 and 20 at the manifold 4 . With the mounting of the bayonet 6 into the recess B and the sealing of a number of O-rings 22 , 24 and 26 mounted along the fitting 6 within the stages of the recess 8 , the flanges 12 , 14 are aligned to channelways 27 and 28 at the flanges 18 and 20 . The cartridge 10 can then be rotated to interlock with the manifold 4 , which concurrently permits flow between the manifold 4 and the cartridge 10 .
[0027] Depending from one side of the bayonet fitting 6 is a stem valve assembly 30 . The valve assembly 30 is configured to prevent flow through an adjoining aperture 32 that communicates with a supply conduit 34 , except when the cartridge 10 is fully seated to the manifold 4 . With the depression of the valve assembly 30 , liquid flow is directed from the supply conduit 34 through the aperture 32 and a number of inlet ports 35 arrayed about the first stage 36 of the recess 8 . Liquid flow is directed from the ports 35 through a cavity 37 formed between a cartridge housing 38 and an internal liner 40 .
[0028] The flow cavity 37 is particularly formed upon seating a number of radial spacers 42 at the liner 40 to the inner walls of the cartridge housing 38 , reference FIG. 2 . Flow is interrupted and re-directed at the base of the cartridge 10 by an end cap 44 that is spun welded to the housing 38 . The flow is directed to the core of the liner 40 through a number of ports 46 arrayed about the lower periphery of the liner 40 .
[0029] With the entry of liquid to the liner core, the liquid passes through a number of filtration and purification stages. Two alternative arrangements of which stages are shown at FIGS. 3 and 4 . The filtered and purified water is directed from the liner 40 to a bore or flow aperture 48 of the bayonet fitting 6 , which is exposed at the second stage 49 of the cartridge recess 8 . Flow is directed through the bayonet fitting 6 to an outlet conduit 50 via an intermediate check valve assembly 52 shown at FIG. 2 . FIGS. 5 through 7 depict another and presently preferred check valve assembly 53 which assembly 53 is discussed below.
[0030] The check valves 52 and 53 are constructed to provide noise free operation under flow pressures in the range of 10 to 125 psi. It has been found that various conventional check valves can produce nuisance sounds. Such noises are preferably avoided in confined spaces, such as a refrigerator.
[0031] A particular advantage obtained from the system 2 is the ability to automatically interrupt flow from the supply and return conduits 34 , 50 upon disconnecting a cartridge 10 from the manifold 4 . Nuisance drainage is thereby prevented upon removing the cartridge 10 from the manifold 4 . Standing water within the cartridge 10 , downstream of the check valve 52 , is retained in the cartridge 10 due to the recessed mounting of the bayonet fitting 6 into the cartridge 10 .
[0032] The supporting of the bayonet fitting 6 and the appurtenant O-rings 22 , 24 and 26 to the two stage recess 8 simplifies the construction of the cartridge 10 versus the conventional cartridges mentioned above. The latter cartridges provide a sealed bayonet fitting at each cartridge which mate to a recess at the manifold. A large number of relatively costly O-ring seals are thus required to accommodate the disposable cartridges. The system 2 avoids the cost by mounting the seals to the manifold 4 . Other seals 92 , 93 , which are discussed below, are instead included to prevent viral contaminants from bypassing the treatment media. A more cost effective and efficient filtration and purification system is thereby obtained.
[0033] Turning attention to FIG. 2 , a longitudinal cross section view is shown through the manifold 4 and from which details to the fitting of the cartridge 10 to the bayonet fitting 6 and the reasons for the commensurate lack of drainage with the removal of the cartridge 10 are more apparent. Particularly apparent are the construction of the valve assemblies 30 and 52 and the cooperation of the cartridge housing 38 with a stem valve 60 of the valve assembly 30 .
[0034] With attention to the valve assembly 30 , the stem valve 60 is fitted to the manifold 4 to protrude from the cutlet aperture 32 . A normally closed valve condition is obtained with a spring 62 which forces a valve seat 64 at the aft end of the stem valve 60 into engagement with an O-ring seal 66 at the manifold 4 to prevent flow through the aperture 32 . Internal surfaces of the manifold 4 adjacent the seat 64 might also be shaped to mate with the seat 64 in lieu of or in combination with the O-ring 66 .
[0035] Projecting from the first of the 2 stages 36 , 49 at the recess 8 is a raised, tapered projection 72 that engages the stem valve 60 with the fitting and the rotation of the cartridge 10 to the manifold 4 , reference also FIGS. 3 and 4 . The mounting of the flanges 14 , 16 and 18 , 20 are such that the projection 72 does not engage the valve stem 60 until the shouldered flanges 12 and 14 are fully seated and rotated into the channelways 27 , 28 to lock to the manifold 4 . A gradual depression of the stem valve 60 is thereby assured.
[0036] Captured to the manifold 4 adjacent an outlet port 74 that contains the outlet conduit 50 is the outlet valve assembly 52 . The valve assembly 52 includes a valve body 76 which is resiliently supported between a spring 78 and a retainer 80 . The retainer 80 presently comprises a ring which is retained to a grooved surface 82 . The spring 78 biases an O-ring 84 fitted to the valve stem 76 to seal to a tapered surface or seat 86 of the manifold 4 . The elastomer material of the O-ring 86 enhances the seal and reduces noise due to valve operation.
[0037] The valve assembly 52 particularly prevents audible clicking sounds at the manifold 4 . Such sounds can present a nuisance where the system 2 is used with home appliances, such as refrigerators, cooling fountains, faucets, or other applications where the system 2 is confined within a living space. A variety of commercially available check valve assemblies have been tested but found to be inadequate. FIG. 5 , which is discussed below, discloses another and presently preferred check valve assembly 53 .
[0038] Also shown at FIG. 2 is the mounting of the liner 30 to the cartridge housing 38 . Particularly apparent is the manner of the mounting of a collar 41 at the liner 30 to a housing projection 90 and a pair of O-rings 92 and 93 , which are separated by a spacer ring 95 . The multiple sets of O-rings 22 , 24 and 26 and 92 , 93 and spacer ring 95 not only contain the flow from the cartridge 10 to the fitting 6 but also provide a seal against undesired back bypass migration of viral contaminants.
[0039] With the fitting of the liner 40 to the housing 38 , the flow channel 37 is created at the outer periphery of the liner 40 and which is more apparent at the cartridges 96 and 98 of FIGS. 3 and 4 . Liquid flow is contained between the channel 37 and the bore 49 and contaminants are restrained to the cartridge 10 .
[0040] With attention to FIG. 3 and mounted within the core of the liner 40 are a number of seriatim stages of filtration and purification media which are arranged to provide the most advantageous dwell time and exposure of the water to the treatment media. With the entry of the water to the liner core at the apertures 46 , the water is initially exposed to a pair of circular discs of filter media 98 and 102 , which are mounted to contain a bed of granular activated carbon (GAC) 100 . The filter media 98 , 100 and 102 filter large particulates and organisms from the water. Positioned between the disc filter 102 and another disc filter 104 is a bed of granular bactericide 105 such as a multi-valent iodine resin 106 that can be present in a concentration in the range of 40 to 400 cubic centimeters. Presently, a bed of 80 cc's of a PENTAPURE material is used at the bactericide 105 .
[0041] Supported above the disc filter 104 are a pair of porous plastic spacers 106 and 108 and which capture a cast cylindrical carbon filter 110 to the liner 40 . The filter 110 is constructed of a cast GAC material and exhibits a nominal porosity in the range of 0.5 to 20 microns. Depending upon the application, a pleated cylinder paper filter media might be substituted at the filter 110 .
[0042] O-ring seals 112 at the spacer 108 contain and direct water flow from a channel space 114 at the outer periphery of the filter 110 inward to a bore 116 . The water flows from the bore 116 , through the spacer 108 into a second bed of purification media 118 , containing a mixture of halogen bactericides, GAC and/or halogen scavenger media. From the media 118 , the water passes through a further disc filter 120 to the cartridge outlet bore 49 and the outlet port 48 of the manifold 4 .
[0043] Depending upon the application and the particular contaminants found in the available water supply, the arrangement of the treatment media and the types of media can be varied to provide either filtration or purification or both. FIG. 4 discloses an alternative treatment cartridge 98 that is intended to principally serve as a filter. The cartridge 98 contains a bed of GAC media 122 between a pair of porous disc filters 124 and 126 . The space containing the media 122 might also be subdivided to contain another filter media, such as a paper filter or the like.
[0044] Mounted above the media 122 is a solid cylindrical block of GAC media 128 which is supported to a porous plastic retainer 130 . The filter 128 is constructed of a cast GAC media and exhibits a nominal porosity in the range of 0.5 to 20 microns. Liquid flow is directed from a channel space 132 between the liner 40 and filter 128 inwardly to a bore 134 . supported within the bore 134 between the manifold 4 and the outlet bore 49 is a porous conical nozzle 136 which directs flow to the outlet bore 49 and seals to the fitting 6 .
[0045] With attention to FIGS. 5 and 6 , enlarged cross section and perspective views are shown to the above mentioned alternative check valve assembly 53 . The assembly 53 provides a cylindrical valve stem 140 that includes a longitudinal slot 142 that extends along a sidewall of the valve stem 140 to direct flow along the slot 142 to a surface 143 adjacent an O-ring seal 144 . Flow is directed in a non-symmetric fashion such that greater pressure is exerted against the surface 143 which provides a slight tipping of the valve stem 140 . This tipping has been found to reduce the tendency of audible clicking sounds at the manifold 4 .
[0046] The seal 144 is fitted forward of a shoulder 146 to conform and seal the juncture between the shoulder 146 and the manifold 4 . A spring 148 and retainer 150 bias the shoulder 146 and seal 144 to prevent back flow at the valve 53 . The retainer 150 is press fit to the body of the manifold 4 and is also secured with the fitted conduit 50 .
[0047] Appreciating the potential of encountering water supply systems containing many large contaminants, such as well systems, FIG. 7 depicts a treatment system 160 that supports a pair of cartridges 96 and 162 from a pair of interconnected manifolds 164 and 166 . The manifolds 164 and 166 are interconnected by an O-ring sealed coupler 168 . The manifold 164 is fitted with a valve assembly 30 and the manifold 166 is fitted with a check valve assembly 53 . Nuisance drainage is thus prevented with the changing of either of the cartridges 162 and/or 96 .
[0048] The arrangement of the cartridges 96 , 162 are such that the cartridge 162 principally filters the water and the cartridge 96 purifies the water. The assemblies of the cartridges 162 and 96 are essentially the same as earlier described. The principal difference is that the liner of the cartridge 162 is fitted with a disc filter 170 , a bed of GAC pre-filter media 172 , and a cast cylindrical GAC filter 174 . The filter 174 is fitted between a disc end cap 176 and the conical nozzle seal 136 . Depending again upon the application, the filter treatments can be varied, such as by including paper filter media and/or varying the volume and porosity of the filtration medias.
[0049] While the invention has been described with respect to a presently preferred construction of the manifold and alternative cartridge constructions, still other constructions may be suggested to those skilled in the art. The following appended claims accordingly should be interpreted to include all those equivalent embodiments within the spirit and scope thereof.
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A cartridge based water purification and filtration system which permits cartridge changes without drainage at the input and output ports. Interlocking flanges at the manifold and cartridge lock the cartridge to the manifold and raised surfaces at the cartridge operate the inlet valve with a rotational seating of the cartridge. A spring biased inlet valve depends from a supply manifold input port and cooperates with the filter cartridge to prevent forward flow until the cartridge is seated to the manifold. The check valve includes a split stem which prevents chatter with valve operation. A check valve at the output port cooperates with a sealed bayonet fitting that mates to a concentric outlet port at the cartridge to prevent back flow with cartridge removal.
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BACKGROUND OF THE INVENTION
[0001] The invention concerns a stent having a metallic, relatively radiolucent carrier structure and at least one marker element comprising comparatively radiopaque material.
[0002] Stents are endovascular prostheses which serve inter alia for the treatment of stenoses, that is to say, vessel constrictions. Stents usually have a tubular carrier structure which is open at both longitudinal ends of the tube and which is formed by legs and openings enclosed by the legs. Stents of that kind can usually assume two conditions, more specifically a compressed condition of a small diameter and an expanded condition of a comparatively larger diameter. In the compressed condition, such a stent can be introduced by means of a catheter into for example a blood vessel and can be positioned at a location to be treated. The stent is expanded or is allowed to expand of its own accord, at the treatment location. Stents which are not self-expanding are usually expanded by means of an inflatable balloon at a distal end of a catheter for insertion of the stent. Stents of that kind are therefore referred to as balloon-expanded. Other stents have the property of expanding of their own accord, for example by virtue of inherent spring forces. Stents of that kind are referred to as self-expanding. The self-expanding stents include in particular those which have a carrier structure comprising a shape memory metal such as nitinol, a known titanium nickel compound. Shape memory metals of that kind have the property of retaining a first shape or being plastically deformable below a given change temperature, and assuming a second shape when the change temperature is exceeded. In regard to stents, shape memory metals are used in such a way that the first shape corresponds to the compressed condition of a stent and the second shape corresponds to the expanded condition of a stent.
[0003] In the expanded condition of a stent, it serves, for example, for the treatment of vessel constrictions (stenoses), acting as a vessel support which keeps a blood vessel to be treated open at a constricted location. The expanded stent acts in opposition to the vessel constriction and supports the vessel wall in the region of the vessel constriction. For that purpose, the stent must enjoy adequate radial strength or carrying force. The carrier structure of the stent must also afford adequate surface coverage in order adequately to support the vessel constriction. On the other hand, the requirement for being able to expand the stent means that openings are necessarily present between the legs of the carrier structure of a stent. In the compressed condition of the stent, those openings can be substantially closed. In the expanded condition of the stent, the opening is enlarged in any case.
[0004] Besides an adequate carrying force, stents must also involve adequate flexibility with respect to their longitudinal axis in order to be able to follow movements of the vessel. In addition there is a wish for longitudinal changes in a stent upon expansion to be kept as small as possible. Finally the material of the stent or at least the surface thereof should be as body-compatible as possible.
[0005] Those requirements have resulted in various, very sophisticated and diversified stent configurations. The stents which are of interest here have a carrier structure produced from a metal tube as the starting material. Cutting the metal tube for example by means of a laser or spark erosion produces the legs, as remaining material. Cut legs of that kind have the great advantage over stents of the first generation, which were shaped from wire, that the geometry of the carrier structure can be optimized in regard to the various different demands involved.
[0006] That large number of demands made on stents further includes the requirement that the stent is to be capable of being positioned with the utmost accuracy. In general, the operation of positioning a stent is effected by means of imaging processes which, for example, operate with X-rays. In this connection, there is generally the disadvantage that materials which are suitable for the carrier structure of a stent frequently can only be detected with difficulty by means of the imaging processes used as the material forming the carrier structure is relatively radiolucent. It is therefore known to provide stents with what are referred to as X-ray markers containing a relatively radiopaque material which is easy to locate by means of the above-specified imaging processes. A known radiopaque material is for example, gold.
[0007] Usually, the need to provide X-ray markers in stents of the above-described kind forces compromises in terms of the stent design, which are possibly detrimental to others of the above-mentioned desired properties.
[0008] An aspect of the present invention is to provide a stent which is X-ray visible and which moreover combines together as many as possible of the desirable properties.
BRIEF SUMMARY OF THE INVENTION
[0009] In accordance with the invention, that object is attained by a stent of the kind set forth in the opening part of this specification, wherein after the cutting-out operation, the marker element ( 22 ) is welded to the rest of the carrier structure ( 12 , 16 ) and the radiopaque material is completely enclosed by a cover layer of a material other than the radiopaque material, the cover layer including metal or a metal compound.
[0010] The invention is based on the basic idea of integrating radiopaque material as an X-ray marker for a stent into the carrier structure of the stent in such a way that the outwardly acting surface of the stent in the region of the X-ray marker is not characterized by the radiopaque material but by another metal or a metal compound. The metal of the cover layer of the marker element advantageously makes it possible for the marker element to be welded to the rest of the carrier structure after it has been cut out. The outwardly acting surface of the X-ray marker in that case can be for example of a body-compatible nature by virtue of a silicon carbite coating. In a particularly advantageous variant, the metal forming the cover layer is identical to the metal of the carrier structure and can therefore be easily connected to the rest of the carrier structure by welding without contact corrosion or the like occurring.
[0011] The last-mentioned property is particularly advantageous in connection with a stent having a self-expanding carrier structure, for example, comprising a shape memory metal such as nitinol. In that case, it is possible for the X-ray marker to be provided in the form of a hollow nitinol wire which is filled in the interior with gold and which is to be easily welded to the rest of the carrier structure of the stent. In that way the X-ray marker can even be integrated into the carrier structure.
[0012] In preferred variants, a stent of that kind, in particular a self-expanding nitinol stent of that kind, is drug-coated. Suitable drugs contain active substances with inflammation-inhibiting and proliferation-inhibiting effect. Such active substances are for example Sartane or cyclospurin A which are joined to the carrier structure of the stent by means of a polymer carrier matrix. After implantation of the stent, the active substance or substances can elute into the body tissue and deploy their desired inflammation-inhibiting or proliferation-inhibiting effect. The active substances can thus contribute to avoiding unwanted re-stenosis or unwanted inflammation.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0013] The invention will now be described by means of embodiments by way of example with reference to the accompanying Figures in which:
[0014] FIG. 1 is a diagrammatic view of a stent;
[0015] FIG. 2 shows an example of a development of the carrier structure of a stent, which forms a stent peripheral wall;
[0016] FIG. 3 shows a view in cross-section through a leg portion forming an X-ray marker for stents as shown in FIGS. 1 and 2 ; and
[0017] FIG. 4 shows an alternative configuration to FIG. 1 .
DETAILED DESCRIPTION OF THE INVENTION
[0018] The stent 10 shown in FIG. 1 is in the form of a hollow body which is open at its ends and the peripheral wall of which is formed by a carrier structure with partially folded legs 12 . The legs 12 form support portions 14 which are each formed by a respective leg which is closed in an annular configuration in the peripheral direction and which is folded in a zigzag-shaped or meander-shaped configuration.
[0019] The stent 10 is formed by a plurality of such support portions 14 which occur in succession in the longitudinal direction. The support portions or leg rings 14 are connected together by way of connecting legs 16 . Each two connecting legs which are mutually adjacent in the peripheral direction and the parts, which are in mutually opposite relationship between those connecting legs 16 , of the leg rings or support portions 14 define a mesh 18 of the stent 10 . Such a mesh 18 represents an opening in the carrier structure or peripheral wall of the stent 10 . A corresponding mesh 18 is shown emphasized in FIG. 1 .
[0020] The number of leg rings or support portions 14 and the length 1 thereof in relation to the total length L of the stent 10 depends on the purpose of use of the stent. Coronary stents are usually of a shorter overall length L and have a smaller number of support portions 14 .
[0021] The support portions 14 arranged at the two longitudinal ends of the stent 10 form end portions 20 of the stent. The annularly closed, zigzag-folded legs which form the end closure portions 20 are provided in portion-wise manner with marker elements 22 . While the legs 12 and 16 of the stent 10 are preferably made from a nitinol tube as starting material by cutting it out by means of a laser or by spark erosion, the marker elements 22 are subsequently welded to the legs 12 .
[0022] For that purpose, in the case of the example shown in FIG. 1 , in production of the carrier structure by cutting out the legs 12 and 16 from a nitinol tube, corresponding apertures are provided, into which the marker elements 22 are later welded.
[0023] As an alternative thereto, it is also possible for the end portions 20 to be produced independently of the rest of the carrier structure of the stent 10 and to be prefabricated, for example completely from a nitinol wire, for example one with a gold core. In that case, the entire end portions 20 respectively form a continuous X-ray marker which, after the operation of cutting out the rest of the carrier structure from a nitinol tube, is connected to the outermost connecting legs 24 by welding. That variant is not specifically shown in FIG. 1 as the only difference in relation to the illustration in FIG. 1 is that the entire end portion 20 forms a continuous marker element 22 .
[0024] In a further variant, one or more individual marker elements are welded to the carrier structure of a stent 10 , as is shown in FIG. 1 . This variant is shown in FIG. 4 . Accordingly, the entire carrier structure of the stent including the end portions 20 is cut out of a nitinol tube and only the marker elements 22 ′ are subsequently welded to that carrier structure.
[0025] As can be seen from the cross-section through an X-ray marker 22 and 22 ′ respectively in FIG. 3 , it is formed by a wire 30 which, in its interior, includes a core 32 of X-ray-opaque material such as for example gold. That core 32 is completely enclosed by carrier material 34 . In that respect, the carrier material 34 corresponds to the metallic material from which the rest of the stent 10 is produced. A preferred carrier material is nitinol, a titanium nickel alloy, which is also referred to as a shape memory metal. The advantage of such an X-ray marker is that it can be readily joined to the rest of the carrier structure of a stent, for example by welding, without the per se known problems such as transition or contact corrosion occurring. That is of great significance, in particular in the case of self-expanding stents comprising a shape memory metal such as nitinol.
[0026] Shape memory metals such as nitinol are preferably used for self-expanding stents. The particularity of such a shape memory metal is that it can assume two shape conditions and it makes a transition from the first shape condition into the second stable shape condition when a change temperature is exceeded. In regard to stents, the first shape condition corresponds to the compressed condition of the stent in which it is introduced for example into a blood vessel or is fitted onto a stent delivery catheter. When the change temperature is reached, the stent has a tendency to assume its expanded condition and develops corresponding expansion forces which have the desired, vessels supporting effect. In that way the stent possibly does not need to be expanded and plastically deformed by means of a balloon. The advantages and preferred design variants of self-expanding stents, in particular of shape memory metals such as nitinol, are basically known to the person skilled in the art. The advantage of a marker element of the kind described herein is that this marker element can basically be combined with all known forms of self-expanding stents, in particular also those of nitinol, without corrosion problems occurring in stents.
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A stent comprises a metallic, relatively radiolucent carrier structure and at least one marker element which includes comparatively radiopaque material. The radiopaque material is completely enclosed by a cover layer of a material other than the radiopaque material, the cover layer including metal or a metal compound. The stent may be used to treat a patient.
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FIELD OF THE INVENTION
The present invention relates to cationic radiodiagnostic agents and, in particular, to novel 99m Tc-labelled cationic radiodiagnostic agents, kits for preparing such 99m Tc-labelled cationic radiodiagnostic agents, and methods for using such 99m Tc-labelled cationic radiodiagnostic agents.
BACKGROUND OF THE INVENTION
Various complexes of monodentate and bidentate ligands with technetium have been made and studied. These complexes generally were made for use in studies to determine the various oxidation states of technetium and for other research regarding the structure of such complexes and metal-coordination chemistry. Such studies have been reported in, for instance, Chemistry and Industry, pp. 347-8 (Mar. 26, 1960); J. Inorg. Nucl. Chem., Vol. 28, pp. 2293-96 (1966); Aust. J. Chem., 23 pp. 453-61 (1970); Inorganic Chem., Vol. 16, No. 5, pp. 1041-48 (1977); J. Inorg. Nucl. Chem., Vol. 39, pp. 1090-92 (1977); and J.C.S. Dalton, pp. 125-30 (1976).
Recently, in a presentation to the American Pharmaceutical Association, E. A. Deutsch disclosed that certain complexes of DIARS, i.e. ##STR1## and Tc-99m, and certain complexes of DMPE, i.e. (CH 3 ) 2 PCH 2 CH 2 P(CH 3 ) 2 and Tc-99m, may be useful as radiodiagnostic agents for myocardial or hepatobiliary imaging. [ 99m Tc-(DMPE) 2 Cl 2 ]+ and [ 99m Tc-(DIARS) 2 ]+ were prepared by Deutsch by heating in an open flask a reaction mixture containing the appropriate hydrogen halide in aqueous alcohol solution, 99m Tc-sodium pertechnetate, and ortho-phenylenebis(dimethylarsine), i.e. DIARS, or bis-(1,2-dimethylphosphino)ethane, i.e. DMPE. The reaction was reported to take about 30 minutes. The labelled complex was then purified by chromatographic methods involving ion exchange columns.
The labelled complex produced according to the procedure of Deutsch has several practical disadvantages. The procedure requires handling several ingredients including an organic solvent to make the reaction mixture and then purifying the resulting radiolabelled complex by chromatography. Each of these handling steps can contaminate the system and final product. The purification step further requires additional time for preparation of the final product. These steps require a skilled technician and are performed at the site of use, just prior to use. Thus, a complex, time consuming chemical preparation is required during which sterility of ingredients and containers is difficult to maintain. Thus, to assure freedom from contamination, a final sterilization step is required, which further adds to preparation time. Because Tc-99m has a short half-life, lengthy preparation methods are undesirable. Thus, the complexity of the preparation, both with regard to maintaining sterile conditions and to purification of the 99m Tc-labelled complex make the Deutsch procedure undesirable.
It would be highly desirable to have a sterilized kit with all the necessary materials prepared by the manufacturer, to which only the Tc-99m need be added at the site of use to produce the desired labelled complex directly in high enough yield to obviate the need for purification. It would also be desirable for the kit materials to be in a closed container or vial, pre-sterilized, so that the only step to be performed at the site of use would be the addition of the radionuclide. To increase stability and shelf-life of the kit, it would be highly desirable that the materials be readily lyophilized, preferably from an aqueous solution.
By achieving the desirable features outlined above, a convenient-to-use heart imaging radiopharmaceutical agent would be provided that is capable of concentrating in healthy heart tissue to provide a negative image of an infarct, damaged or ischemic tissue.
A copending application, Ser. No. 311,770, filed Oct. 15, 1981 in the name of Vinayakam Subramanyam, which is hereby incorporated by reference, describes an acid salt of a mono or polydentate ligand that is water soluble, stable in a lyophilized state, and is capable of binding with Tc-99m to form a cationic complex. The acid salt may be generally represented by the formula: ##STR2## wherein:
i is an integer from 1 to 6;
R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are the same or different neutral donor atoms, each having a free electron pair available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex;
Z is preferably a parenterally acceptable anion;
k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one;
n 1 , n 2 , n 3 , n 4 , n 5 and n 6 are independently 0 or 1; and
n 7 and n 8 are integers from 1 to 6 where ##EQU1## and the charge represented by n 8 Z is equal in magnitude and opposite in sign to +n 7 ; or ##STR3## wherein:
R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A, A' and A" are independently selected from the group of neutral donor atoms having a pair of electrons available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex;
j, j' and j" are independently 0 or 1;
n, n' and n" are independently the integer 1 or 2;
Z is the same as defined above;
n 9 and n 10 are integers selected from 1 to about 3, where n 9 =j+j'+j" and the charge represented by n 10 Z is equal in magnitude and opposite in sign to +n 9 .
These acid salts are normally solid compounds, water-soluble, readily lyophilized, and capable of reducing pertechnetate and binding with technetium to form stable cationic complexes.
SUMMARY OF THE INVENTION
The present invention provides a cationic lipophilic complex of technetium wherein all of coordination positions of the technetium atom are filled with a donor atom having a pair of electrons available for forming a coordinate bond with technetium to form a cationic complex, said donor atoms being provided by ligands or a salt thereof, said ligands having the following structure: ##STR4## wherein
i is an integer from 1 to 6;
R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R i may be taken together to form a cyclic compound or separately to form a linear compound;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are the same or different donor atoms, each having a free-electron pair available for complexing with Tc-99m or Tc-99 to form a cationic comples; and
k 1 , k 2 , k 3 , k 4 , k 5 and k 6 are each independently zero or one; ##STR5## wherein:
R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
X and X' are saturated or unsaturated alkyl groups; A, A' and A" are independently selected from the group of donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; t and t' are independently 0 or 1; n is 0, 1 or 2; and n' and n" are independently the integer 1 or 2; or ##STR6## wherein
R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups;
A', A" and A'" are independently selected from the group of donor atoms having a pair of electrons available for complexing with TC-99m or TC-99 to form a cationic complex;
B is an atom selected from the group of donor atoms having a pair of electrons for complexing with Tc-99m or Tc-99, boron or from the elements listed in Group IV A of the periodic table (i.e C, Si, Ge, Sn, and Pb);
m is 0 or 1; and
n', n" and n'" are independently the integer 1 or 2.
The R's in formulas I, II and III are preferably substituted or unsubstituted alkyl radicals having 1 to about 6 carbon atoms such as methyl, ethyl, etc., and the like, and substituted or unsubstituted aryl radicals such as benzyl, phenyl, etc., and the like. When more than one R group is attached to the same donor atom, the R groups so attached can be the same or different. Salts of the ligands of formulas I, II and III are preferably water soluble salts such as described by Subramanyam in copending Ser. No. 311,770, as aforesaid.
The cationic complexes of this invention, when radiolabelled are useful for radiodiagnostic tests in connection with myocardial and hepatobiliary tissues.
DETAILED DESCRIPTION OF THE INVENTION
A wide variety of monodentate and polydentate ligands are useful in the practice of this invention. Water-soluble ligand acid salts can be prepared from said ligands in accord with Subramanyam Ser. No. 311,770, as aforesaid. Typical examples of such ligands include, for instance, aryl compounds having arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, substituted ortho to each other. For example, o-phenylene compounds having the structure: ##STR7## in which M and M' are arsenic, phosphorus, nitrogen, sulfur, oxygen, selenium, tellurium, or any combination of them, n and n' are independently 1 or 2 depending upon the particular donor atom used for M and M', and R and R' are independently hydrogen, or an organic group, preferably an alkyl group having 1 to 6 carbon atoms, an aryl group such as phenyl, or the like, and substituted such groups. When more than one R group is attached to the same donor atom, such R groups can be the same or different. Additional examples of suitable ligands include bidentate tetraethylene ligands of the formula:
R'.sub.n,M'--CX'.sub.2 --MR.sub.n V
in which M, M', R, and R' are as defined above, n and n' are 1 or 2 depending upon the particular M and M', and X and X' are independently selected from hydrogen, halide, or substituted or unsubstituted lower alkyl groups having 1 to about 6 carbon atoms. Further examples of suitable ligands include those having the formula: ##STR8## where M, M', R, and R', are as defined above, M" is independently selected from arsenic, phosphorous, nitrogen, sulfur, oxygen, selenium, and tellurium, n is 0 or 1, n' and n" are independently 0, 1 or 2, and R" is independently selected from hydrogen, halide or an organic radical, preferably an alkyl radical having 1 to about 6 carbon atoms, an aryl radical such as phenyl, or the like, and substituted such groups.
Throughout this application, whenever more than one R group is attached to the same donor atom, such R groups can be the same or different.
Particularly preferred ligands for the practice of this invention are the bis-dialkylphosphinoethanes, their substituted derivatives, and similar ligands, including, for example,
1,2-bis(dimethylphosphino)ethane,
1,2-bis(di(trifluoromethyl)phosphino)ethane,
1,2-bis(dimethylphosphino)-1,1-difluoroethane,
1,2-bis(dimethylphosphino)-1-fluoroethane,
1,2-bis(dimethylphosphino)propane,
1,2-bis(di(trifluoromethyl)phosphino)-1,1,2,2-tetrafluoroethane,
1,2-bis(di(trifluoromethyl)phosphino)propane,
2,3-bis(di(trifluoromethyl)phosphino)butane,
1,2-bis(di(trifluoromethyl)phosphino)butane,
1,3-bis(dimethylphosphino)butane,
1,3-bis(dimethylphosphino)propane,
1,3-bis(di(trifluoromethyl)phosphino)propane,
1,2-bis(dimethylphosphino)-1,1-dichloro-2,2-difluoroethane,
1,2-bis(diethylphosphino)ethane,
1,2-bis(diisopropylphosphino)ethane,
1,2-bis(dipropylphosphino)ethane,
1-dimethylphosphino-2-diisopropylphosphinoethane,
1,2-bis(diisobutylphosphino)ethane,
1-dimethylphosphino-2-dimethylarsinoethane,
and other similar compounds wherein the phosphorus is replaced by nitrogen, arsenic, sulfur, oxygen, selenium, tellurium, or any other atom having a free electron pair, and the like.
Other useful ligands include the alkylaminobis(difluorophosphine), i.e., RN(PF 2 ) 2 , ligands and the like where R is an organic group, preferably an alkyl group having 1 to about 6 carbon atoms, an aryl group as phenyl, or the like, and substituted such groups; and the o-phenylene compounds such as, for example, orthophenylenebis(diarsine), orthophenylenebis(dimethylarsine), orthophenylenebis(diamine), orthophenylenebis(dimethylamine), orthophenylenebis(diphosphine), orthophenylenebis(dimethylphosphine), and the like.
Additional ligands suitable for use in the present invention are those described by Nozzo et al., in J. Amer. Chem. Soc., 101, p. 3683 (1979) and by Wilson et al., J. Amer. Chem. Soc., 100, p. 2269 (1978), which are hereby incorporated by reference.
Any donor element can be used in the ligand in accord with this invention provided that it is an atom having a free-electron pair available for accepting a proton to provide a charged ligand and further provided that it has the capability of complexing with technetium (Tc-99 or Tc-99m) to form a cationic complex in the presence of suitable anions. Suitable such elements include, for instance, phosphorous (P), arsenic (As), nitrogen (N), oxygen (O), sulfur (S), antimony (Sb), selenium (Se), tellurium (Te), and the like. Preferred elements are P and As.
The cationic technetium complexes of this invention that are useful for radiodiagnostic treatments are prepared by mixing the ligand and 99m Tc-pertechnetate in an aqueous or alcoholic solution having a basic pH, preferably 9.0 or more, and heating the mixture to form the cationic complex. Preferably, the ligand is provided as a lyophilized ligand acid salt as described by V. Subramanyam in copending application Ser. No. 311,770 and is contained in a sealed, sterilized vial prior to adding the pertechnetate. The pertechnetate solution can then be injected into the vial under aseptic conditions to maintain sterility. To obtain high yields, the vial is generally heated and maintained at an elevated temperature for sufficient time to form a complex of the ligand with technetium. The vial should preferably be heated to at least 80° C. for a suitable length of time, i.e. about 30 minutes or more at 80° C. Preferably, the vial is heated to 100° C. or more, and more preferably to a temperature in the range of from about 130° C. to about 150° C. At about 150° C., the reaction can be completed in about five to ten minutes, depending upon the choice and concentrations of the reactants. After cooling, the resulting radiopharmaceutical preparation may be adjusted for pH and is ready for use. Typically, when the pH is adjusted, it is adjusted into the range of from about 4.0 to about 9.0, and preferably to physiological pH.
It has been found that the preparation of the cationic technetium complex is improved by the addition of a polyhydroxy-compound to the reaction mixture. The use of the polyhydroxy-compound, for reasons not fully understood, results in a more consistent yield of the cationic technetium complex. Preferred polyhydroxy-compounds include, for example, Hetastarch (hydroxyethyl starch), mannitol, glycerol, D-mannose, sorbitol, and the like.
In order to form the cationic complexes of this invention a basic pH is desired for the complexing reaction to provide high yields of the desired complex. Preferably the pH is maintained at a pH of about 9 or more during the complexing reaction, and more preferably at a pH in the range of from about 10 to about 12.
To image the heart of a mammal, in-vivo, a radiopharmaceutical preparation in accord with the invention, having a suitable quantity of radioactivity for the particular mammal, is injected intravenously into the mammal. The mammal is positioned under a scintillation camera in such a way that the heart is covered by the field of view. High quality images of the heart are obtained analogous to those seen in clinical studies using Thallium-201.
In order to obtain high quality images the yield of radioactive labelled cationic technetium complex should preferably be greater than 70% after reconstituting the lyophilized mixture and labelling. Lower yields will result in poorer image quality and undesirable purification steps will be required to produce high quality images.
This invention will be further illustrated by the examples that follow:
EXAMPLE 1
Preparation of 1,2-Bis(dimethylphosphino)ethane-bis(tetrafluoroborate), i.e. (DMPEH) 2 2+ .2BF 4 -
Place 210 mg of bis(dimethylphosphino)ethane in a 50 ml round-bottomed flask maintained under a nitrogen atmosphere, and dissolve it in 10 ml of ethanol. Add 0.5 ml of a 49% solution of tetrafluoroboric acid. After 15 minutes, remove the solvent in a rotary evaporator and recrystallize the product friom 15 ml of ethanol. Filter and dry under vacuum. 406 mg of a crystalline solid is obtained, which melts at 199.5°-210° C.
EXAMPLE 2
Preparation of 1,2-Bis(dimethylphosphino)ethane bis-bisulfate, i.e. DMPEH 2 2+ .2HSO - 4 or DMPE.2H 2 SO 4
Dissolve 470 mg of DMPE in 10 ml of ethanol in a 50 ml round-bottomed flask maintained under a nitrogen atmosphere. From a glass syringe, add, with stirring, 0.34 ml of concentrated sulfuric acid. After 10 minutes, filter the precipitate and recrystallize it from 10 ml. of methanol. Filter and dry under vacuum. 920 mg of a crystalline solid is obtained, which melts at 135°-136.5° C. Structure and purity of the compound was confirmed by its infra-red and nuclear magnetic resonance spectra and elemental analysis.
EXAMPLE 3
Preparation of [Tc(DMPE) 3 ] +
Add 10 ml. of degassed ethanol into a 25 ml. round-bottomed flask followed by 0.5 m mole (90 mg.) of NH 4 99 TcO 4 (purified by recrystallization) and 2 m mole (300 mg) of Bis-(dimethylphosphino)ethane (DMPE). Reflux the solution under Argon atmosphere for 6 hours with stirring. Cool and add 0.5 m mole of sodium tetraphenylborate dissolved in 5 ml of ethanol to precipitate [ 99 Tc(DMPE) 3 ] + [BPh 4 ] - as an off-white colored solid. Filter and wash the residue with water and ethanol. Dry in a vacuum desiccator. Yield is 90% of [ 99 Tc(DMPE) 3 ] + as determind by high pressure liquid chromatography (HPLC). Recrystallize the salt from acetonitrile.
The product is a white solid melting at >250° C. It moves toward a cathode (-dc) in an electrophoretic field indicating it is positively charged. Infra-red spectrum of the complex shows all absorptions characteristic of DMPE ligand and no Tc=0 stretch is seen. It is diamagnetic.
Elemental Analysis of the complex was done and the results calculated for [Tc(DMPE) 3 ] + [BPh 4 ] - are given below:
______________________________________ Calculated Observed______________________________________Carbon 58.07 58.72Hydrogen 7.89 7.98Phosphorus 21.14 21.24______________________________________
Specific activity of 99 Tc-Liquid scintillation count Method.
Calculated for [Tc(DMPE) 3 ] + [BPh 4 ] - =1683 μCi/μ mole. Observed=1694±2 μCi/μ mole.
EXAMPLE 4
Alternative Preparation of [Tc(DMPE) 3 ] +
Place 4 ml. of degassed ethanol in a 10 cc vial and add 0.2 ml. of 1N sodium hydroxide solution followed by 20 mg. of purified Tc-99 ammonium pertechnate [NH 4 99 TcO 4 ]. Add 1 ml (800 mg) of DMPE and 50 mg. of sodium chloride. Dissolve 90 mg. of sodium dithionite [Na 2 S 2 O 4 ] in 0.35 ml. of 1N sodium hydroxide solution and add to pertechnate solution. Let stand at room temperature for 15 minutes. Crude yield of desired compound is about 80% based on thin layer chromatography.
EXAMPLE 5
Preparation of [ 99m Tc(DMPE) 3 ] +
Dissolve 5 g mannitol and 115 mg DMPE-bis(bisulfate) of Example 2 (or an equivalent quantity of the bistetrafluoroborate salt of Example 1) in about 35 ml low-oxygen distilled water, and adjust the pH to 1.0 with 3N sulphuric acid. Under cover of nitrogen and with stirring add low-oxygen distilled water gravimetrically to a solution weight of 50 g. Dispense 1 ml of this solution into each of several 10 cc vials. Freeze-dry in keeping with procedures well-known to those skilled in the art, stoppering under nitrogen. Reconstitute each of the vials with 1 ml of physiological saline containing about 10-20 mCi of 99m Tc-pertechnetate, and add 0.15 ml 1N sodium hydroxide solution. The pH is about 12. Autoclave for 30 minutes at 135° C. TLC analyses show almost 95% yield of [ 99m Tc(DMPE) 3 ] + , the structure and charge of the complex having been confirmed by elemental analysis, infra-red and nuclear magnetic resonance spectra of the Tc-99 analogue, and by electrophoretic mobility.
EXAMPLE 6
Preparation of 99m Tc[(1-dimethylarsino)(2-dimethylphosphino)ethane 3 ] + ( 99m Tc(ASP) 3 + ), i.e.
1.0 ml of well degassed normal saline (0.15M NaCl), containing 50 mCi of 99m Tc-pertechnetate is dispensed into a nitrogen purged, crimp sealed 10 cc vial. 10 μl of 1-dimethylarsino-2-dimethylphosphinoethane is added via syringe, and the vial boiled for 45 minutes in a 100° C. water bath. Analysis by thin layer chromatography shows yields of 79-81% labeled product, 99m Tc (ASP) 3 + .
EXAMPLE 7
Preparation of 99m Tc(bis(1,2-diethylphosphino)ethane) 3 + , i.e. 99m Tc(DEPE) 3 + )
Under nitrogen with stirring, 30 μl of 1,2-diethylphosphinoethane is added to 20 ml of 95% ethanol. The solution is adjusted to pH 12.3 with 0.25N solium hydroxide and 0.5 ml of solution dispensed into each of several N 2 purged crimp sealed vials. 0.5 ml of normal saline, containing 40-60 mCi of 99m Tc-pertechnetate solution is added to each vial. Labelling, by heating in an autoclave for 40 minutes at 150° C. yields 30 to 45% labelled product, 99m Tc(DEPE) 3 + , as analyzed by high pressure liquid chromatography.
EXAMPLE 8
Preparation of 99m Tc(bis(1,2-dimethylphosphino)propane) 3 + , i.e. 99m Tc(DMPP) 3 +
Under nitrogen, with stirring, 40 μl of bis(1,2-dimethylphosphino)propane is added to 20 ml of 95% ethanol. 2 ml of this solution is dispensed into each of several nitrogen purged, crimp sealed 10 cc vials, and 10 μl of 0.25N sodium hydroxide added to each vial. 0.5 ml of normal saline containing 20-40 mCi of 99m Tc-pertechnetate solution is added to each vial. Labelling by heating in an autoclave for 40 minutes at 150° C. yields 30% labelled product, 99m Tc(DMPP) 3 + , as analyzed by high pressure liquid chromatography.
EXAMPLE 9
Imaging of Rabbit Heart Using T1-201 (Prior Art)
2 mCi of Thallium-201 (as thallous chloride in physiological saline containing 0.9% benzyl alcohol) is injected intravenously into a 2.5 Kg male New Zealand Albino rabbit. The rabbit is positioned under a Searle Pho-Gamma scintillation camera in such a way that the heart and lung area are covered by the field of view. Approximately 10 minutes after injection, sufficient counts are accumulated to produce an image of the heart analogous to that seen in clinical studies of humans.
EXAMPLE 10
Imaging of Rabbit Heart Using 99m Tc-labelled Products with ≧80% Yield of Desired Labelled Complex
Greater than 1 mCi of the 99m Tc-labelled product of Example 5 or Example 6 is injected into a rabbit and imaged as in Example 9. The quality and appearance of the heart image is similar to that obtained in Example 9.
EXAMPLE 11
Imaging of Baboon Heart Using 99m Tc-labelled Products with ≧80% of Desired Labelled Complex
Greater than 10 mCi of the 99m Tc-labelled product of Example 5 or Example 6 is injected intravenously into an adult baboon positioned under a scintillation camera as was the rabbit in Example 10. Excellent quality images of the heart are obtained, which are equivalent to those characteristically obtained with Tl-201 in humans.
This invention has been described in detail with particular reference to the preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon reading this disclosure, may make modifications and improvements within the spirit and scope of the invention.
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A cationic lipophilic complex of technetium is disclosed wherein all of the coordination positions of the technetium atom are filled with a neutral donor atom having a pair of electrons available for forming a coordinate bond with technetium. The donor atoms are provided by target-seeking ligands or salts thereof, said ligands having the following structure of one of formulas I, II or III. Such complexes are useful for imaging heart and hepatobiliary tissues.
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FIELD OF THE INVENTION
The invention relates to ratchet wrenches and more particularly to improved ratchet wrenches of the socket drive type.
BACKGROUND OF THE INVENTION
One of the most common types of mechanic's wrenches currently in use is the socket with a ratchet drive. The ratchet drive accommodates a number of sockets having a range of sizes to make up a set. A selected socket is received on a drive stud and is normally retained thereon by means of a detent device. Ratchet drives of the prior art of which I am aware, and particularly their ratchet pawls, have been susceptible to excessive wear. Such prior art ratchet drives have also had other problems including being subject to accidental disassembly under certain conditions; being subject to ratchet pawl failure under certain conditions; and requiring strict manufacturing tolerances.
It is accordingly the general object of the present invention to provide an improved ratchet wrench of the type utilizing sockets with a ratchet drive.
Another object of the present invention is to provide, for ratchet wrenches utilizing sockets with a ratchet drive, a ratchet pawl having an improved configuration which results in significant reduction of excessive wear and the attendant problems.
Another object of the present invention is to provide an improved ratchet wrench of the type utilizing sockets wherein the problem of accidental disassembly is obviated.
Another object of the present invention is to provide an improved ratchet wrench of the socket drive type wherein problems with ratchet pawl failure under certain conditions are obviated.
Another object of the present invention is to provide an improved ratchet wrench of the socket drive type wherein the strictness of required manufacturing tolerances is significantly reduced.
For a further understanding of the invention and further objects, features, and advantages thereof, reference may now be had to the following description, taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of a typical ratchet wrench with socket drive and incorporating socket ejector means, in accordance with a preferred embodiment of the invention.
FIG. 2 is a side elevational view of the ratchet wrench of FIG. 1, without a socket installed and with a portion of the handle removed.
FIG. 3 is a side elevation view, partly in section and partly cut away, showing the interior of the drive assembly of the ratchet wrench of FIG. 2, with a socket ejector in the retracted position and with a socket (shown in phantom) in working position on the drive stud.
FIG. 4 is like FIG. 3, but with the socket ejector in the extended or ejecting position (the socket has been ejected).
FIG. 5 is an exploded perspective view of the ratchet drive assembly.
FIGS. 6 and 7 are top plan views of a typical ratchet drive of the prior art, with portions cut away to show the ratchet pawl and coacting parts.
FIGS. 8 and 9 are top plan views corresponding with those of FIGS. 6 and 7, but showing the ratchet pawl and coacting parts in accordance with a preferred embodiment of the invention.
FIGS. 10, 11, 12 and 13 are enlarged fragmentary schematic top plan views showing the ratchet pawl and coacting parts of the device shown by FIG. 9 in several stages of their operation.
DESCRIPTION OF PREFERRED EMBODIMENT
For convenience, a ratchet wrench with socket drive which incorporates improvements in accordance with a preferred embodiment of the invention will first be described and then the improvements will be discussed.
Referring now to the drawings it can be seen that the ratchet drive is made up of a handle 11 and a ratchet plug assembly 13. The handle 11 has a lever portion 15 which is integrally merged with a cylindrical head portion 17. The cylindrical head portion 17 has a central bore with spline-like teeth 19 formed therein.
The ratchet plug assembly 13 (see FIGS. 3 and 4) includes ratchet plug 21, ratchet pawl 23, control knob 25, ratchet reversing pin 27, reversing pin bias spring 29, first socket ejector pin 31, second socket ejector pin 33, ejector pin retainer plate 35, control knob return spring 37 and ratchet plug assembly retainer ring 39.
The ratchet plug 21 comprises a generally cylindrical body portion 41 and a drive stud portion 43. The cylindrical body portion 41 comprises a cylindrical exterior portion 45, a retainer ring groove 47, a bearing shoulder 49, a spinner control flange 51, a control knob recess 53, a control knob bore 55, a ratchet pawl slot 57, first and second ejector pin bores 59, 61, and a drive stud end surface 62.
The cylindrical exterior portion 45 has a diameter that is slightly less than the minor diameter of the spline-like teeth 19 of the handle head portion 17 and a length that is substantially equal to that of the spline-teeth 19. The cylindrical exterior portion 45 merges at one end with the retainer ring groove 47 and at the other end with the bearing shoulder 49 which in turn merges with the spinner control flange 51. The ratchet pawl slot 57 has parallel side faces that are spaced a distance slightly greater than the width of the ratchet pawl 23 and bottom surfaces that lie in a plane parallel to and passing near the central axis of the ratchet plug 21. The ratchet pawl slot 57 is closely adjacent the retainer ring groove 47, which in turn is closely adjacent the body portion drive stud end surface 62. The end surface 62 is generally planar and is perpendicular to the ratchet plug central axis.
The control knob has a head portion 63 and a stub shaft portion 65. The head portion 63 has the shape of a disc, the top surface of which merges with an integral generally rectangular boss 67. The stub shaft portion 65 is cylindrical and is coaxial with the head portion 63.
The control knob recess 53 is cylindrical; is coaxial with the ratchet plug 21; has a diameter slightly greater than that of the control knob head portion 63; and has a planar bottom surface 69 that is perpendicular to the ratchet plug central axis. The control knob bore 55 is cylindrical; is coaxial with the ratchet plug 21; has a diameter slightly greater than that of the control knob stub shaft portion 65; and merges at its open end with the control knob recess bottom surface 69. The first and second ejector pin bores 59, 61 are cylindrical; have the same diameters, which are slightly greater than those of the ejector pins 31, 33; are disposed on opposite sides of the control knob bore 55; have their axes parallel to that of the control knob bore 55; open at one end to the control knob recess bottom surface 69 and at the other end to the drive stud end surface 62 of the cylindrical body portion 41. A plane containing the axes of the ejector pin bores 59, 61 is perpendicular to a plane containing the bottom surface of the ratchet pawl slot 57.
The drive stud portion 43 of the ratchet plug 21 is integral with the cylindrical body portion 41; extends outwardly from the drive stud end surface 62; is coaxial with the ratchet plug 21; has the conventional generally square transverse section shape; is dimensioned to receive the sockets of a set having the corresponding drive size; and is provided with the conventional detent ball 71 and spring (not shown).
The ratchet pawl 23 has a generally arcuate outer surface having a set of axially extending spline-like teeth 73, 74 at each end portion thereof; an inner surface having an axially extending center notch portion 75 with a respective planar portion 77, 79 extending outwardly from each side of the notch portion; a rocker bore 81 extending axially of the ratchet pawl 23 and opening to respective parallel planar pawl side faces 83, 85 with the rocker bore axis being parallel to said spline-like teeth 73, 74 and lying in a plane that bisects the ratchet pawl 23.
The first and second ejector pins 31, 33 are alike and each have a cylindrical exterior surface portion 87 and a flanged head portion 89. The ejector pin retainer plate 35 has a generally rectangular shape with tapered ends; a pair of oppositely disposed end slots 91 and a side slot 93.
To assemble the ratchet plug assembly 13, the respective ejector pins 31, 33 are mounted in the retainer plate end slots 91 which conform with the pin exterior surface portions 87 and space the pins in alignment with the ejector pin bores 59, 61. The retainer plate 35 is then mounted to the control knob 25, with the side slot 93 being conformingly received by a peripheral groove 97 at the inner end of the control knob stub shaft portion 65. The width of the peripheral groove 97 is such that the ejector pin heads 89 are in substantially abutting relation to the inner face 99 of the control knob head portion 63. Next, the ratchet reverse pin 27 and its bias spring 29 are inserted in a transverse bore 101 in the control knob stub shaft portion 65 and the control knob return spring 37 is inserted in the control knob bore 55. Next, the control knob 25, with attachments, is inserted in the ratchet plug control knob recess 53 (see FIGS. 3 and 4); with the ejector pins 31, 33 having been received by the ejector pin bores 59, 61; with the first ejector pin 31 having been passed through the ratchet pawl rocker bore 81, the ratchet pawl having been correctly positioned in the ratchet pawl slot 57; with the ratchet reverse pin 27 having been compressed so as to pass through the control knob bore 55 and then extended so as to bear against the ratchet pawl inner surface; and with the control knob return spring 37 having been received at its outer end by a locator 103 in the outer end of the control knob stub shaft portion 65 and having been compressed so as to bias the control knob 25 to move in the outward direction until the ratchet reversing pin 27 bears against a side face 95 of the ratchet pawl slot 57, at which time the outer surface of the control knob head 63 is substantially flush with the surface of the spinner control flange 51.
To assemble the ratchet plug assembly 13 onto the handle 11, the ratchet plug cylindrical exterior portion 45 is inserted into the bore of the handle cylindrical head portion 17 until the bearing shoulder 49 abuts one side face 105 of the handle cylindrical head portion 17, at which time the retainer ring groove 47 will extend outwardly just beyond the other side face 107 of the handle cylindrical head portion 17. The ratchet plug assembly retainer ring 39 is then installed in the retainer ring groove 47. The ratchet retainer ring may be a conventional commercially available type made of spring strip material formed to have the shape of a circular flat spiral, as shown. The retainer ring 39 can be expanded radially to increase its inner diameter sufficiently to pass over the periphery of the drive stud end surface 62 and then will relax so that its inner diameter will substantially conform to the bottom of the retainer ring groove 47. When the retainer ring 39 is installed, its inner side surface will bear against the adjacent side face 107 of the handle cylindrical head portion 17 so as to substantially prevent axial movement of the ratchet plug assembly 13. When inserting the ratchet plug assembly 13 into the bore of the handle cylindrical head portion 17 it is necessary to rock the ratchet pawl 23 slightly in a direction to compress the ratchet reverse pin bias spring 29, which then permits the teeth 73, 74 of the pawl 23 to pass into the bore of the handle cylindrical head portion 17. When installing pressure on the pawl 23 is released, the bias spring 29 acting on the ratchet reversing pin 27 will rock the ratchet pawl 23 so that its respective teeth 73 or 74 are in proper engagement with the spline-like teeth 19 of the handle cylindrical head portion 17.
In operation, a socket 109 (shown in phantom in FIG. 3) is installed on the drive stud portion 43 and is held in place in a conventional manner by action of the detent ball 71. The control knob 25 is then in the ejector pin retracted position and the ratchet pawl 23 (as shown by FIG. 3) is in the drive clockwise and ratchet counter clockwise position. To drive counter clockwise and ratchet clockwise the control knob 25 is simply rotated to its extreme clockwise position, causing the ratchet reverse pin 27 to shift its position on the inner surface of the ratchet pawl 23 so as to pivot the ratchet pawl on the first ejector pin 31 so as to disengage one set of pawl teeth 74 and engage the other set 73. To eject the socket 109, the control knob 25 is depressed to the ejector pin extended position (see FIG. 4) and the socket 109 is pushed by the ejector pins 31, 33 out of engagement with the detent ball 71 and off the end of the drive stud 43.
The essence of the present invention resides in an improved ratchet pawl configuration. To aid in the explanation of some of the advantages of the improved ratchet pawl configuration, it will be helpful to refer to FIGS. 6 and 7 wherein there is shown a ratchet wrench having a ratchet pawl configuration which is typical of the prior art. The ratchet wrench of FIGS. 6 and 7 includes a handle 111 having a cylindrical head portion 113 with a central bore having spline-like teeth 115 formed therein, a ratchet plug 117, a ratchet pawl 119, first and second socket ejector pins 121, 123, a control knob stub shaft portion 125, a ratchet reversing pin 127 and a reversing pin bias spring 129.
In FIG. 7, the prior art device is shown with the ratchet pawl 119 positioned for the torquing of the ratchet wrench in the clockwise direction and ratcheting in the counter clockwise direction. The ratchet pawl 119 has an arcuate inner surface 131 which coacts with the ratchet reversing pin 127. The ratchet reversing pin 127 is urged into constant contact with the arcuate surface 131 by the action of the reversing pin bias spring 129. The ratchet reversing pin 127 is cylindrical and has a circular end face, which means that the area of the contact between the arcuate surface 131 and the ratchet reversing pin 127 is theoretically a point, and in actual practice, is very, very small. As the ratcheting action of the wrench takes place, there is a relative short reciprocating motion between the point of contact of the reversing pin 127 and the arcuate surface 131. Since the bearing area is very, very small and the ratcheting action takes place often and repeatedly when the wrench is in use, a depression is soon worn into the arcuate surface 131 at both the clockwise and counter clockwise ratcheting position. Then, each time a reversing action takes place it is necessary that the reversing pin 127 be moved out of the respective depression before it can be traversed to the other wrench torquing position. The wrench reversing action becomes more difficult and frustrating to the operator as the respective depression is worn deeper. The useful life of the wrench is prematurely terminated when a depression is worn so deep that the reversing action becomes inoperative. In some ratchet wrenches in the prior art of which I am aware, attempts have been made to alleviate the wear problem above mentioned by changing the shape of the end portion of the reversing pin, but these attempts have not proved to be completely successful.
Another problem with prior art ratchet wrenches is that of accidental disassembly. This problem can be explained with reference to FIG. 6, wherein the ratchet pawl 119 is positioned for torquing of the wrench in the clockwise direction while the reversing pin 127 has moved to an extreme position which is clockwise beyond where it would normally be when the ratchet pawl 119 is positioned for counter clockwise torquing. Under these conditions, the clockwise end portion of the pawl arcuate surface 131 has forced the reversing pin 127 inwards so that it no longer extends beyond the periphery of the outer surface of the control knob stub shaft portion 125. This means that the wrench is free to disassemble, since it is normally retained against disassembly by the extending of the reversing pin 127 beyond the periphery of the outer surface of the control knob stub shaft portion 125.
Another problem with prior art ratchet wrenches is that under certain conditions forces can be applied to the ratchet pawl 119 in a manner that will result in pawl failure. For example, with reference to FIG. 7, if the control knob stub shaft portion 125 were not provided with the reduced transverse section shown, then torquing of the wrench could cause the end portion of the ratchet pawl arcuate surface 131 to bear against the control knob stub shaft portion 125 and thus transmit force to the ratchet pawl 119 causing it to fail in the region between the pawl rocker bore 133 and its arcuate inner surface 131. Providing the control knob stub shaft portion 125 the reduced transverse section at its central region alleviates the pawl failure problem, but only at the expense of additional manufacturing costs and a weakening of the control knob stub shaft portion 125.
The improved ratchet pawl configuration of the present invention not only obviates all of the above mentioned problems, but makes possible additional significant advantages as well. A basic feature of the improved ratchet pawl configuration is the provision of an axially extending center notch portion on its inner surface. In the embodiment shown, the center notch portion 75 has the shape of a truncated "V". The reversing pin 27 is substantially a right cylinder having a substantially planar and circular outer end face 135. The diameter of the reversing pin outer end face 135 slightly exceeds the transverse width of the truncated "V", thus precluding the simultaneous entry of more than a portion of the outer end face 135 into the notch portion 75.
The operation of the improved ratchet pawl configuration may be explained with reference to FIGS. 10-13. In FIG. 10, the ratchet pawl 23 and reversing pin 27 are shown in the normal position for clockwise wrench torquing (as also shown by FIG. 9). A first set of ratchet pawl teeth 74 is engaged with the spline-like teeth 19 of the wrench handle cylindrical head portion 17, which establishes the extreme clockwise angular position (relative to its rocker pivot 31) for the ratchet pawl 23. The reversing pin 27 has been moved to its extreme counter clockwise position where its movement is stopped by the contact of its side surface with the bottom of the ratchet pawl slot 57 of the ratchet plug 21. Under these conditions, an outer edge portion of the notch portion first side face 137 is in contact with the reversing pin outer end face 135 in the region of a diameter of the reversing pin outer end face 135, and the counter force applied to the reversing pin 27 by the ratchet pawl notch portion first side face 137 is substantially parallel to the longitudinal axis of the reversing pin 27. As a result, there is no side thrust on the reversing pin 27 to cause binding and the force applied toward engagement of the first set of ratchet pawl teeth 74 is maximized. Furthermore, the contact between the reversing pin outer end face 135 and the notch portion first side face 137 is theoretically at least a line that extends always fully across the reversing pin outer end face 135, and as a practical matter is a relatively large area (particularly as compared to the corresponding contact area of the prior art devices discussed hereinbefore with reference to FIG. 7). As a consequence, the bearing load is distributed over a relatively large area of the ratchet pawl notch portion first side face 137 and the reversing pin outer end face 135, thus greatly reducing wear due to ratcheting and reversing actions. Such wear as may occur on the ratchet pawl notch portion first side face 137 will not adversely affect the wrench reversing operation.
In FIG. 11, a wrench reversing operation has begun and, without disturbing the angular position of the ratchet pawl 23 (from that of FIG. 10), the reversing pin 27 has been moved clockwise to where its side surface has just made contact with the notch portion second side face 139. As the reversing pin 27 is moved further in the clockwise direction, it will positively urge the ratchet pawl 23 to pivot in the counter clockwise direction until the reversing pin outer end face 135 clears the notch portion 75, at which time neither set of ratchet pawl teeth 73, 74 is engaged and the reversing pin outer end face 135 is generally bridging the notch portion 75, as shown by FIG. 12. As the reversing pin 27 is moved still further in the clockwise direction, the reversing pin outer end face 135 moves off the outer edge of the notch portion first side face 137 and then rapidly into contact with the notch portion second side face 139 and quickly urges the second set of ratchet pawl teeth 73 into engagement with the cylindrical head portion spline-like teeth 19. Clockwise movement of the reversing pin 27 is stopped by contact of its side surface with the bottom of the ratchet pawl slot 57 of the ratchet plug 21. The wrench is now in the position for counter clockwise torquing, as shown by FIG. 13. The action of the ratchet pawl and the reversing pin 27 and their relative positions for counter clockwise torquing and clockwise ratcheting are the same as has been previously described with reference to FIG. 10.
Some typical parameters and dimensions (given in thousandths of inches) for a typical one-half inch drive size ratchet wrench embodying the principles of the present invention are: ratchet pawl notch portion--width 107, depth 52, included angle 80 degrees; handle cylindrical head portion--number of teeth 45, teeth major diameter 1218, tooth depth 28; angle through which ratchet pawl pivots from clockwise to counter clockwise engagement--20 degrees; reversing pin--length 252, diameter 125; angle through which reversing pin moves from clockwise to counter clockwise stop positions--53 degrees; distance from ratchet plug (or control knob stub shaft) pivot axis to ratchet pawl pivot axis --392.
It should be apparent from the foregoing that a ratchet wrench embodying the principles of the present invention will be free of the problems of prior art ratchet wrenches hereinabove discussed. Specifically, the problem with wrench reversing action due to pawl inner surface wear is obviated. The problem of disassembly does not occur because it is not possible for the ratchet pawl and the reversing pin to assume relative positions that would force the reversing pin inwards of the outer periphery of the control knob stub shaft portion. In FIG. 8, the reversing pin 27 is shown in an extreme position relative to the ratchet pawl 23 (the likelihood of the occurrence of such a position is very remote) and yet the reversing pin 27 still extends beyond the periphery of the control knob stub shaft portion 65, so that disassembly cannot occur. The problem of ratchet pawl failure in the region between the rocker bore and the notch portion cannot occur, since the ratchet pawl cannot bear against the control knob stub shaft portion when it is being torqued, even though the control knob stub shaft portion has no reduced transverse section.
Ratchet wrenches embodying the principles of the present invention have the important advantage that they can be manufactured using liberal dimensional tolerances for the coacting parts, which can significantly reduce manufacturing costs in various ways including making possible the implementation of higher production rates with fewer defects and rejected parts, while at the same time increasing the reliability and dependability of individual parts and consequently of the whole ratchet wrench.
Another advantage of ratchet wrenches embodying the principles of the present invention is that the control knob needs to be rotated through only about 53 degrees to accomplish reversing; whereas prior art devices of the same general type require as much as 130 degrees.
While I have shown my invention in only one form, it will be obvious to those skilled in the art that it is not so limited, but is susceptible of various changes and modifications without departing from the spirit thereof.
The ratchet pawl notch portion shape is preferably a truncated "V" with substantially planar side faces, but this shape may be varied to some extent while still retaining the essential operational aspects of the device. Also, while the shape of a right cylinder is preferred for the reversing pin, this shape may be varied to some extent while retaining the essential operational aspects of the device. For example, the notch portion could be a parabolic surface having a relatively narrow bottom and side surfaces having very little curvature. It should be understood that the notch portion outer edges may be beveled. A reversing pin of rectangular, polygonal, or elliptical transverse section shape would work satisfactorily, but would require additional manufacturing expense. Some curvature of the reversing pin outer face, though not desirable, could be tolerated. The greatest dimension of the reversing pin outer face must be greater than the notch portion width, excluding any beveled outer edges, but should be only slightly greater since there is a trade off with control knob stub shaft portion strength because of the size of the bore that receives the reversing pin. The notch portion depth must be sufficient to clear the reversing pin, but by as little as possible so as to maximize the distance to the ratchet pawl rocker bore thereby maximizing the relevant transverse section area. The notch portion bottom should be flat or curved to avoid stress concentration.
It should be apparent that the present invention is equally applicable to both socket ejector and non-socket ejector types of ratchet wrenches.
The foregoing disclosure and the showings made in the drawings are merely illustrative of the principles of this invention and are not to be interpreted in a limiting sense.
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A ratchet wrench of the socket drive type has an improved ratchet pawl configuration which significantly reduces excessive wear and various attendant problems and also obviates the problem of accidental wrench disassembly. Improved structure also provides certain further advantages.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a pushcart, particularly to a pushcart capable of braking.
[0003] 2. Description of the Prior Art
[0004] Referring to FIG. 9 , a conventional pushcart 90 includes a push bar 91 , a base plate 92 , wheels 93 and support struts 94 . Each of the wheels 93 is provided on a bottom of the base plate 92 , while the two support struts 94 are disposed at each of two ends on top of a side of the base plate 92 . The push bar 91 and an auxiliary bar are then provided between the two support struts 94 . When transporting objects using the pushcart 90 , the to-be-transported objects are piled up on the base plate 92 of the pushcart 90 and are transported to the destination by pushing the push bar 91 . However, when moving objects to the base plate 92 , it is not possible to fix the pushcart 90 at a particular location and prevent it from sliding, especially on an unleveled road surface. In this way, the user has to tightly grasp the push bar 91 so as to keep the pushcart 90 at the original location while moving objects onto the base plate 92 , making the use of pushcart 90 inconvenient. When moving objects on unleveled locations, the pushcart may slide downward, because the user has to remove his/her hand from the push bar 91 of the pushcart 90 so as to move objects onto the base plate 92 , thereby making the use of the pushcart 90 inconvenient. Additionally, if objects are to be carried to several destinations, the pushcart 90 often has to be carefully stopped on a stable ground for temporarily unloading the objects midway, in order to prevent the pushcart 90 from sliding.
[0005] In addition to the above drawbacks of the conventional design, after using the pushcart 90 , the pushcart 90 has to be properly folded and stored so as to save storage space. Consequently, improvements should be made to the conventional pushcart 90 , such that the pushcart is capable of braking, folding and storage.
SUMMARY OF THE INVENTION
[0006] The primary object of the present invention is to provide a pushcart capable of easily controlling braking or moving, such that a braking assembly is released by applying a force on a first push bar, moving the pushcart. When releasing the first push bar, the braking assembly comes into contact with wheels of the pushcart, thereby preventing the wheels from moving and stopping the sliding movement of the pushcart. Additionally, another object of the present invention is to provide a pushcart capable of folding and storage.
[0007] To achieve the above objects, the pushcart includes a base plate for carrying an object; a plurality of wheel assemblies are disposed below the base plate and include a plurality of wheels; a first support strut and a second support strut, being hollow and disposed on two ends of the base plate; a first push bar disposed between the first support strut and the second support strut; and a first braking assembly, having at least a first wiring and a first spring. The first wiring includes a first end and a second end, wherein the first end is disposed on the first push bar, and the second end is connected to a first brake pad. The first wiring is provided on the inside of the hollow first support strut, while the first spring is disposed between the first brake pad and the wheel assembly, thereby moving or stopping the pushcart.
[0008] According to a preferred embodiment of the present invention, a second braking assembly includes at least a second wiring and a second spring, wherein the second wiring includes a third end and a fourth end. The third end is provided on the first push bar, whereas the fourth end is connected to a second brake pad. The second wiring is provided on the inside of the hollow second support strut, whereas the second spring is provided between the second brake pad and the wheel assembly.
[0009] According to another preferred embodiment of the present invention, the pushcart includes a pivotal member, which is pivotally connected to the first push bar and is connected to the first wiring thereon. The pivotal member is an eccentric sleeve that is pivotally connected to the first push bar. A slot is then provided on an eccentric position of the eccentric sleeve, such that the slot is pivotally connected to the first wiring.
[0010] According to another preferred embodiment of the present invention, the first braking assembly further includes a connecting assembly to be connected to the first wiring and the first brake pad.
[0011] According to another preferred embodiment of the present invention, the wheel assembly includes a wheel holder, and the first spring is disposed between the first brake pad and the wheel holder of the wheel assembly.
[0012] According to another preferred embodiment of the present invention, the first brake pad is provided on the wheel holder of the wheel assembly.
[0013] According to another preferred embodiment of the present invention, the pushcart further includes a second push bar, which is provided between the first support strut and the second support strut.
[0014] According to another preferred embodiment of the present invention, at least one bearing is provided between the wheel assembly and the base plate.
[0015] According to another preferred embodiment of the present invention, the base plate, having a first portion and a second portion, is pivotally connected to the first portion and the second portion via a pivotal assembly, wherein the pivotal assembly is a hinge.
[0016] According to another preferred embodiment of the present invention, the pushcart further includes a pedal assembly, which is provided on the first portion. The pedal assembly includes a locating member provided below the base plate; a control member provided below the base plate; and a locating lock connecting to the control member. By controlling the control member, the locating lock is located on the locating member, such that the first portion and the second portion of the base plate are folded by using the pivotal assembly.
[0017] According to another preferred embodiment of the present invention, the locating member is provided on the second portion and is extended below the first portion. The locating member has an opening for inserting into the locating lock.
[0018] According to another preferred embodiment of the present invention, the pedal assembly further includes a pedal frame, and the control member further includes a pedal, having an end pivotally connected to the pedal frame; a first wiring and a second wiring, wherein the second wiring includes a first portion and a second portion, such that the first portion is connected to the pedal, and the second portion is connected to the locating lock.
[0019] According to another preferred embodiment of the present invention, the pushcart further includes a first strut, which is disposed below the first portion and includes an opening for inserting into the locating lock; and a second strut, which is disposed below the first portion and includes an opening for inserting into the locating lock.
[0020] According to another preferred embodiment of the present invention, the locating lock further includes a second spring disposed between the first strut and the second strut.
[0021] According to another preferred embodiment of the present invention, the pedal assembly further includes a roller for changing the direction of the second wiring.
[0022] In this way, the present invention has the advantages of braking the pushcart without applying any force on the first push bar, moving the pushcart by applying a force on the first push bar, and folding and storing the pushcart after using it.
[0023] Further scope of the applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus are not limitative of the present invention, and wherein:
[0025] FIG. 1 shows a schematic perspective view of the pushcart made according to the present invention.
[0026] FIG. 2 shows a cross-sectional schematic view along the A-A line of FIG. 1 .
[0027] FIG. 3 is a cross-sectional schematic view showing the pressing of the pushcart along the A-A line of FIG. 1 .
[0028] FIG. 4 shows a side schematic view of the pushcart made according to the present invention.
[0029] FIG. 5 is a side schematic view showing folding of the pushcart made according to the present invention.
[0030] FIG. 6 shows a cross-sectional schematic view along the B-B line of FIG. 1 .
[0031] FIG. 7 is a schematic view showing the pedal assembly of the pushcart made according to the present invention.
[0032] FIG. 8 is a schematic view showing the actions of the pedal assembly of the pushcart made according to the present invention.
[0033] FIG. 9 shows a schematic perspective view of a conventional pushcart.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] Referring to FIG. 1 , the pushcart 1 of the present invention includes a base plate 10 , a push bar assembly 20 , a plurality of wheel assemblies 30 , a braking assembly 40 and a pedal assembly 70 . The base plate 10 includes a first portion 12 , a second portion 11 and a pivotal assembly 13 . The pivotal assembly 13 is pivotally connected to the first portion 12 and the second portion 11 . Each of the wheel assemblies 30 is provided below the base plate 10 . Preferably, four wheel assemblies 30 are respectively disposed on the inside of four corners of the rectangular base plate 10 . The push bar assembly 20 is disposed at a side of the two ends of the first portion 12 of the base plate 10 , and the pedal assembly 70 is provided below the first portion 12 of the base plate 10 , thereby controlling the folding and storage of the pushcart 1 . The braking assembly 40 is disposed between the base plate 10 and each of the wheel assemblies 30 . By using the push rod assembly 20 , the braking assembly 40 can control the movement or braking of the pushcart 1 .
[0035] The pivotal assembly 13 is preferably a hinge or a pivotal shaft body or an equivalent structure that can be rotatably and pivotally connected to the first portion 12 and the second portion 11 of the base plate 10 .
[0036] Each of the wheel assemblies 30 includes a wheel holder 31 and a wheel 32 , being both disposed below the base plate 10 . A bearing 60 is provided between the first portion 12 of the base plate 10 and each of the wheel assemblies 30 , such that movement direction of the pushcart 1 can be freely controlled. The push bar assembly 20 includes a first support strut 21 and a second support strut 22 , which are hollow shaft bodies respectively disposed on the two ends of the first portion 12 of the base plate 10 . An auxiliary bar 25 is provided between the first support strut 21 and the second support strut 22 , while the first push bar 23 and the second push bar 24 are both connected to the two ends of the first support strut 21 and the second support strut 22 .
[0037] Referring to FIG. 2 , the first braking assembly 40 includes a first wiring 41 , a first spring 42 and a first brake pad 43 , whereas the second braking assembly includes a second wiring, a second spring and a second brake pad (the second braking assembly is made of the same structures as those of the first braking assembly; not shown in the figure). The first wiring 41 and the second wiring are respectively disposed inside the hollow shaft body of the first support strut 21 and the second support strut 22 . The first wiring 41 is connected to an end side of the first push bar 23 , while the second wiring is connected to another end side of the first push bar 23 . Another end of the first wiring 41 is connected to a first brake pad 43 so as to actuate the first brake pad 43 , while another end of the second wiring is connected to a second brake pad to actuate the second brake pad. The first brake pad 43 , which is movably disposed on the wheel holder 31 , comes into contact with or becomes separated from the wheel 32 . Likewise, the second brake pad, which is movably disposed on the wheel holder, comes into contact with or becomes separated from the wheel. In other words, the relationship between the second braking assembly and other structures such as the support strut, wheel holder, etc. is the same or similar to the relationship between the first braking assembly and other structures such as the support strut, wheel holder, etc. The present invention preferably includes two braking assemblies. However, to protect the spirit of the present invention, the present invention includes only one braking assembly, given the equivalence of these two braking assemblies. When the first wiring 41 pushes the first brake pad 43 to become separated from the wheel 32 , the wheel 32 slides. A first spring 42 is provided between the first brake pad 41 and the wheel holder 31 for flexibly stretching or recovering the first brake pad 41 and the wheel holder 31 . When releasing the first push bar 21 , the first spring 42 restores the contact of the first brake pad 43 with the wheel 32 , thereby stopping the pushcart 1 . On the contrary, when pressing the first push bar 21 , the first spring 42 becomes pressed by the first brake pad 43 and becomes separated from the wheel 32 , thereby moving the pushcart 1 . Preferably, the first braking assembly 40 includes a connecting assembly 44 , which is connected to the first wiring 41 and the first brake pad 43 . A third spring 45 is provided on top of the connecting assembly 44 to recover the contact of the first brake pad 43 with the wheel 32 .
[0038] The pivotal member 50 , which is pivotally connected to the first push bar 23 , is provided with a slot 52 on the eccentric position for being connected to the first wiring 41 . In this way, when pressing the first push bar 23 , the pivotal member 50 rotates, such that the first wiring 41 controls the movement of the first brake pad 43 . Preferably, the pivotal member 50 is an eccentric sleeve 51 , which is pivotally connected to the first push bar 23 . The slot 52 is provided on an eccentric location of the eccentric sleeve 51 , such that the slot 52 is pivotally connected to the first wiring 41 .
[0039] Referring to FIG. 3 , when pressing the first push bar 23 , the user can grasp the first push bar 23 and the second push bar 24 together, such that the first push bar 23 becomes near to the second push bar 24 , thereby pushing the push bars in an effort-saving manner. Consequently, when pressing the first push bar 23 , the eccentric sleeve 51 , which is pivotally connected to the two ends of the first push bar 23 , rotates, thus actuating the upward stretch of the first wiring 44 . Additionally, the first wiring 41 pulls up the connecting assembly 44 , such that the first brake pad 43 is pulled away from the surface of the wheel 32 , thus moving the pushcart 1 . When the first brake pad 43 , the first wiring 41 and the connecting assembly 44 are pulled upward, this will apply a force on the first spring 42 and then stretch the third spring 45 (See FIG. 3 ). While braking the pushcart 1 and releasing the first push bar 23 , this can restore the contact of the first brake pad 43 with the wheel 32 , due to the restoring force exerted by the first spring 42 and the third spring 45 . In this way, the wheel 32 is unable to rotate and finally stops (See FIG. 2 ).
[0040] Referring to FIGS. 4 & 5 , the pushcart 1 is capable of braking, folding and storing or stretching. To fold and store the pushcart 1 , the user steps on the pedal assembly 70 . By pushing the push bar assembly 20 forward, the pushcart 1 is folded and stored. By using the pivotal assembly 13 , the first portion 12 and the second portion 11 of the base plate 10 are folded and stored into a rectangular form, thereby saving space for storing the pushcart 1 .
[0041] Referring to FIG. 6 , a locating member 80 , which is disposed on the second portion 11 of the base plate 10 , is located near to the first portion 12 . The locating member 80 , having an opening 81 , is extended below the first portion 12 of the base plate 10 , while the pedal assembly 70 has a locating lock 78 disposed on the pedal assembly 70 of the first portion 12 of the base plate 10 . When the locating lock 78 is inserted into the opening 81 of the locating member 80 , the first portion 12 and the second portion 11 of the base plate 10 are then fixed. On the contrary, while stepping on the pedal assembly 70 , the locating lock 78 becomes separated from the opening 81 of the locating member 80 , such that the first portion 12 and the second portion 11 of the base plate are folded and stored by using the pivotal assembly 13 (See FIG. 5 ).
[0042] Referring to FIG. 7 , the pedal assembly 70 includes a pedal frame 71 , a pedal 72 , a pair of third wirings 73 , a set of first struts 74 , a set of second struts 75 , a set of second springs 76 , a set of rollers 77 and a set of locating locks 78 . Also, an end of the pedal 72 is pivotally connected to the pedal frame 71 . Preferably, the pedal frame 71 includes a set of slides, such that the pedal 72 can be inserted into the slides for forward and backward sliding. The pedal frame 71 is provided with a pair of rollers 77 , while the two ends of the third wiring 73 are respectively connected to the pedal 72 and the locating lock 78 . Additionally, the third wirings 73 slide along with the rollers 77 , such that the third wirings 73 smoothly slide to and fro. Preferably, a locking member 79 is additionally disposed at the connection of the third wiring 73 to the pedal 72 and the locating lock 78 , so as to reinforce their connection. The first strut 74 and the second strut 75 , which are both fixed on a bottom of the first portion 12 of the base plate, are respectively provided with an opening 83 and an opening 82 , thereby locating the locating lock 78 . Additionally, a fourth spring 76 is disposed between the first strut 74 and the second strut 75 . An end of the fourth spring 76 is fixed on the locating lock 78 . In this way, when a force is applied on the first strut 74 and the second strut 75 by using the locating lock 78 , the second spring 76 restores the locating lock 78 to its original location. A protruding portion of the locating lock 78 becomes inserted into the opening 81 of the locating member 80 for locating purpose. The first strut 74 and the second strut 75 of the first portion 12 of the base plate 10 as well as the locating member 80 of the second portion 11 of the base plate 10 become located by using the locating lock 78 (See in FIG. 7 ).
[0043] Referring to FIG. 8 , when stepping on the pedal 72 , the pedal 72 pulls the third wiring 73 , thereby causing the rollers 77 to slide. In this way, by using the third wiring 73 , the pair of locating locks 78 is pulled away from the opening 81 of the locating member 80 , such that a force is applied on the fourth spring 76 of the locating lock 78 . In this way, the user can push the push bar assembly 20 , thus folding and storing the first portion 12 and the second portion 11 of the base plate 10 . To use the folded pushcart 1 again, the user stretches the pushcart 1 by pushing the push bar assembly 20 and then steps on the pedal 72 , such that the locating lock 78 slides toward the rollers 77 . When the pushcart 1 is completely stretched, the user releases the pedal 72 , such that the locating lock 78 becomes inserted into the opening 81 of the locating member 80 again, thereby stretching the pushcart 1 .
[0044] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.
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The present invention provides a pushcart having a rotatable push bar disposed between a first support strut and a second support strut as well as a plurality of braking assemblies connecting to the push bar. By applying a force on the push bar, the braking assemblies release wheels disposed below a base plate, thereby moving the pushcart. On the contrary, by releasing the push bar, the braking assemblies stop the wheels, thereby stopping the pushcart. When not using the pushcart, the push bar and the base plate are folded and stored, thereby saving storage space and enhancing convenience.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention pertains to intravascular medical devices. More particularly, the present invention pertains to devices for capturing and removing blood clots from a blood vessel. This same system may also be used to remove material from other cavities of the body, for example, stones from the urinary or the biliary tract.
[0003] 2. Background of the Art
[0004] The present invention pertains generally to thrombus collection and removal. Blood thrombus, may form a clot in a patient vasculature. Sometimes such clots are harmlessly dissolved in the blood stream. At other times, however, such clots may lodge in a blood vessel or embolize a distal blood vessel where they can partially or completely occlude the flow of blood. If the partially or completely occluded vessel feeds blood to sensitive tissue such as, the brain, lungs or heart, for example, serious tissue damage may result.
[0005] When symptoms of an occlusion are apparent, such as an occlusion resulting in a stroke, immediate action should be taken to reduce or eliminate resultant tissue damage. One approach is to treat a patient with clot dissolving drugs. These drugs, however, do not immediately dissolve the clot from the patient.
[0006] Published U.S Patent Application 2005/0038447 describes A medical device for removing clots from a blood vessel, comprising: a first longitudinally-oriented spine having a distal end; a pushing member coupled to the proximal end of the first longitudinally-oriented spine and extending proximally therefrom; and a clot-grabbing basket generally disposed between and coupled to the first longitudinally-oriented spine.
[0007] Published U.S. Patent Application 2004/0138692 discloses an embolus extractor, comprising: an elongated shaft having a proximal end and a distal end; first and second struts, each strut having a proximal end and a distal end coupled to the distal end of the shaft; the first and second struts having a first position and a second position, wherein in the first position, the distal ends and the proximal ends of the struts are spaced at a first distance, and in the second position the distal ends and the proximal ends of the struts are spaced at a second distance, the second distance being less than the first distance; and third and fourth struts, each strut coupled to one of the first and second struts via a proximal end and distal end.
[0008] Published U.S. Patent Application 2004/0098023 discloses a vaso-occlusive device, comprising: a core member; and a fibrous structure carried by the core member, the fibrous structure comprises one or more strands of nanofibers. The vaso-occlusive device may provide the fibrous structure in a product generated at least in part by an electrospinning process comprises the steps of: supplying a polymer solution through a needle; electrostatically charging the needle; electrostatically charging a metal plate that is placed at a distance from the needle, the metal plate having a charge that is opposite that of the needle, thereby sending a jet of the polymer solution towards the metal plate; and collecting the fibrous structure from the metal plate.
[0009] Published U.S. Patent Application 2004/0039435 discloses a self-expanding, pseudo-braided device embodying a high expansion ratio and flexibility as well as comformability and improved radial force. The pseudo-braided device is particularly suited for advancement through and deployment within highly tortuous and very distal vasculature. Various forms of the pseudo-braided device are adapted for the repair of aneurysms and stenoses as well as for use in thrombectomies and embolic protection therapy.
[0010] There are a variety of ways of discharging shaped coils and linear coils into a body cavity. In addition to those patents that describe physically pushing a coil out of the catheter into the body cavity (e.g., Ritchart et al.), there are a number of other ways to release the coil at a specifically chosen time and site. U.S. Pat. No. 5,354,295 and its parent, U.S. Pat. No. 5,122,136, both to Guglielmi et al., describe an electrolytically detachable embolic device.
[0011] A variety of mechanically detachable devices are also known. Various examples of these devices are described in U.S. Pat. No. 5,234,437, to Sepetka, U.S. Pat. No. 5,250,071 to Palermo, U.S. Pat. No. 5,261,916, to Engelson, U.S. Pat. No. 5,304,195, to Twyford et al., U.S. Pat. No. 5,312,415, to Palermo, and U.S. Pat. No. 5,350,397, to Palermo et al.
[0012] Various configurations have been used to remove calculi from the biliary or urinary system. See, for instance, U.S. Pat. No. 5,064,428. Additionally, devices having various configurations have been used to remove objects from the vasculature. For example, surgical devices comprising one or more expandable and collapsible baskets have been described for removing or piercing a thrombus in the vasculature. See, U.S. Pat. No. 6,066,149. U.S. Pat. No. 5,868,754 describes a three prong-shaped device for capturing and removing bodies or articles from within a vessel.
[0013] Published U.S. Patent Application 2004/0225229 describes a device comprising a core wire having a distal end and a proximal end; a catheter shaft having a proximal catheter end, a distal catheter end and a lumen through which the core wire is passed such that the distal end of the core wire extends beyond the distal catheter end; a retrieval element disposed at the distal end of the core wire, the retrieval element movable from a radially contracted position to a radially expanded position; and a first stop element attached to the core wire, the first stop element configured to prevent over-expansion of the retrieval element.
[0014] Among commercial thrombus-removal systems are at least the following:
1) The MERCI system of Concentric Medical that has a form of a corkscrew or helix spring. In this system, which may use a large 0.018 F microcatheter, the microcatheter tip is first positioned across the thrombus with the help of a guidewire. Then the guidewire is exchanged with the system which is deployed distal and into the thrombus. The shape of the system allows it to get inserted into the thrombus. Then the thrombus is retrieved out of the artery into a large 9 French working catheter, and then out of the body. 2) The In-Time system of Boston Scientific which is a sort of a clam-shell guide, that once placed through the thrombus divides itself into 4 strings that form an oval, as with a rugby balloon. The system is pulled back to carry out the thrombus. This is similar to the disclosed structure in Published US Application 2004/0138692. 3) Another system is what is called a lasso, which is a simple catheter with a wire attached to its end. This wire makes a loop and enters back into the catheter (e.g., a large 0.018 F microcatheter). The operator changes the aspect of the loop by pulling on the wire. This system was originally conceived to catch foreign bodies. 4) The Catch system of Balt is a stent closed on one end and forming a basket that is deployed distal to the thrombus. The operator then pulls the system and retrieves the thrombus. This is similar to the structure in FIG. 7 of U.S. Pat. No. 6,805,684.
The above systems may have various disadvantages, such as either to slide on the thrombus, either to fractionate, to be difficult to guide or deploy or to be traumatic to the artery while some of them are quite expensive. In addition, all these system are bulky and cannot be used in small caliber arteries.
SUMMARY OF THE INVENTION
[0019] A device capable of capturing and assisting in the removal of a thrombus in arteries, and even in small arteries uses a soft coil mesh to engage the surface of a thrombus, and a guidewire is used to retract the soft coil mesh with the captured thrombus. The soft coil is formed by an elongated microcoil element that forms the helical elements of a macrocoil element. The microcoil element provides a relatively elastic effect to the helical element forming the macrocoil and allows for control of gripping forces on the thrombus while reducing non-rigid contact of the device with arterial walls.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 shows the microcoil/macrocoil structure of the soft coil capture device described herein.
[0021] FIG. 2 shows a soft coil capture device in an insertion position within an artery.
[0022] FIG. 3A shows a soft coil capture device in a pre-capture position within an artery in a first mode of soft coil delivery.
[0023] FIG. 3B shows a soft coil capture device in a thrombus engaged position within the first mode of soft coil delivery of FIG. 3A .
[0024] FIG. 4A shows a soft coil capture device in a pre-capture position within an artery in a second mode of soft coil delivery.
[0025] FIG. 4B shows a soft coil capture device in a thrombus capture position within an artery within the second mode of soft coil delivery of FIG. 4A .
[0026] FIG. 5 shows a soft coil capture device (which may be of larger dimensions than parenchymal vasculature delivery devices) midway through deployment.
[0027] FIG. 6 shows a microcatheter delivery system with constrained coils within the microcatheter.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The following description should be read with reference to the drawings wherein like reference numerals indicate like elements throughout the several views. The detailed description and drawings illustrate example non-limiting specific embodiments of the generic claimed invention.
[0029] FIG. 1 shows a structural material 2 that can be used as a soft soil capture element in the practice of the technology described herein. The material 2 has microcoils or microloops forming a continuing chain 6 of microcoils that form the macrcoil or macrohelix 10 . The term ‘microcoil’ as used herein should not be confused with the RF or MRI responsive coils or microcoils that are used in the medical imaging art. These are microcoils in the sense that they are small coils as compared to the macrocoils 10 which are large coils. The microcoils are made from structural material 8 that forms the filaments, threads, fibers, or the like that are used to provide the microcoils that build into the macrocoils. The benefits of this material and the structure in which they perform will become apparent from the discussion herein.
[0030] The microcoils add a significant degree of compliance, effective elasticity and cushioning ability to the macrocoil. The microcoils elongate to give the appearance of elasticity to the material 2 , without providing hard and large abrasive surfaces that would contact arterial walls, as would traditional coil or mesh structures.
[0031] FIG. 2 shows the soft coil material 2 within an artery 50 . The macrocoils 56 are shown with the entire length of the coil section 60 of the device being shown in a slightly extended position that is useful for insertion of the device 66 . The pusher wire or guidewire 66 stabilizes the insertion end 68 of the soft coil material 2 while a pull wire 64 stabilizes the back end 70 of the device 66 and the material 2 . The push wire 62 tends to be thicker than the pull wire 64 as a matter of course, but they may be of the same or similar thicknesses, and the pull wire may be thicker than the push wire 62 . A thrombus 72 is shown, with the distended coil section 60 having been pushed past the thrombus 72 .
[0032] FIG. 3A shows a first mode of delivery of the system 68 wherein the pulling wire 62 has been extended from the microcatheter 66 past the thrombus 72 , and the push wire 64 has been slightly extended beyond the thrombus, being carried by the microcatheter 66 . The pulling wire 62 and the push wire 64 are sufficiently close together so that the entire length of the extended coil 60 is restrained, but beyond the major mass of the thrombus 72 . FIG. 3B shows the microcatheter 66 having been withdrawn from past the thrombus 72 , the push wire also pulled rearward of the thrombus 72 , and the end of the pulling wire 62 being retracted to pull the soft coil material 2 into a tangled engagement with the thrombus, engaging the thrombus 72 so that withdrawal of the microcatheter and the two wires 62 and 64 will withdraw the thrombus 72 while enmeshed in the soft coil material. The entire enmeshing length 74 b of the soft coil securely entrains the thrombus 72 , and the soft coil material 2 assists in reducing breakage of the thrombus 72 and damage to vascular walls.
[0033] FIG. 4A shows the system 68 delivered in a second delivery mode, without the microcatheter 66 passing the thrombus 72 mass, where both the push wire 64 and the pull wire 62 are positioned so that the push wire 64 restrains the soft coil material 2 relatively in front of the thrombus 72 and the pulling wire 62 has been extended from the microcatheter 66 to employ the soft coil material 2 . FIG. 4B shows that the pulling wire 62 has been retracted slightly, causing the soft coil material 2 to engage the thrombus 72 and enmesh the thrombus 72 within the soft coil material. By withdrawing the microcatheter 66 , and the two wires 62 and 64 , the thrombus can be withdrawn from the vessel 50 with minimal damage to the vessel 50 and reduced breakage in the thrombus 72 . The nature of the mixture of the microcoils and macrocoils causes a constriction of the material around the thrombus, without segmenting (cutting) the thrombus easily, and without providing a cage surface that is as potentially damaging to arterial walls as are other structures used for thrombus retrieval and capture. The push wires and pull wires may be of equal wire dimensions (e.g., diameters) or different dimensions, with either one being thicker than the other in different embodiments.
[0034] The system is made of a 3D soft coil such that when the system gets deployed, it has the tendency to form a three dimensional cage, with loops of microcoils extending across the diameters of the arterial interior to assure that loops will be able to engage a thrombus when the loops are retracted. The ends of the coils may be attached on either its proximal end to a pusher wire and to its distal end to a very fine wire or visa versa. The entire system tends to be able to be provided in a very thin format (although the size may vary depending upon the need for fit within particular arterial passages, and can fit into a 0.010 Fr microcatheter or smaller. Both wires exit at the proximal end of the microcatheter and can be manipulated by the operator. First the microcatheter is positioned across the thrombus with the help of a microguidewire. Once the distal end of the microcatheter lies beyond the thrombus (usually while it is in a distended state, fairly elongate and narrow), the microguidewire is exchanged with the thrombus retrieval system. The thrombus retrieval system is activated and deployed so that a significant portion of the entire length of coil (e.g., ⅕, 1 / 4 or one third of the coil) is positioned distal to the thrombus. A remaining significant portion of the coil (using, by way of non-limiting examples of amounts, with one third distal to or past the thrombus), such as at least ⅕, at least ¼ or one third or more of the coil length is wrapped around or codistant with (within the artery) the thrombus and ¼, 1/5 or one third or more proximal to the thrombus. Once the coil is deployed with a significant portion at least at the distal end of the thrombus and more desirably a significant portion past the distal end of the thrombus, the operator pulls the thin distal wire or pushes the thick proximal wire, so that the mesh of coil loops that has formed around the thrombus or expanded beyond the thrombus retracts on itself and grabs securely the thrombus. The thrombus now can be pulled out of the artery by pulling the microcatheter, the pusher wire and the thin distal wire on the same time out of the artery.
[0035] One other advantage of the system (in addition to what has been described already) is its very small size so it can retrieve thrombus from very small arteries, its capacity to pull out the thrombus in one piece, and its softness, allowing manipulation without trauma to the vessel wall. Larger versions have the advantage of retrieving a very large thrombus in one piece. This system may be used in any vessel of the body for the retrieval of thrombus or other material like foreign bodies.
[0036] The distal end of the soft coil material (where the pulling wire is attached) may be limited in its ability to extend away from the proximal end of the soft coil material (where the push wire is attached) by using an internal connector, such as a thread, that attaches to both ends of the soft coil, and provides a physical limit to how far the coil may be distended.
[0037] Whatever the consistency of the clot, i.e., soft or hard, once someone has passed the clot with the microcatheter, the distal mesh of coils when deployed will form a “sponge” or “piston” that should bring back at least a large part of the thrombus. It is also likely that the loops of the coil should prevent the loss of parts of the thrombus if it breaks into pieces. The tendency of the system to break soft thrombus will depend on characteristics such as the soft coil material thickness, the microcoil thickness the macrocoil thickness, density of the macrocoil, the 3D configuration of the macrocoils and the loop diameter of the coil. Even in the worst case envisioned, one could only deploy a distal and a proximal mesh or use a flow reversing system.
[0038] For a number of reasons, it may be desirable to capture and/or remove clots from the vasculature. The blood vessel can be essentially any vessel or even duct. The device may include two or more longitudinal wires, for example a guidewire, a push wire and a pull wire, as well as other functional wires (e.g., conductive wires for other features provided with the device, such as a resistive wire to enable heating of the coils, if conductive/resistive. The basket member or region of soft coils is attached to or otherwise coupled with the wires. In general, the device (wires and soft coil material) can be advanced through the vasculature to a suitable location, for example adjacent a clot, and expanded (when past or adjacent to the clot, so that the clot may be captured in the soft coils, upon operator action, and the captured clot can be removed from the vasculature.
[0039] The device may be configured to shift between a first generally collapsed configuration and a second generally expanded configuration, especially by the elastic memory of the coil material, and the guidance imposed by the at least two wires. In at least some embodiments, shifting between these configurations includes the longitudinal movement of one or both of the wires relative to one another. Movement of the wires may occur in either the proximal or distal direction and, in the case of both wires moving, may be in the same or opposite directions. Shifting may also result in one or both of the wires moving somewhat laterally (especially with distally controlled wires on the coil material (e.g., with materials that bend when heated, or the like, and a heating element attached thereto) so that the wires become closer or move apart one another.
[0040] Shifting between the collapsed and expanded configurations may occur in a number of differing manners. For example, the device or portions thereof may be made of a shape-memory material (such as nickel-titanium alloy or oriented coils) that can assume a pre-defined shape when unconstrained or when subjected to particular thermal conditions. According to this embodiment, the device can be manufactured to be “self-expanding” (when the longitudinal distension and restraint by the wires is removed) so that it can be delivered in a collapsed configuration then shift to the expanded configuration when a constraint is removed (e.g., the distal ends of the two wires brought closer together) or when the device is subject to the natural thermal conditions within blood vessel. Alternatively, shifting may occur by mechanically moving one or both of wires. Moving the wires may occur in a number of different ways such as by moving one or other of the wires attached to the distal or proximal end of the coil material on the device.
[0041] As described above, all or portions of the device (including but not limited to the coil materials and the wires) may be manufactured from polymeric, metallic, natural (e.g., gut wires), synthetic, or composite materials. Preferred materials tend to be polymeric, metallic, composite or mixtures or combinations of these materials. A conventional medical structural material such as nickel titanium alloy may be employed. However, any suitable material may be used including metals, metal alloys, polymers, etc. Some examples of suitable metals and metal alloys include stainless steel, such as 304V, 304L, and 316L stainless steel; linear-elastic or super-elastic nitinol or other nickel-titanium alloys, nickel-chromium alloy, nickel-chromium-iron alloy, cobalt alloy, tungsten or tungsten alloys, MP35-N (having a composition of about 35% Ni, 35% Co, 20% Cr, 9.75% Mo, a maximum 1% Fe, a maximum 1% Ti, a maximum 0.25% C, a maximum 0.15% Mn, and a maximum 0.15% Si), hastelloy, monel 400, inconel 825, or the like; or other suitable material.
[0042] Some examples of suitable polymers may include polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polyoxymethylene (POM), polybutylene terephthalate (PBT), polyether block ester, polyurethane, polypropylene (PP), polyvinylchloride (PVC), polyether-ester (for example a polyether-ester elastomer such as ARNITEL® available from DSM Engineering Plastics), polyester (for example a polyester elastomer such as HYTREL® available from DuPont), polyamide (for example, DURETHAN® available from Bayer or CRISTAMID® available from Elf Atochem), elastomeric polyamides, block polyamide/ethers, polyether block amide (PEBA, for example available under the trade name PEBAX®), silicones, polyethylene (PE), Marlex high-density polyethylene, Marlex low-density polyethylene, linear low density polyethylene (for example REXELL®), polyethylene terephthalate (PET), polyetheretherketone (PEEK), polyimide (PI), polyetherimide (PEI), polyphenylene sulfide (PPS), polyphenylene oxide (PPO), polysulfone, nylon, perfluoro(propyl vinyl ether) (PFA), other suitable materials, or mixtures, combinations, copolymers thereof, polymer/metal composites, and the like. In some embodiments, portions of or all of the device can be blended with a liquid crystal polymer (LCP). For example, the mixture can contain up to about 5% LCP.
[0043] In some embodiments, a coating, for example a lubricious, a hydrophilic, a protective, or other type of coating may be applied over portions or all of the device. Hydrophobic coatings such as fluoropolymers provide a dry lubricity which improves device exchanges. Lubricious coatings improve steerability and improve lesion crossing capability. Suitable lubricious polymers are well known in the art and may include silicone and the like, hydrophilic polymers such as polyarylene oxides, polyvinylpyrolidones, polyvinylalcohols, hydroxy alkyl cellulosics, algins, saccharides, caprolactones, and the like, and mixtures and combinations thereof. Hydrophilic polymers may be blended among themselves or with formulated amounts of water insoluble compounds (including some polymers) to yield coatings with suitable lubricity, bonding, and solubility. Some other examples of such coatings and materials and methods used to create such coatings can be found in U.S. Pat. Nos. 6,139,510 and 5,772,609, which are incorporated herein by reference. In some embodiments, the sheath or coating may be applied over basket region. This may provide extra surface area to contain clots that might be captured therein.
[0044] The sheath or polymeric layer coating may be formed, for example, by coating, electrophoresis, by extrusion, co-extrusion, interrupted layer co-extrusion (ILC), or fusing several segments end-to-end. The layer may have a uniform stiffness or a gradual reduction in stiffness from the proximal end to the distal end thereof. The gradual reduction in stiffness may be continuous as by ILC or may be stepped as by fusing together separate extruded tubular segments. The outer layer may be impregnated with a radiopaque filler material to facilitate radiographic visualization. Those skilled in the art will recognize that these materials can vary widely without deviating from the scope of the present invention.
[0045] The device, or portions thereof, may also be coated, plated, wrapped or surrounded by, doped with, or otherwise include a radiopaque material. For example, the wires or coils may be made from a radiopaque material or may include a radiopaque marker member or coil coupled thereto. Radiopaque materials are understood to be materials capable of producing a relatively bright image on a fluoroscopy screen or another imaging technique during a medical procedure. This relatively bright image aids the user of the device in determining its location. Some examples of radiopaque materials can include, but are not limited to, gold, platinum, palladium, tantalum, tungsten alloy, plastic material loaded with a radiopaque filler, and the like.
[0046] In some embodiments, a degree of MRI compatibility may be imparted into the device. For example, to enhance compatibility with Magnetic Resonance Imaging (MRI) machines, it may be desirable to make portions of the device, in a manner that would impart a degree of MRI compatibility. For example, the device, or portions thereof, may be made of a material that does not substantially distort the image and create substantial artifacts (artifacts are gaps in the image). Certain ferromagnetic materials, for example, may not be suitable because they may create artifacts in an MRI image. The device, or portions thereof, may also be made from a material that the MRI machine can image. Some materials that exhibit these characteristics include, for example, tungsten, Elgiloy, MP35N, nitinol, and the like, and others.
[0047] The control wire(s) may be produced from any number of suitable materials having reasonable strength in tension, e.g., stainless steels, carbon fibers, engineering plastics, tungsten alloys, variously in the form of a multi-strand cable or single strand thread. Preferably, however, the wire may be made from a “so-called” super-elastic alloy. These alloys are characterized by an ability to transform from an austenitic crystal structure to a stress-induced martensitic (SIM) structure and to return elastically to the austenitic crystal structure (and the original shape) when the stress is removed. A typical alloy is nitinol, a nickel-titanium alloy, which is readily commercially available and undergoes the austenite-SIM-austenite transformation at a variety of temperature ranges. These materials are described, for instance in U.S. Pat. Nos. 3,174,851 and 3,351,463. These alloys are especially suitable because of their capacity to elastically recover almost completely to the initial configuration once the stress is removed. Since this is so, the size of the actual wire may be made fairly small, e.g., as small as 0.005 inches in diameter or smaller, and the resulting device is able to access very small regions of the body. The wire may also vary in diameter along its length, for example have a larger diameter at the proximal end as compared to the distal end or vice versa.
[0048] The wires can have a proximal section and a distal section. The proximal section preferably has a uniform diameter of at least about 0.0001 inch, or about 0.005 to 0.025 inches, preferably 0.0010 to 0.018 inches. Commercially available wires with a microcoil (wire) diameter of 0.008 mm and a macrocoil diameter of 1 mm are available as microcoil materials. Optionally, the distal section may have different (more or less) flexibility than the proximal section and extends beyond the catheter. Typically, both sections will extend from the distal and proximal ends of the catheter lumen. The wire may have a middle section having a diameter intermediate between the diameter of the two portions of the wire adjoining the middle section or the middle section may be continuously tapered, may have a number of tapered sections or sections of differing diameters, or may be of a uniform diameter along its length and be tapered at or near the distal section. The entire wire may be between about 50 and 300 cm, typically between about 175 to 190 cm in length. The wire may be wrapped to form a coil section or may be independently attached to a coil.
[0049] The overall length of the control wire may extend through a catheter and the wire and catheter inserted into the vasculature. The catheter and wires (with attached soft coil may extend proximal or distal to the site of the clot or the catheter may be positioned and the wires extend to the site from the catheter. The configurable soft coil component of the device is positioned near the target thrombus site, and the wires position and control the positioning and attitude of the soft coil capture components.
[0050] FIG. 5 shows a soft coil capture device 4 (which may be of larger dimensions than parenchymal vasculature delivery devices) midway through deployment. In small coils, but particularly with larger coils, greater strength may be built into the elastic memory of the material 2 and the macrocoils 6 and the length of remembered coil distribution 80 . The coil material 2 may be delivered through a catheter 92 , with the elongation of the coils 2 controlled by relative positioning of the push and pull (guide) wires 62 and 64 as explained above. One end of the coil material 2 is shown secured to the push wire 86 and the distal (leading end) of the coil material 2 is shown secured to the distal end of the pull (guide) wire 64 . When in a fully deployed region 80 , without tension or retension applied by the wires 62 and 64 , a natural distribution (frequency) of the macrocoils 6 will exist. Points of contact 82 between the coils 6 and the pull (guide) wire 64 are preferably not secured to the wires 62 and 64 , but are able to slide freely against them. If the contact points were secured, the frequency between the coils would be fixed before and after deployment, unlee the pull (guide) wire 64 were able to telescope or otherwise extend. As shown in the figure, the macrocoils 6 when in a deploying region 90 , without restraining action through the connection at the distal connecting point 84 has a greater frequency (less spacing) between the macrocoils 6 . The macrocoils 6 are shown being deployed out of a catheter 92 . The microcoils and macrocoils may be manufactured and designed so as to provide nature dimensions when tension is released after deployment to fit a range of dimensions in vasculature. The selection of the microcoil size, maicrocoil spacing, wire thickness, wire material, macrocoil size and macrocoil spacing are used to determine the frequency, size and shape of the deployed structure.
[0051] FIG. 6 shows a microcatheter 66 having the pull wire 62 and the push wire 64 with the soft coil material 2 completely within the confines of the microcatheter 66 . The soft coil material will deploy, expanding under its elastic compressive tension, to the limits of its size or the limits of space within the vasculature when the two wires 62 and 64 force the soft coil material from within the microcatheter 66 . In actual delivery of the system, the soft coil material may be present within the microcatheter in a relatively more linear distribution of the microcoils within the lumen of the catheter, rather than as the combination of macrocoils and microcoils shown.
[0052] Although the examples show specific dimensions and materials, the examples and descriptions are not intended to be limiting to the scope of practice and protection of the technology described. Rather, any specific statements or values are intended to be examples within the generic concepts of the inventions and the disclosure taught and provided herein.
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A device captures and assists in the removal of a thrombus in arteries, even in small arteries. The device uses a soft coil mesh to engage the surface of a thrombus, and a guidewire is used to retract the soft coil mesh with the captured thrombus. The soft coil is formed by an elongated microcoil element that forms the helical elements of a macrocoil element. The microcoil element provides a relatively elastic effect to the helical element forming the macrocoil and allows for control of gripping forces on the thrombus while reducing non-rigid contact of the device with arterial walls.
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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
This invention relates generally to recovery devices and more particularly to a system for a rapidly deployable combined retardation and floatation system for recovery of jettisoned or inadvertently dropped cargo.
The use of helicopters for transporting supplies from one ship to another occurs regularly on a daily basis and is considered a common occurrence. On occasions a transitioning cargo is deliberately or inadvertently dropped during the replenishment operation. Without the utilization of a retardation device, the cargo's terminal velocity upon impact with the water surface is sufficient to cause severe damage making the cargo unable to serve the intended purpose. Additionally, after impact the cargo lacking buoyancy sinks to the bottom of the water and is normally unsalvageable. The cost of repair being excessive or replacement not capable of being done easily or conveniently compels the transporter under the circumstances to provide a safer technique to insure against the damage or loss of the cargo.
SUMMARY OF THE INVENTION
Accordingly, the general purpose and object of this invention is to provide a system for recovery of helicopter transported externally slung cargo which is jettisoned or inadvertently dropped during inter-ship replenishment operations. Another object is to provide a self-contained gas inflatable parachute which functions as a retardation and floatation device. Still another object is to provide a cargo recovery system for attachment to a helicopter. Yet another object is to provide a recovery system which is independently coupled to the cargo. It is a further object of the invention to provide a cargo recovery system which is automatically initiated by an increase in relative distance between the cargo and the helicopter. It is still another object to provide a cargo recovery system which goes to full deployment and inflation in approximately one and a half seconds.
Briefly, these and other objects of the present invention are accomplished by utilizing a single element having an inflatable substructure which functions in a dual mode as a combination retardation and floatation system.
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 a representation of a helicopter with a retardation and floatation system according to the invention connected to the underside of the fuselage prior to connection to a cargo;
FIG. 2 is an enlarged cutaway view of a container of the system of FIG. 1 mounted on the underside of the helicopter fuselage;
FIG. 3 is an enlarged view of a door release mechanism of the container of FIG. 2;
FIG. 4 is a retardation and floatation device of the system of FIG. 1 in an inflated condition;
FIG. 5 is a cross-sectional view of a portion of the device of FIG. 4 along the line 5--5 thereof;
FIG. 6 is an enlarged cross-sectional view of the portion of FIG. 5 along the line 6--6 thereof; and
FIG. 7 is an enlarged, cross-sectional view of an inflation supply subsystem of the portion FIG. 5 along the line 6--6 thereof.
FIG. 8 is an illustration of the deployment to recovery sequence of system of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings, wherein like reference characters designate like or corresponding parts throughout the several views, there is illustrated in FIG. 1, a helicopter 13 having connected to the underside of its fuselage by means of a swivel attachment 30 a retardation and floatation device container 21 configured as a cylindrical shape approximately 13 inches in diameter and 45 inches long with streamlined ends.
Container 21, more clearly illustrated in FIG. 2, is fabricated as a fiberglass reinforced laminate having a wall thickness of approximately 1/10 of an inch. Swivel attachment 30 permits container 21 to pivot freely a full 360° about a vertical axis and will orient, in the direction of exerted pull to facilitate withdrawal of an inflatable retardation and floatation device 32 stored in container 21 under all directions of flight. At one end of container 21 is a door 19 having a hinge 40. Door 19 is held in the closed position by a latch release pin 24 held in position by a retainer ring 42, when the device 32 is in the stowed condition and when not activated for deployment. Door 19 can be opened to permit device 32 to be withdrawn. As shown in FIGS. 3 and 4 shroud lines 37 connected at one end to a shroud to pendant transition connector 25 comprising a rod with an eyelet on each end. Lines 37 are attached to the top eyelet and a retardation and floatation device pendant 16 is attached to the bottom eyelet. Connector 25 is held in position between two halves of a ferrule 33. One half of ferrule 33 is connected to door 19 and the other half is connected to container 21. Both ferrule 33 and connector 25 have a hole through their diameter each of which is aligned with the other and through which is inserted the latch release pin 24 which is held in position by the retaining ring 42. Referring back to FIG. 1, pendant 16 connected to the bottom eyelet of fitting 25 has a reach tube 15 at its distal end which is securely affixed to a pendant retention latch 22. A reefed section 23 of pendant 16 consisting of approximately 6 feet of pendant wrapped and held by safety ties 35 is located adjacent to the bottom of connector 25. In order to perform a lifting operation, a cargo support bridle 14 is connected on one end to a cargo support sling 17 and on the other end to a cargo 11. A reach tube 18 at the distal end of sling 17 is connected to a helicopter cargo suspension hook 20. To implement the retardation and floatation system (RAFT), a retardation and floatation device bridle 10 is attached in parallel with bridle 14 to the cargo 11. The other end of bridle 10 is terminated with an automatic closing bridle cargo hook 12 which is connected to the distal end of pendant 16 or reach tube 15. When a cargo 11 falls free for whatever reason from helicopter 13, tension on the reefed section 23 of pendant 16 breaks loose its safety ties 35 and extends for approximately 6 feet. Subsequent to the full extension, pin 24 is sheared when the weight of cargo 11 is transferred to parachute shroud line-to-pendant connector 25. Subsequent to shearing of pin 24, door 19 of container 21 swings open and the device 32 is withdrawn from container 21. The container and door are fitted with a weathertight gasket seal 26 in order to preserve watertight integrity. One end of a lanyard 28 is securely fastened to the inside of container 21 and is tensioned by withdrawal of device 32 thereby initiating inflation of device 32.
Referring to FIG. 4, device 32 includes an elastomer-coated single-ply canopy 58, approximately 15 feet in diameter, having a substructure with eight equally spaced, radial inflatable ribs 56 centered about an inflatable sphere 54 protected against puncture by a layer of heavier, two-ply coated fabric. Shroud lines 37 connect canopy 58 to the connecter 25. Referring to FIGS. 5 and 6, four internal bulkheads 76 are located within the sphere 54 and sealed along their edges to the sphere 54 such that the ribs 56 are separated in pairs to provide four independant air-tight compartments. A fifth air-tight compartment is formed as the core volume of the sphere by the bulkheads 76 enclosing inflation subsystems 50, 60 and 62. All five compartment volumes are equal. Each bulkhead 76, contains an elastomer duckbill-type low pressure relief valve 70 to permit all chambers to be inflated by the centrally located inflation subsystems comprising an aspirator 60, a ball type valve 62 and a high pressure stored gas reservoir 50. Thus, if any one of the compartments are punctured, a buoyancy will be retained that exceeds the total weight of the maximum cargo 11, and retardation and floatation device 32.
FIG. 7 more clearly illustrates that the other end of lanyard 28 is connected to a ball-type valve 62 which when activated by lanyard 28 allows air flow directly into primary discharge passages 51 of an aspirator 60 from a high pressure stored gas reservoir 50. Aspirator 60 is employed to achieve rapid deployment necessary at low altitudes and high flight speeds. Aspirator 60, valve 62 and reservoir 50 are directly connected together pneumatically and structurally to eliminate the need for any interconnecting hoses and simplify their mounting as an inflation subsystem within the sphere 54 as shown in FIG. 6. Aspirator 60 is configured with a formed steel recovery pickup point 45 attached directly to a secondary or ambient air inlet section 61. Aspirator 60 configuration provides maximum pumping efficiency with flow geometry such that adverse reactions to gas flow accelerations are eliminated within the device itself. A radial flow of gas at pressure P 1 through passages 51 inducts the secondary, or ambient air, portion of the inflation gas mixture at pressure P 3 through inlet 61. Inlet 61 is closed by means of a spring loaded poppet 63 that is opened against the force of spring 65 at initiation of inflation by the inductive effect of the mixture at pressure P 2 created downstream of poppet 63 by inrushing high pressure primary constituent of the inflation gas. The primary gas manifolding is oriented such that it flows radially outward in a direction essentially perpendicular to the flow direction of the incoming secondary gas. As shown in FIG. 7, poppet 63 is contoured to assist in changing the direction of the secondary flow as it is inducted by the expansion of the primary gas stream in the venturi mixing area of aspirator 60. The poppet 63 exhibits a stable, positive closure action when backflow of primary gases occurs after inflation of the device 32. The radial, omnidirectional flow pattern of gases from aspirator 60 facilitates "round-out" of device 32 previously stored in container 21 in its deflated condition. The entire inflation subsystem 50, 60, 62 may be withdrawn for recharge or maintenance from the sphere 54 by separating a six-point bridle 68 at the base of sphere 54 from a sphere-to-recovery transition fitting 72 followed by detachment of aspirator 60 from its mounting flange at the top of sphere 54. The volume of reservoir 50 is 225 cubic inches and is pressurized to 3000 psig at 70° F. containing 2 lbs of air resulting in inflation of device 32 to approximately 1 psig. About one-third of the total gas charge within device 32 comes from reservoir 50, the remaining two-thirds is inducted ambient air.
As shown in FIG. 8C when device 32 is fully deployed, it forms a conventional parachute. The inflatable sphere 54 and ribs 56 expedite canopy 58 deployment time and provides the dual capability of being a floatation device. As shown in FIG. 8D, upon water impact, the weight of cargo 11 is transferred from the shroud lines 37 and the canopy 58 to a recovery cable 47 which runs from the top portion of connector 25 to fitting 72 at the base of the sphere 54. A battery powered strobe locator light 78 having a 300,000 candlepower output and a 50 hour operting life is positioned adjacent to the recovery pickup attachment 45. The light is housed within a pocket in the sphere 54 and is activated by a gravity sensitive switch.
A description of the retardation and floatation system operation during the various operating modes as shown in FIGS. 8A-8E follows. During normal replenishment operations a cargo 11 is fitted with a device bridle 10 and connected in parallel with a support bridle 14. A helicopter 13 maneuvers into position and hoovers over the cargo 11 at which time a crewman disengages a reach tube 15 of a pendant 16 from a suspension hook 22. The crewman then engages a reach tube 18 of pendant 17 into the suspension cargo hook 20 and then engages the reach tube 15 of the raft pendant 16 into a raft bridle hook 12 to complete the cargo to helicopter hook-up and retardation and floatation system hook-up. Helicopter 13 takes off, transports the cargo 11 to its destination, hoovers over the deck of a ship, at which time a crewman grabs the reach tube 18 of the support sling 17, at which time the helicopter pilot disengages suspension hook 20 releasing sling 17. Reach tube 15 is then disengaged by a crewman from the raft bridle cargo hook 12 and is engaged into the pendant retention latch 22. Helicopter 13 is now free to return empty for additional cargo. The only additional operations require to accommodate the retardation and floatation system are those of bridle 10 attachment and detachment from reach tube 15 at times of cargo 11 transfer.
During jettison the following sequence occurs. The cargo hook release 20 is actuated by the pilot. This allows cargo to fall free from the helicopter tensioning the raft pendant 16 causing reefed section 23 to break loose its safety ties 35 and extend. Subsequent to full extension of pendant 16 the container latch release pin 24 is sheared as the weight of the cargo 11 is transferred to the parachute shroud line 37 through pendant connector 25. Subsequent to latch release the container door 19 becomes free to swing open permitting device 32 to be withdrawn from container 21. Just as the last of device 32 clears the container 21 the inflation lanyard 28 is tensioned and inflation is initiated, FIG. 8B. The system is fully deployed and functional for retardation and floatation shortly after start of inflation. Upon water impact the cargo 11 weight is transferred to recovery cable 47 which runs from the base of the floatation body center sphere 54 to the upper end of the shroud to pendant transition fitting 25. As this occurs, the spider legs 56 are buckled downward and below the surface of the water as shown in FIG. 8D. Floatation attitude of the system is such that approximately the upper third of the sphere 54 floats above the water thus maintaining the recovery pick-up attachment 45 in a readily accessible position. Strobe locator light 78 begins to flash as a result of the gravity activator switch which connects power from a self-contained power source to energize light 78. The cargo 11 is suspended under equilibrium conditions below the surface of the water. During recovery operations (FIG. 8E) the cargo is carried by recovery cable 47, through the inflatable sphere 54 (FIGS. 4 and 6) and bridle 68, to recovery pick-up attachment 45.
Some of the many advantages of the invention should now be readily apparent. For example, a novel retardation and floatation system has been provided having a conventional parachute shape and which is quickly deployed for retardation and floatation by utilization of an inflatable substructure. The system is automatically acutated by a single action initiated by an increase in relative distance of the cargo from the helicopter. Each system may become a permanent part of a particular helicopter and may be used over and over again with many different cargos. A retardation and floatation device once activated to deployment can be retrieved, recharged, and repacked into its container for future utilization. The system is independent of cargo configuration and minimizes the operations for attachment at time of cargo pick-up or drop-off. Suspensions from the helicopter provide an additional free-fall height or available time to actuate and deploy the retardation and floatation system. The floatation device provides a buoyancy margin exceeding maximum cargo weight. The system employs an aspirator to achieve rapid deployment necessary at low altitudes and high flight-speeds. Ambient air is inducted by the primary gas radial flow configuration providing a substantial portion of the total inflation gas mixture. The inflation subsystem being integrated within the retardation and floatation device has the advantage of providing a symmetrical installation having structural, aerodynamic and buoyancy stability.
Obviously, many modifications and variations of the present invention are possible in the 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 system for transferring cargo at sea by helicopter includes an automatily activated self inflatable apparatus for reducing the velocity of the cargo if jettisoned or inadvertently dropped into the sea and for keeping the cargo afloat until retrieval may be accomplished. The cargo is lifted by a support sling attachable to a helicopter suspension cargo hook and simultaneously connected to a second sling in parallel to the helicopter through the rapidly deployable retardation and floatation device. Release of the support sling causes the cargo to drop and initiate deployment and inflation of the ribs of the parachute thereby retarding the cargo's descend and providing buoyancy for its floatation.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally involves the field of technology pertaining to devices for exercising the human body. More particularly, the invention relates to an improved device for strengthening joints of the leg, and particularly the muscles, tendons and ligaments of the ankle joint.
2. Description of the Prior Art
It is well established that proper exercise serves to strengthen the muscles, tendons and ligaments of the human body, particularly in the areas surrounding the joints in order to prevent or rehabilitate various types of joint injuries. Different joints necessarily have different directional and angular movements which must be taken into consideration during exercise so that complete and balanced strengthening of a given joint can be fully realized.
The joints of the leg, including the knee joint and the ankle joint, are quite prone to injury. This is particularly of concern during athletic activities when an athlete imposes unusual degrees of stress to the joints from different directions which are normally not realized during nonathletic activities. Injuries sustained by the knee and ankle joints can be especially painful and debilitating because of the complex nature of these joints and the necessity for long term rehabilitation or complete recovery of such injuries.
The knee joint is substantially limited to providing pivotal movement of the lower leg with respect to the upper leg, as exemplified by the simple movement between knee extension and knee relaxation wherein the muscles of the upper leg or thigh are utilized. The ankle joint is more complex in its function since it undergoes essentially four basic movements, including planter flexion wherein the foot is rotated in a downward direction, dorsal flexion wherein the foot is rotated in an upward direction, inversion supination wherein the foot is rotated outwardly, and eversion pronation wherein the foot is rotated inwardly. These ankle movements are controlled by the muscles of the lower leg located at the front or anterior, the sides or media and lateral, and the back or posterior thereof. In order to properly strengthen the ankle joint for preventing injuries thereto or realize rapid rehabilitation of an injured ankle joint, it is necessary that all of the muscles, tendons and ligaments controlling all directions of ankle movements be directly exercised under controlled resistance conditions and resistance pressure be asserted over the planes defined by these movements.
The prior art has recognized the benefits of devices for exercising both the muscles and joints of the body wherein resistance is imparted by means of resilient members, such as springs or lengths of rubber bands. It is also known to utilize such devices for directly exercising the muscles and joints of both the upper and lower legs. Examples of devices believed to be indicative of the state of the art in this field of technology are taught by the U.S. Pat. Nos. 1,952,750 Gailey, 2,097,376 Marshman, 2,467,943 Mikell, Hinds et al 4,195,835, 4,251,070 Leseberg, and 4,478,414 Molloy.
It is well recognized that recent activity in the fields of exercising devices and sports medicine has been quite intense, particularly with regard to developments based on stringent scientific and medical considerations in order to provide optimum results. Exercising devices and related equipment are therefore being produced under high technology standards and based on sound principles of kinesiology and related factors. There has also been a recognized need for an improved device which is capable of providing full strengthening and rehabilitating effects to the muscles and joints of the leg, particularly the ankle joint, in a manner and with the results that are consistent with the high standards now expected in this field of technology.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an improved exercising device for strengthening the muscles and joints of the leg and providing rapid rehabilitation of injuries to such muscles and joints.
It is another object of the invention to provide an improved exercising device for specifically exercising and strengthening the muscles, ligaments and tendons associated with the knee and ankle joints of the leg.
It is a further object of the invention to provide an improved exercising device which is capable of exercising the ankle joints and all angular and directional movements of these joints.
It is yet another object of the invention to provide an exercising device for the muscles and joints of the leg wherein the device is extremely easy to use, efficient in operation and economical to manufacture.
These and other objects of the invention are realized by providing an exercising device which includes a plate having the general configuration of the sole of the foot and is detachably secured thereto, preferably by means of belts or Velcro straps. A plurality of elastic limbs have one set of corresponding ends attached to spaced connection points around the periphery of the plate, and their other set of corresponding ends attached to a pair of handles which are gripped by the user. The plate, by virtue of the connection points, defines a triangular-shaped plane to which controlled resistance is imparted by the elastic limbs, thereby permitting the leg joints, and particularly the ankle joints, to be exercised in virtually all their angles and directions of movement.
In a first embodiment, the plate is of substantially the same size and configuration as the sole of the foot and may be directly attached thereto or to the bottom of a shoe worn by the user. Two pairs of elastic limbs may have their one set of corresponding ends detachably connected to the toe and front sides of the plate or, alternatively, to the heel and front sides of the plate.
In a second embodiment, the plate may be substantially one-half the size of the sole of the foot, and have one set of corresponding ends of the elastic limbs connected to the toe and sides thereof, whereby the plate may be selectively attached to either the front portion or rear portion of the foot.
Other objects, advantages and features of the invention shall become apparent from the following detailed description of preferred embodiments thereof, with reference being made to the accompanying drawings wherein like reference characters refer to corresponding parts of the several views.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1-5 are elevational views showing a first embodiment of an exercising device according to the invention in various applications of use;
FIG. 6 is an enlarged fragmentary plan view of the exercising device of FIGS. 1-5;
FIG. 7 is an enlarged front elevational view of a handle used with the exercising device, taken on the line 7--7 of FIG. 6;
FIG. 8 is an enlarged vertical sectional view, through the plate of the exercising device, taken on the line 8--8 of FIG. 6;
FIG. 9 is a fragmentary plan view of an exercising device according to a second embodiment of the invention;
FIG. 10 is an elevational view, showing the exercising device of FIG. 9 depicted in a first position of use wherein the plate is attached to the front portion of the foot; and
FIG. 11 is an elevational view of the exercising device of FIG. 9 shown in a second position of use wherein the plate is attached to the rear portion of the foot.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
An exercising device 1 according to a first embodiment of the invention is shown in various applications of use in FIGS. 1-5. With initial reference to FIGS. 1 and 2, device 1 is shown attached to the right foot of a user 3. Device 1 is basically defined by a planar-shaped plate 5 which is detachably secured either directly to the sole of the foot or to the bottom of a shoe 7 by means of appropriate straps 9. Device 1 also includes two pairs of elastic limbs 11 which have one set of corresponding ends detachably secured to three spaced connection points around the periphery of the front portion of plate 5 so as to define a triangular-shaped plane. The other set of corresponding ends of limbs 11 are secured to a pair of handles 13 which are gripped by user 3. As apparent from FIG. 1, user 3 may stretch limbs 11 in order to impart the desired degree of resistance to plate 5, the latter effectively defining a triangular-shaped plane of resistance. This permits the exercising of the ankle joint by raising and lowering the front portion of the foot against the resistance.
As seen in FIG. 2, the handles of device 1 are spread outwardly, thereby permitting the exercising of the ankle in sideway movements against controlled resistance. Another application of use is shown in FIG. 3 wherein user 3 is in a seated position, thereby permitting an even greater range of movement in the exercising of the ankle by device 1. In this latter case, the heel of the foot may either be supported on a surface 15 or maintained in the air off of surface 15. In either case, it is apparent that the ankle joint can be fully exercised by device 1 in planter flexion and dorsal flexion as indicated by double Arrow 17, and in both inversion supination and eversion pronation as indicated by double Arrow 19. Moreover, in this application of use, it is also possible to exercise the knee through its normal extension and relaxation movements.
In the application of use shown in FIGS. 4 and 5, the pair of limbs 11 attached to the extreme front portion or toe of plate 5 are removed and reattached to the extreme rear portion or heel of plate 5. This configuration permits exercising the ankle joint by applying resistance in a different direction, whereby the heel of user 3 may be raised and lowered against resistance in the manner more clearly shown in FIG. 5.
The structural details of device 1 shall now be described with reference to FIGS. 6-8. As shown in FIG. 6, plate 5 is of a substantially planar-shaped configuration and preferably formed of semi-rigid material, such as leather, rubber, plastic or the like. Plate 5 is also substantially of the same size and configuration of the sole of the foot of user 3 or the bottom of shoe 7 worn by user 3. An essential aspect of plate 5 is that it defines a triangular-shaped plane to which resistance is imparted around the periphery thereof at three spaced connection points. It is further possible that plate 5 may actually form the permanent sole portion of a shoe rather than be detachably secured to the bottom of shoe 7 as shown in FIGS. 1-5.
An appropriate number of straps 9 are secured by means of rivets 21 or similar fasteners around the periphery of plate 5 to permit its detachable connection to the foot or shoe 7 of user 3. Straps 9 are preferably formed from natural or synthetic materials, such as leather or woven nylon, and provided with Velcro attachments 23 which permit rapid connection and disconnection of straps 9 around the foot of user 3. It is also possible that straps 9 be provided with metal buckles or other types of connectors well known in the art and deemed suitable for the practice of the invention as disclosed herein.
As further seen in FIG. 6, a plurality of metal rings 25 are secured at specified locations to the toe, front side and heel portions of plate 5 by means of fabric loops 27 and rivets 29 or other appropriate fastening means. It is important to note that rings 25 are attached around the periphery of plate 5 in such a manner as to permit device 1 to exercise the ankle through application of resistance to both the front and rear portions of the foot as previously described herein. As seen in FIG. 8, each fabric loop 27 is secured by rivets 29 to plate 5 in the same basic manner as each strap 9 is secured by its corresponding rivets 21. A protective cover 31 of plastic or other appropriate material may be laminated onto the bottom of plate 5, thereby sealing and concealing the ends of straps 9, fabric loops 27 and their respective rivets 21 and 29.
Each limb 11 is preferably formed from tubular elastic material, such as surgical tubing or the like. It is also understood that limbs 11 may each comprise a metal spring or other such equivalent elastic mamber well known in the art. The opposite ends of each limb 11 is provided with a tightly fitted plastic plug 33 having an exposed aperture. As seen in FIG. 6, the corresponding ends of limbs 11 secured to plate 5 may either be secured directly to rings 25 or a pair of snap swivels 35 which in turn are secured directly to a ring 25. It is therefore clear that the ends of limbs 11 secured by snap swivels 35 to ring 25 located at the toe of plate 5 may be detached and reconnected to the two rings 25 secured to the heel of plate 5 in order to permit the alternative application of use for device 1.
The other corresponding ends of each pair of limbs 11 are connected to handles 13. As seen in FIG. 7, each handle 13 may be formed of leather or other appropriate material, and provided with a pair of buckle assemblies 37 of known configuration at the opposite ends thereof. Each buckle assembly 37 includes a ring 39 that is in turn secured through the aperture of plastic plug 33 carried by the end of corresponding limb 11. However, the construction of handle 13 and its manner of attachment to limbs 11 may of course be in any form well known in the art so long as handle 13 is securely attached to limbs 11 and may be easily gripped by user 3 for exercising with device 1 in the manner disclosed herein.
An exercising device 41 according to a second embodiment of the invention shall now be described with reference to FIGS. 9-11. As particularly seen in FIG. 9, device 41 differs from device 1 of the first embodiment inasmuch as a plate 43 is provided having approximately half the size of plate 5. In a preferred form, plate 43 is of the same configuration and size as the front half portion of plate 5. This constitutes the primary difference between device 41 and device 1. Moreover, snap swivels 35 are eliminated and plastic plugs 33 of limbs 11 may be connected directly to ring 25 located at the toe of plate 43. The remaining structural details of device 41 are exactly the same as previously described for device 1.
As shown in FIG. 10, plate 43 of device 41 may be attached to the front portion of shoe 7 for exercising the ankle in the same basic manner as previously described for FIGS. 1-3. When plate 43 is shifted and reattached to the heel or rear portion of shoe 7 as shown in FIG. 11, device 41 may be utilized in the same manner as previously described for FIGS. 4 and 5.
It is to be understood that the forms of the invention herein shown and described are to be taken as merely preferred embodiments of the same, and that various changes in shape, material, size and arrangement of parts may be resorted to without departing from the spirit of the invention or scope of the subjoined claims.
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An exercising device for strengthening joints of the body, particularly the ankle joint, wherein a plate engageable against the foot of the user imparts controlled resistance in all directional movements of the joint through elastic limbs having one set of corresponding ends attached to predetermined points around the periphery of the plate and the other set of corresponding ends attached to a pair of handles which are gripped by the user for varying the degree of resistance imparted by the limbs.
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BACKGROUND OF THE INVENTION
[0001] This application claims the benefit of U.S. Provisional Application No. 60/008,944 filed Dec. 20, 1995.
[0002] The present invention relates to fishing lures. More particularly, the present invention relates to a flesh-like jacket for encasing and enhancing the action of a crankbait fishing lure.
[0003] Fishing is an activity enjoyed by many as a recreational sport or as commercial enterprise. Sport fisherman or recreational anglers still use the time-proven method of dropping a baited hook attached to a piece of line into the water in the hopes of catching a fish. Through modern advances, anglers now have a wide assortment of equipment with which to find and catch fish.
[0004] To encourage the fish to bite, the hook may be baited with a tempting morsel of food such as a live bait fish, live worms, roe or other live bait that is part of the natural diet of the fish species sought by the angler. Anglers also may use a fishing lure which is a manufactured artificial bait that mimicks the look and action of the natural bait. Although the dietary choices of most fish can be extremely fickle, part of the attraction of fishing is attempting to discern not only where the fish are located but also the type of bait that the fish are interested in eating. When bait fish are not available to the angler or its use forbidden due to local laws restricting such use, anglers often use fishing lures to catch fish. Fishing lures are used by anglers in both salt water and fresh water.
[0005] There is a large variety of soft plastic lures typically made from plastisol and molded into the shape of, by way of example, worms, grubs or similar such shapes. The plastic material may be impregnated with salt or other scents so that the taste of the lure is similar to natural bait. Soft plastic lures are threaded onto a hook, attached to a fishing line and cast out and retrieved or bounced along the bottom to mimic a worm swimming in the water. Although very effective as a bait, fish often inhale soft plastic lures and become internally hooked. Since many anglers practice “catch and release,” it is undesirable to internally hook the fish because such fish often die due to the internal hook set.
[0006] In addition to soft plastic lures, other lures, often referred to as “crankbaits” are commonly used. Crankbaits are hard-bodied fishing lures attached to the fishing line, cast out onto the water and then cranked or reeled in by the angler. The motion of the crankbait through the water causes the crankbait to dive beneath the surface of the water or, alternatively, create a disturbance on the surface of the water that mimics an injured minnow or a fleeing fish. When a fish attacks a crankbait it is often hooked in the lip thereby facilitating its subsequent release.
[0007] [0007]FIG. 1 illustrates a typical prior art crankbait 10 which may be manufactured from wood, metal or hard plastic (such as poly-carbonate plastic) and coated with several layers of colorful finish paint or decals to attract fish by mimicking the coloration of a bait fish. Alternatively, the body may be painted in a color, such as metallic, or brightened by embedding reflective facets (not shown) in a polyurethane coating so that the crankbait is bright and readily discernible in murky water or low light conditions or is otherwise enticing to fish. The finish layers often include painted representations for eyes 12 , fins 14 , scales 16 or gills 18 so as to emulate a natural appearance of common bait fish. It will be appreciated that such features may be duplicated on the side of crankbait 10 not shown in FIG. 1.
[0008] Crankbait 10 may have a diving bill 20 that extends outward and in some cases downward from the head portion of crankbait 10 . A fishing line attachment loop 22 is shown as a part of the diving bill although attachment loop 22 may be located on crankbait 10 in the area generally defined as between the diving bill 20 and the top of the head portion above eye 12 . Diving bill 20 may vary in size with a smaller surface area causing the crankbait 10 to dive to a relatively shallow depth and larger surface area for deeper diving crankbaits. The angle of attachment of diving bill 20 may also vary respect to the longitudinal axis 24 of crankbait 10 with a larger angle resulting in a faster diving crankbait. A fixed, solid dorsal fin 26 is shown extending above the body of crankbait 10 in FIG. 1 although many crankbaits do not have any such protruding features.
[0009] Although not shown, crankbait 10 may have a variety of configurations. For example, the forward-most head portion could be flattened or concave (to represent a bait fish swimming with an open mouth) rather than the generally convex shape as shown in FIG. 1. In such configurations, diving bill 20 is omitted since such crankbaits are intended to be fished on the surface of the water. In other configurations, diving bill 20 is attached to the head portion of crankbait 10 below axis 24 .
[0010] With so much diversity in size, color and shape designed to appeal to one or more species or size of fish, anglers often carry a large number of crankbaits in their tackle boxes. Notwithstanding the diversity, individual anglers will often develop a preference for a preferred crankbait that, they believe, has a high probability of catching fish. Popular freshwater crankbaits are manufactured by Rapala of V{umlaut over (aa)}ksy, Finland and by Mirrolure of Largo, Fla. as well as by many other companies throughout the world.
[0011] Colorful streamers, noise makers or other novelties can be attached to the crankbait or to the fish line in an attempt to make the crankbaits more attractive to the fish. For example, a propeller (not shown) may be rotatably mounted to the head portion or rear portion of crankbait 10 to create turbulence as the crankbait is pulled through the water. One such crankbait is manufactured by Fred Arbogast and available from Bass Pro Shops located in Springfield, Mo. In still other configurations, crankbait 10 may have a jointed body where a separate rear portion is coupled to the body portion of crankbait 10 by interlocking loops or may have a segmented body such as disclosed in U.S. Pat. No. 5,182,875.
[0012] It is believed that common attributes of a successful crankbait is its coloration, size, appearance and swimming action. With respect to the coloration of a crankbait, one skilled in the art will appreciate that with use, the decals or the painted design of a crankbait often become scratched from collisions with other items in the angler's tackle box, with items under water such as rocks, submerged logs or other such debris or from repeated strikes by fish attracted by the crankbait. The brightness of the painted design may also fade after extended use in water and exposure to sunlight. With continued use, such crankbaits may tend to lose their effectiveness resulting in fewer and fewer strikes over a given period of time because fish tend to avoid crankbaits that appear unattractive or unappealing as food. It is preferable to refurbish a popular crankbait by enhancing the attractiveness of the crankbait rather than abandon its use.
[0013] At times, it may be desirable to change the appearance of the crankbait by changing the coloration or adding decorative features. If an angler were fishing with a crankbait painted to look like a sardine but the game fish are feeding on anchovies, the sardine crankbait would likely be largely ignored and the number of strikes could be few or nonexistent. Thus, the angler may have to remove the sardine crankbait and replace it with a crankbait having the coloration suggestive of an anchovy to increase the number of strikes. However, replacing one crankbait with another similar crankbait differing only in the coloration requires duplication in the number of crankbaits. It would be cheaper, if the angler could reduce the number and variety of crankbaits that must be carried while maintaining the flexibility to quickly and easily change the coloration of the crankbait to match the desired bait fish.
[0014] At still other times the water conditions may make it difficult for fish to locate bait because of, for example, darkness or murky water conditions. When this occurs, anglers may need to fish with a crankbait that has a metallic or shiny finish or that is fluorescent so as to increase visibility of the crankbait in the water. However, it would again be cheaper if the angler could adapt a single crankbait to compensate for the conditions with a bright shiny finish.
[0015] At still other times, even if the proper coloration of the crankbait is selected, fish will often fail to strike at even the most productive of the angler's crankbaits. In such instances, the angler may be tempted to try larger or smaller crankbaits to determine what size of bait attracts the fish. To change from, for example, a small anchovy to a larger anchovy, the angler would have to remove the anchovy crankbait and replace it with another similar but larger crankbait. This change requires the angler to further maintain a stock of crankbaits that have a similar body designs but that differ in size. Clearly, it would be to the advantage of the angler to have the ability to quickly and inexpensively change a single crankbait so as to make it appear to the fish as a larger (and, hopefully, more desirable) bait fish or conversely, a smaller bait. Alternatively, it may be desirable to add features to a crankbait such as protruding fins, tails, scales or other anatomical features to make the crankbait appear more life-like. An example of prior art attempts to change the appearance of a crankbait is disclosed by U.S. Pat. No. 5,333,406, issued to Wylie in which a cloth covering changes the coloration of the lure.
[0016] With respect to the swimming action of a crankbait, it is desirable for action of the crankbait to closely mimic the undulating side-to-side motion of a natural bait fish. However, most crankbaits have an erratic side-to-side action or wobble significantly different from the natural motion of a bait fish. Accordingly, it is desirable to modify the motion of a crankbait such that it has a fluid, undulating side-to-side motion of a bait fish as it is cranked in by the angler.
[0017] Another problem that arises with many crankbaits is that even though the body design closely duplicates the natural bait which the crankbait is intended to replace, fish often hit the bait but do not strike to the degree necessary to permit the angler to set the hook and catch the fish. One reason for this is that fish have sensitive mouths and are able to discern that the texture of the crankbait is hard and unfamiliar. Having tasted the bait, fish lose interest and move on to seek other bait. It would be to the angler's benefit to present a lure that has both the swimming action of a crankbait as well as the texture and taste of a soft plastic lure that more closely simulates fish flesh than does a wood, metal or hard plastic crankbait or a crankbait having a cloth covering.
SUMMARY OF THE INVENTION
[0018] To overcome the limitations associated with prior art crankbaits described above, and to overcome other limitations that will become apparent upon reading and understanding this specification, the present invention discloses a combination of a common crankbait such as is found in the tackle box of every angler and a jacket or skin that covers the crankbait. In one preferred embodiment, the jacket comprises a highly elastic covering molded into a seamless, elongated shell with a rearwardly projecting tail portion, which may include a caudal fin, that is stretchable over a crankbait. The thickness of the jacket provides a natural flesh-like texture to wood, hard plastic or metal crankbaits while protecting the crankbait from scratches caused by fish strikes or by collision with other objects.
[0019] For purposes of illustration the following description describes the present invention as used with conventional prior-art crankbaits which have a generally fish-like appearance with a head and-a rear portion separated by a body portion. Treble hooks are attached at one or, in most instances, two or more hook attachment points one of which is usually positioned on the rear portion of the crankbait. Additional hooks may be attached proximate to the head portion of the crankbait or, if the crankbait is of sufficient size, to the body portion of the crankbait midway between the head and rear portions. Some crankbaits may have a diving bill attached to the forward end of the head portion so that the crankbait will dive beneath the surface of the water when moving through the water.
[0020] The jacket has a cavity with at least a first opening providing access to the cavity. The crankbait is removably positioned in the cavity of the jacket by stretching the jacket in the region surrounding the opening until it is large enough to insert the crankbait into the cavity. Insertion is simplified by first rolling the jacket into a minimized configuration prior to stretching the jacket and unrolling the stretched jacket over the crankbait.
[0021] Once the crankbait is encased within the jacket, the hooks project through “slits” in the jacket which can be made using a sharp knife or by forcing the hook attachment loop through the jacket material. If the crankbait has a diving bill, it preferably projects through the opening. Due to the tear resistant nature of the jacket, the opening or slits will not further significantly tear even if the jacket is removed and applied to a much larger crankbait.
[0022] The shape of cavity is generally elliptical with a girth dimension that is preferably smaller than the corresponding girth dimension of the crankbait. The length of the cavity is preferably about equal to or less than the length of the crankbait although the length of the cavity may be substantially greater without noticeable negative effects. With the elastic material of the jacket, the cavity is stretched until the cavity's dimensions substantially equal the dimensions of the crankbait so that the jacket tightly clings to the body of the crankbait. When the jacket is applied to a crankbait, the overall length of the crankbait is extended by the jacket's tail portion which extends rearward. The tail portion of the jacket changes the appearance of the crankbait by increasing the length and by adding a realistic looking fish-tail or a trailing skirt of colorful material. The tail portion also acts as a rudder that tends to moderate the erratic wobble of a crankbait thereby creating a very realistic undulating swimming action of a natural bait fish.
[0023] The jacket in one preferred embodiment is substantially clear or amber in color. With a clear jacket the coloration and shape of the crankbait may readily be perceived by the fish. Highlights, such as reflective particles or dye, may be added to the tail portion of a clear jacket to provide definition to the otherwise transparent tail. Amber jackets may be used to present a brightly colored lure with a slightly faded appearance or to provide a more visible tail section. Bright or reflective particles may be added to the jacket during manufacture so as to enhance the original coloration of the crankbait. Alternatively, the jacket may be dyed so that the perceived color of the lure is changed.
[0024] The jacket may also have a textured outer surface to represent scales as well as protruding elements representing fins and gills. When the jacketed crankbait is allowed to float in the water, the protruding fins will flutter outward giving the appearance of a suspending fish but will fold back against the crankbait as it is retrieved.
[0025] In yet another embodiment, the jacket may include one or more cavities into which scent attractant, such as fish blood, cricket legs, worm parts or commercial fish food may be inserted. Slits or openings in jacket provide access to the cavities so that the jacketed crankbait emits the attractant as it is retrieved.
[0026] Together with the flesh-like texture of the material, the jacket of the present invention makes it possible to provide a hard bodied crankbait with a texture, appearance, smell and swimming action of a natural bait fish.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] [0027]FIG. 1 is a representation of a prior art hard-bodied fishing crankbait;
[0028] [0028]FIG. 2A is a side view of a preferred embodiment of the protective jacket of the present invention;
[0029] [0029]FIG. 2B is a front view of the embodiment shown in FIG. 2A.
[0030] [0030]FIG. 3 is a bottom view of the protective jacket of the present invention;
[0031] [0031]FIGS. 4A and 4B are illustrative representations of a method of applying the protective jacket of the present invention over a crankbait;
[0032] [0032]FIG. 5 is a side view of another preferred embodiment of the protective jacket of the present invention;
[0033] [0033]FIG. 6 is a side view of a segmented crankbait to which the protective jacket is applied in yet another preferred embodiment of the present invention;
[0034] [0034]FIG. 7 is a front view of one segment of the crankbait shown in FIG. 6; and
[0035] [0035]FIG. 8 is a side view of another embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0036] In the following description of one preferred embodiment, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration a specific embodiment in which the invention may be practiced. It is to be understood that other embodiments may be utilized and that changes may be made without departing from the scope of the present invention. For purposes of illustration the following description describes the present invention as used with conventional prior-art crankbaits that have a generally fish-like appearance. However, it is contemplated that the present invention can be used in conjunction with other baits such as jerk baits, spoons, jigs or as a soft bait.
[0037] Referring again to FIG. 1, treble hooks 28 and 30 are attached to the body of crankbait 10 at one and preferably two or more hook attachment points. Hook 28 is typically attached to a loop 27 A that protrudes from the belly of crankbait 10 while hook 30 is typically attached to a rear protruding loop 27 B or to a hole (not shown) positioned proximate to the rear of the crankbait. If crankbait 10 is of sufficient size, an additional hook attachment point (not shown) may also be provided in the body portion of crankbait 10 midway between loops 27 A and 27 B. Split rings 29 are commonly used to couple hooks to the protruding loops. Alternatively, treble hooks with an open shank (not shown) may be pressed over loops 27 A and 27 B without split rings 29 . Although the length of treble hooks will vary depending on the size of fish an angler anticipates catching as well as the size of crankbait 10 , treble hooks 28 and 30 , in one representative example, extend from crankbait 10 by about 2.54 cm (one inch).
[0038] Referring now to FIGS. 2A and 2B, a protective cover or jacket 32 of the present invention is shown having a head portion 34 , a tail portion which may include a caudal fin 36 , pectoral fins 33 , a dorsal fin 35 and pelvic and anal fins 35 and 37 , respectively, or other features that creates a realistic replica of a bait fish.
[0039] As shown in FIG. 3, jacket 32 also includes a cavity 38 . Tail portion 36 may be molded into a desired shape such as a fish tail, a streamer or other selected shape and undulates as the crankbait is trolled through the water. It is possible to embed capsules with steel weights, or other similar material (not shown) in tail portion 36 or cavity 38 to add weight or to create noise as the crankbait is trolled through the water.
[0040] Opening 46 provides access into cavity 38 as is shown more clearly in FIG. 4A and crankbait 10 is inserted “rear first” into cavity 38 through opening 46 . Opening 46 has a dimension that is significantly smaller than crankbait 10 but is stretchable to permit crankbaits of different sizes to be insert or removed from cavity 38 . In one example, the diameter of opening 46 is preferably less than approximately 0.3175 cm (0.125 inches) through which a small crankbait with a length of about 5.08 cm (2 inches) and a maximum girth 6.35 cm (2.5 inches) may be inserted. In general, the dimension of opening 46 is elastically deformable and need only be large enough to dilate sufficiently to permit insertion of the crankbait, and optionally the attached treble hook 28 , into cavity 38 yet sufficiently small so that after insertion of the crankbait into cavity 38 jacket 32 is able to conform around the rear portion of the crankbait. A larger opening may be desirable for jackets designed for larger crankbaits to prevent microtearing of the material in the vicinity of opening 46 .
[0041] Slits 40 , 42 and 44 (see FIG. 2A) are preferably narrow openings such that, in the unstretched state, opposing edges substantially remain in contact. Slits 40 , 42 and 44 may be made using a pair of scissors, a knife or stretching the jacket over an attachment loop until an opening is created or formed during the molding process.
[0042] In the preferred embodiment, hooks 28 and 30 are removed before crankbait 10 is positioned in cavity 38 and then reattached to the crankbait after the jacket envelops crankbait 10 . Once crankbait 10 is positioned within cavity 38 , hook 28 extends outward from jacket 32 through slit 42 and hook 30 extends through slit 40 . If a particular crankbait has a fishing line attachment loop positioned near the top of the head portion, the attachment loop will protrude through slit 44 . Once crankbait 10 is inserted into cavity 38 , jacket 32 clingly conforms to the surface of crankbait 10 and openings 40 and 46 and slits 42 - 44 attempt to return their unstretched dimensions thereby creating a tight fit around protruding elements of crankbait 10 . The tight fit and the adherence of jacket 32 to crankbait 10 substantially eliminates ballooning or separation of jacket 32 from crankbait 10 when trolling or casting the jacketed crankbait.
[0043] In another preferred embodiment, slit 40 has a diameter of about 0.3175 cm (0.125 inches). To ensure adequate strength in the region surrounding opening 46 , the thickness of material may be increased by between 2% to 25%. The elasticity of the material comprising jacket 32 is thus believed to be sufficient to dilate during insertion of crankbait 10 and return, or attempt to its original dimensions in order to form a tight seal around diving bill 20 . When crankbait 10 is inserted through slit 40 it is important that the seal around the front of crankbait 10 is as tight as possible so as to reduce the possibility that cavity 38 will fill with water and cause jacket to separate from the surface of crankbait 10 as it is retrieved. Opening 46 and slit 40 are elastically deformable such that diving bill 20 may be inserted therethrough without tearing or permanent deformation even if diving bill 20 is wide relative to the diameter of opening 46 .
[0044] In one preferred embodiment of the present invention, a durable synthetic flesh-like material is castable in a variety of shapes to form jacket 32 . The material is preferably a transparent hot melt adhesive material, product numbers HL-2249-X and HL-2502-X, obtained from H. B. Fuller Company of St. Paul, Minn. and marketed under the name of Full Flesh. Although the material is considered experimental by the manufacturer, HL-2249-X is a very soft, clear to amber rubber material with a tacky texture and a high degree of elasticity. The material has high elongation and tensile strength and excellent shape retention after extreme deformation. It has a Molten Gardner color of 1.5 and viscosity of 68,000 cP (mPa.s) at 325° F. (162.8° C.); 18,500 cP (mPa.s) at 350° F. (176.7° C.); 3,000 cP (mPa.s) at 375° F. (190.6° C.); and 625 cP (mPa.s) at 400° F. (204.4° C.). The recommended application temperature for HL-2249-X is in the range of 350° F. (176.7° C.) to 375° F. (190.6° C.). Higher application temperatures may tend to burn the material and cause a loss of clarity. HL-2502 is a stiffer rubber compound that has a less tacky surface. Although HL-2449-X is suitable, and indeed preferable for construction of jacket 32 due to the suppleness of the resulting jacket, it is possible to mix HL-2449-X and HL-2502-X in various proportions to achieve a compound having intermediate stiffness and tackiness properties. A powder, such as baby powder or flour, may be applied in small quantities to the exterior of jacket 32 to reduce surface tackiness and promote ease of application of jacket 32 over crankbait 10 . Alternatively, jacket 32 may be dipped in a bath to coat the outside of jacket 32 and/or the inside of cavity 38 with a tackfree polyethylene wax. The wax is applied by first dispersing the wax in water and then dipping jacket 32 into the bath. The wax may be injected or sprayed into cavity 38 to coat the internal surface of cavity 38 .
[0045] In another preferred embodiment, jacket 32 is molded from a soft silicon based material that is injectable using high volume injection molding equipment. The material must have a soft pliable composition and must have sufficient degree of elasticity to stretch over a crankbait. It is believed that one such material, for example, ______ is available from Reedy International in Keyport, N. J. (telephone number (201) 264-1777).
[0046] Due to flexibility afforded by the material and molding techniques, it is possible to add protruding elements in the form of fins 56 and 58 , such as shown in FIG. 5, or other decorative features such as a long streaming tail 50 such as shown in FIG. 3. The material is castable into a variety of shapes using, by way of example, a two- or three-piece, non-porous, heat resistant, high temperature mold as is well understood by those skilled in the art. The molds may be made from metal, aluminum or from fiber glass using material available from Fiber Resin Corporation of Burbank, Calif. A three piece mold, also referred to as a matrix mold, is used when elements protruding from the base of jacket 10 make it otherwise difficult to pull a two-piece mold apart. For the sake of conciseness, further description of the construction of such molds will be omitted.
[0047] The mold pieces are put together around a core element and injected with the material. It should be noted that care must be taken to prevent incursion of moisture during the molding process to minimize bubbling of the material or explosive vaporization of the water upon application of the material.
[0048] The core element (not shown) defines the dimension of cavity 38 and the thickness of the jacket as well as the dimensions of openings 46 and 47 . The core element is supported in the mold by projecting rods that define opening 46 and tail opening 47 . After the material has cooled and solidified, jacket 32 is removed from the mold and the core removed from jacket 32 . Any resulting mold seams or burrs on jacket 32 may be removed using a sharp knife or a heated iron.
[0049] Jacket 32 is elastically stretchable such that it may cover either a small crankbait or a large crankbait. For example, an early prototype of jacket 32 was initially constructed for a crankbait having a length of about 4.45 cm but applied to a crankbait having a length of about 13.34 cm (5.25 inches). The longer crankbait also had a maximum girth of about 8.25 cm. (3.25 inches) which was about twice as large as the original crankbait. Jacket 32 was then removed and subsequently reapplied to the original small crankbait. Regardless of the crankbait to which jacket 32 was applied, no ballooning was observed during multiple casting and underwater retrievals. However, if jacket 32 is unduly stretched by, for example, a factor of five or more, microtearing of jacket 32 may change the coloration such that jacket 32 appears more translucent. Accordingly, to prevent jacket 32 from turning translucent, the angler may need to take some degree of care to match jacket 32 with appropriately sized crankbaits.
[0050] In one preferred embodiment of the present invention, jacket 32 is either substantially clear in appearance such that the original coloration of crankbait 10 is visible with little or no distortion or a transparent amber in appearance that tends to impart an amber hue to brightly colored crankbaits. Metallic particles or bright reflective crystals may be added to all or a portion (such as to the top) of jacket 32 so as to add additional sparkle to the original coloration of crankbait 10 . In yet another preferred embodiment, a dye or pigmentation is added to jacket 32 to produce a coloration independent from the coloration of crankbait 10 . In this manner, jacket 32 may quickly and inexpensively change the coloration of crankbait 10 to match that of a desired bait fish without requiring the angler to buy multiple crankbaits that differ only in coloration.
[0051] Referring now to FIGS. 4A and 4B, a preferred method for inserting crankbait 10 into cavity 38 of jacket 32 is represented. Initially, jacket is rolled into a minimized configuration such as is indicated at 53 in FIG. 4A. Specifically, starting from opening 46 , jacket 32 is rolled toward the tail portion 36 and the rear of crankbait 10 is inserted through opening 46 . If necessary, opening 46 is elastically stretched to accommodate a range of diving bills from deep diving crankbaits to shallow diving crankbaits. As jacket 32 is unrolled along crankbait 10 , opening 46 attempts to resume its original dimensions thereby causing a tight conforming fit of jacket 32 along the junction of diving bill 20 and the head portion of crankbait 10 . If crankbait 10 has projections, jacket 32 is flexible enough to stretch over and substantially conforms to such projections. When the unrolling of jacket 32 reaches the proximity of hook 28 , jacket 32 and opening 46 are stretchable so as to encompass the combined girth of crankbait 10 and hook 28 . Since hook 28 is rotatably coupled to crankbait 10 at loop 27 A, it is possible to minimize the combined girth by rotating hook 28 until its length is substantially parallel to longitudinal axis 24 (see FIG. 1). However, it is preferrable that hooks 28 and 30 are removed before crankbait 10 is inserted and later re-attached.
[0052] The unrolling of jacket 32 continues, as shown more clearly in FIG. 4B, until slit 42 is proximate to loop 27 A. By dilating slit 42 , that is, by locally stretching jacket 32 , it is possible to insert loop 27 A through slit 42 . Once passed through slit 42 , the local stretching force is no longer be applied and slit 42 substantially resumes its original dimensions again providing a tight conforming fit around loop 27 A. Jacket 32 is furthered unrolled until diving bill 20 protrudes from opening 46 . The position of jacket 32 may need to be adjusted until the dorsal fin is centered over the longitudinal centerline of crankbait 10 .
[0053] In an alternative preferred method for applying jacket 32 (not shown), opening 46 has a diameter of about 0.3175 cm (0.125 inches) and crankbait 10 is inserted “head first” into cavity 38 through slit 40 , which preferrably has wider dimensions than slits 42 and 44 , rather than opening 46 . Specifically, slit 40 is dilated to provide access to the cavity 38 while rolling the jacket into a minimized configuration. Dilation is obtained by stretching the jacket 32 in the region surrounding the opening until opening 40 is large enough to insert the crankbait into the cavity. The head of crankbait is then positioned in the cavity of the jacket with diving bill 20 projecting from opening 46 and the stretched jacket is unrolled over crankbait 10 and allowed to conform to the crankbait 10 . The position of jacket 32 may need to be adjusted until the dorsal fin is centered on the longitudinal centerline of crankbait 10 .
[0054] Once applied to crankbait 10 , jacket 32 substantially conforms to the shape of crankbait 10 as is more clearly shown in FIG. 4C. Further, if jacket 32 has a trailing tail portion 36 or 50 (see FIGS. 2 and 3) or similar feature, the crankbait 10 appears as a larger bait. If no such tail is present, the size of crankbait 10 is substantially unchanged with the application of jacket 32 although the texture is more flesh-like with jacket 32 applied. Depending on the color or decorative features of jacket 32 , the coloration and texture of crankbait 10 may be easily changed. Additional life-like features, such as scales 16 A, may be readily added.
[0055] As generally indicated by reference numeral 56 , jacket 32 has a certain thickness associated therewith. With the preferred material, the thickness associated with jacket 10 provides realistic compression and elongation. Thus, when a fish strikes at the crankbait, the crankbait presents a life-like texture to crankbait 10 rather than the hard unnatural texture of a wood, plastic or metal crankbait. Due to the elastic tendency of the preferred material, jacket 32 substantially adheres to crankbait 10 so there is little separation between jacket 32 and crankbait 10 even if the crankbait has multiple protrusions. Also, since the preferred material is durable and tear resistant, jacket 32 resists repeated strikes by fish without tearing and returns to its original shape despite repeated applications onto or removal from different sized crankbaits.
[0056] As indicated at 52 (by the dashed line) in FIG. 3 and in FIG. 4C, the thickness of jacket 32 in the head and body portions is preferably a membrane of between 20.32 mm (0.08 inches) and 63.5 mm (0.25 inches) that provide flesh-like compression once it is applied to a crankbait. It being understood that such thickness is not shown to scale in FIGS. 3 and 4C. Preferably, the membrane thickness of jacket 32 will be at least 31.75 mm (0.125 inches) in the body portion and thicker than 31.75 mm in the head portion 34 around opening 46 . It will be appreciated by one skilled in the art that the actual thickness when applied on crankbait 10 may vary depending on the relative size of crankbait 10 and cavity 38 and protrusions, if any, (on crankbait 10 ). However, thicker head and body portions of jacket 32 are expected to be more durable and capable of being stretched over a wider variety of differently sized crankbaits without incurring excessive microtearing, ballooning when applied to crankbait 10 and trolled through the water or inducing a partially opaque appearance to an otherwise transparent jacket 32 . Tail portion 36 of jacket 32 is preferably a substantially solid extension having a girth of about 3.175 cm (1.25 inches). It is believed that tail portion 36 should comprise about 40% to 60% of the overall length of jacket 32 in the unstretched state. Specifically, tail portion 36 may have a length of between 2.54 cm to 4.45 cm (1.0 to 1.75 inches) with a preferred length of about 3.05 cm (1.3 inches) for a jacket having an overall length of about 6 cm (2.4 inches). When applied to a crankbait, tail portion 36 will comprise about one third of the overall length of jacket 32 when stretched to an overall length of about 9.9 cm (3.9 inches). Longer, thinner tail portions 50 , such as shown in FIG. 3, are also contemplated and may comprise about 50% of the overall length of jacket 32 when stretched onto a crankbait body.
[0057] Referring now to FIG. 5, another preferred embodiment of jacket 32 is shown. In this embodiment, jacket 32 has dorsal fin 56 and fins 33 extending outward from jacket 32 . One skilled in the art shall further appreciate that added features may include additional fins or other protrusions. Preferably, dorsal fin 56 and fins 33 are integrally molded into jacket 32 during the manufacturing process and are comprised of the preferred jacket material made as thin as possible (that is, preferably less than 31.75 mm) so as to present a life-like appearance as the crankbait is alternately moved through or suspended in the water. Specifically, when the jacketed crankbait is allowed to float in the water, the protruding fins will flutter outward giving the appearance of a suspending fish but will fold back against the crankbait as it is retrieved. Dorsal fin 56 may include a stiffning ridge (not shown) along the forward edge to ensure that the fin protruds away from crankbait 10 but will also flutter when allowed to float in water.
[0058] Also shown in the embodiment illustrated in FIG. 5 are cavities or pockets 60 and 62 . Pockets 60 and 62 comprise voids formed in jacket 32 into which the angler may insert fish attractant such as blood, fish or other bait parts or solid matter such as commercial fish food. Slits 64 and 66 provide access to pockets 60 and 62 , respectively, so that the attractant can be easily inserted. Due to the adhesive and elastic nature of the preferred material comprising jacket 32 , slits 64 and 66 are sealed by applying pressure to the slits. In yet another embodiment, pockets 60 and 62 have a very thin or blister-like membrane (not shown) such that when a fish strikes the jacketed crankbait, the blister-like membrane is easily punctured thereby releasing a large amount of fish attractant in a very short period from pocket 60 and or pocket 62 . Alternatively, attractant may be inserted into cavity 38 behind crankbait 10 or absorbed into jacket 32 directly by submersing jacket 32 into an attractant oil or solution. The attractant is absorbed into the synthetic flesh-like material due to the porous nature of the material. Advantageously, tail opening 47 (FIG. 3) provides a passage for scent attractant positioned in cavity 38 to be expressed out through tail 36 as crankbait 10 is moved through the water. It is anticipated that such a quick release of an attractant such as blood, will encourage the fish to strike the crankbait again thereby permitting the angler to readily hook the fish. It will be understood by one skilled in the art that using the matrix molding technique described above, the cavity that the jacketed crankbait could continually release a fish attractant and when hit by a fish, release a large amount of attractant from blister pockets 60 and 62 to further attract strikes by the fish.
[0059] Referring now to FIGS. 6 and 7, a segmented crankbait 70 is shown having a plurality of segments 72 coupled together by a flexible wire rope or plastic impregnated string 74 and substantially symmetrically aligned along longitudinal axis 24 . Segment 72 A is coupled to a head portion 76 at one end of crankbait 70 while segment 72 n is coupled to tail portion 78 at a second end. The diameter of each segment 72 is generally equal to or smaller than the preceding segment when proceeding from the head end to the tail end of crankbait 70 . Specifically, the diameter of segment 72 A is substantially equal to or larger than the diameter of segment 72 B which, in turn, is larger than the diameter of segment 72 C. Segment 72 C is larger than segment 72 D and so on to segment 72 n so that the overall effect is that segmented crankbait 70 has a shape substantially similar to a solid crankbait. The forward facing surface of each segment 72 may be slightly concave while the rear surface may be convex. Alternatively, each segment 72 comprises a disk with parallel forward and rear surfaces.
[0060] As shown in FIG. 7, each segment 72 has a center hole 80 through which the wire rope or string 74 may pass. Between each segment, a spacer 82 having a diameter larger than center hole 80 , is inserted to prevent relative movement of each segment along rope or string 74 . One skilled in the art will appreciate that spacers 82 may comprise items such as washers, knots, beads or additional segments. The rope or string 74 is terminated at each end in a knot or other retention means such as a staple so that the segments 72 are permanently retained on the rope or string 74 . Hook and line attachment loops, weights, for example weighted tape, and diving bills may be attached to one or more of the segments 72 . Jacket 32 is applied over segmented crankbait 70 in the manner described above in conjunction with FIGS. 4 A- 4 C. Movement of segmented crankbait 70 when trolled or reeled toward the rod is enhanced if jacket 32 has a tail portion 36 or 50 such as is shown in FIG. 2A or FIG. 3.
[0061] In yet another embodiment, the material completely surrounds each segment 72 such that segmented crankbait 70 is fully and permanently embedded in the material. In this embodiment, segmented crankbait 70 provides the structural support for mounting the hooks and for attaching to crankbait to the fishing line while the material presents a realistic “feel” to the fish. In one preferred method, segmented crankbait 70 is dipped into a vat of liquid synthetic material heated to approximately 350° (176.5° C.) until the material substantially fills in the area between segments and a desired thickness of the material is obtained over the circumference of segmented crankbait 70 . In this preferred embodiment, the coated segmented crankbait will have a substantially cylindrical shape with the hooks and line attachment loops projecting therefrom.
[0062] Alternatively, segmented crankbait 70 may be positioned in the mold in place of the core so that realistic fins, tails and/or scales may be added to the crankbait. Preferably, a removable skewer is inserted through a second hole 80 A in each segment to ensure proper positioning in the mold. After the material is injected into the mold, segmented crankbait 70 is removed from the mold and the skewer is extracted. The skewer comprises a thin metal rod of sufficient length such that, when inserted through segmented crankbait 70 and placed in the mold, it is supported at its end portions by the mold. Also, since the external geometry of the segmented crankbait 70 is defined by the mold, segments 72 may have substantially uniform dimensions and may also be any desired shape, such as, by way of example, a rectangular cube, elongated rod, circular disk or combinations thereof. Further, the number of segments may be limited to a head segment 76 and a tail segment 78 .
[0063] Referring now to FIG. 8, another preferred embodiment of the present invention is illustrated. Specifically, lure 80 comprises a plug or skull cap 82 which is placed into a mold and embedded in a substantially solid fish-shaped body. Skull cap 82 may have a fishing line attachment loop 22 and diving bill 20 directly attached thereto. A thin wire cable or rope 84 , which terminates in a hook attachment loop 86 that protrudes near the tail portion 36 of the lure 80 , is threaded to skull cap and eye loop 90 . A second hook attachment loop 88 protrudes below the belly of the lure body proximate to skull cap 82 . Loop 88 is attached to rope 84 and maintained in place by eye loop 90 . Skull cap 82 is embedded in the flesh-like material such that a layer of material covers the skull cap 82 as indicated at 92 .
[0064] As with the other preferred embodiments, discussed above, realistic tail portion 36 , including a caudal fin, decorative tail 50 , dorsal fin 56 , anal fin 94 , pelvic fin 96 and/or pectoral fins (not shown) may be molded into the body of lure 80 . The protruding fins and tail portion are made as thin as possible (that is, preferably less than 31.75 mm) so as to present a life-like appearance as the crankbait is alternately moved through or suspended in the water. Specifically, when lure 80 is allowed to float in the water, the protruding fins will flutter outward giving the appearance of a suspending fish but will fold backwards as lure 80 is retrieved.
[0065] While certain exemplary preferred embodiments have been described and shown in the accompanying drawings, it is to be understood that such embodiments are merely illustrative of and not restrictive on the broad invention. Further, it is to be understood that this invention shall not be limited to the specific construction and arrangements shown and described since various modifications or changes may occur to those of ordinary skill in the art without departing from the spirit and scope of the invention as claimed. It is intended that the scope of the invention be limited not by this detailed description but by the claims appended hereto.
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The present invention discloses a combination fishing lure comprising a common crankbait and jacket. The removable jacket is a highly elastic covering molded into a seamless, elongated shell that is stretchable over the crankbait. The thickness of the jacket provides a natural flesh-like texture to wood, hard plastic or metal crankbaits while protecting the crankbait from scratches caused by fish strikes or by collision with other objects.
The jacket has a cavity with at least a first opening providing access to the cavity. The crankbait is removably positioned in the cavity of the jacket by stretching the jacket in the region surrounding the opening until it is large enough to insert the crankbait. The jacket may include a rearwardly projecting tail portion that changes the appearance of the crankbait by increasing the overall length of the crankbait and that moderates the erratic wobble of the crankbait creating a realistic undulating swimming action.
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BACKGROUND OF THE INVENTION
The invention is generally directed to a paper feeding apparatus for use in a printer and in particular to a cut sheet feeder which can select an appropriate cut sheet from various types of mounted cut sheets, and feed the appropriate sheet into the printer.
Paper feeding apparatuses are well known in the art and cut sheet feeders are applicable for use with various printers used as typewriters or as word processors. The cut sheet feeders remove the need for an individual to separately align each sheet of paper in the printer or typewriter. Instead, a cartridge tray or other type of paper holding device can be filled with many sheets which are fed singly to the printer at appropriate times. In particular, a single cut sheet feeder has compartments for different sizes of paper further speeding the paper feeding process.
Conventional cut sheet feeders are driven in two different ways. The first type of cut sheet feeder incorporates an electrical selecting element such as a motor or a solenoid. The feeder is directly electrically connected to a printer so that the printer has direct control over the motor or solenoid. The second type of conventional cut sheet feeder provides power to the cut sheet feeder by use of a paper feeding mechanism usually coupled to the printer's platen. The cut sheet feeder is driven by a combination of clockwise and counterclockwise rotation of the paper feeding motor. In both cases, a one-way clutch or a ratchet device is used to prevent the paper feeding assembly from drawing back the sheet already wound into the paper feeding mechanism of the printer.
One-way clutches and ratchets are expensive mechanical elements and result in an increase in the cost of a cut sheet feeder utilizing these elements. The requirement that a cut sheet feeder be powered electrically by the printer increases the complexity of the cut sheet feeder unit and limits its application to printers specifically adapted to control such a cut sheet feeder.
Accordingly, there is a need for a cut sheet feeder which enables selection and feeding of single sheets from a variety of compartments or trays in the cut sheet feeder, powered by a mechanical linkage with the paper feeding mechanism of the printer, and without the need for expensive components such as a one-way clutch or a ratchet.
SUMMARY OF THE INVENTION
The invention is generally directed to a paper feeding apparatus for a printer. There are at least two mounting units each of which is adapted to hold a plurality of sheets of paper. A paper feeding roller is associated with each of the mounting units and contacts the paper in the mounting unit for feeding a single sheet of paper. A paper feed gear is operatively coupled to the paper feed roller for co-rotation with the paper feed roller. A sun gear is proximate each of the paper feed gears. A transmission mechanism transmits rotational power in first and second directions, the second direction being opposite to the first direction, from a paper feed motor in the printer to each of the sun gears. Each of a series of selector levers, one of which is associated with each of the paper feed rollers, has a planet gear at one end and a protrusion at the other end. The selector lever is rotatable about a fulcrum point which is also the center of rotation of the corresponding sun gear. Each planet gear engages with the corresponding sun gear. A selective camming member is associated with each of the paper feed mechanisms. The selective camming member in operative association with the protrusion controls the rotation of the corresponding selector lever to cause the selective engagement of the corresponding planet and sun gears when the paper feed motor rotates in a proper combination of the first and second directions. As a result, a single sheet of paper is fed to the printer from a selected mounting member determined by the sequence of rotation in the first and second directions by the paper feed motor.
Accordingly, it is an object of the invention to provide an improved paper feeding apparatus for feeding single sheets of paper.
Another object of the invention is to provide an improved cut sheet feeder which can select a cut sheet of paper out of a variety of types of paper as necessary and feed the paper to the printer.
A further object of the invention is to provide a cut sheet feeder which is mechanically powered by the printer.
Still another object of the invention is to provide a cut sheet feeder which is mechanically powered by the printer and obviates the need for expensive one-way clutches and ratchet mechanisms.
Yet another object of the invention is to provide a cut sheet feeder mechanically powered by the printer paper feed mechanism which can select appropriate sheets of paper from various compartments based on software control by the printer.
Yet a further object of the invention is to provide an improved cut sheet feeder in which power is provided through the paper feeding mechanism of the printer and sheets from various sheet mounting devices can be selected by use of selector devices composed of planet gears, cams and levers in mesh with cams.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specification.
The invention accordingly comprise the features of construction, combination of elements, and arrangement of parts which will be exemplified in the construction hereinafter set forth, and the scope of the invention will be indicated in the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
For a fuller understanding of the invention, reference is had to the following description taken in connection with the accompanying drawings, in which:
FIG. 1 is a perspective view of a paper feeding apparatus constructed in accordance with a preferred embodiment of the invention;
FIG. 2A is a top plan view of the gear train of the power transmission in the paper feeding apparatus constructed in accordance with the invention;
FIG. 2B is a side elevational view of the gear train of FIG. 2A;
FIG. 3A is a side elevational view partially cut away, showing the operation of a portion of the power transmission of the paper feeding apparatus constructed in accordance with the invention in various positions;
FIG. 3B is a side elevational view of the portion of the power transmission shown in FIG. 3A;
FIGS. 4A-E are side elevational views of the selection mechanism sequentially showing the manner of selecting the front paper feeding tray; and
FIGS. 5A-C are side elevational views of the selection mechanism shown in FIGS. 4A-4E showing the sequential selection of the back paper feeding tray for paper feeding.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Reference is made to FIGS. 1, 2A and 2B wherein a print feed apparatus generally indicated as 100 constructed in accordance with a preferred embodiment of the invention is depicted. Print feed apparatus 100 includes left and right side frames 101 and 102, respectively. Side frames 101 and 102 have various openings to receive shafts supported between frames 101 and 102. Side frames 101 and 102 are shaped so as to rest on top of a printer proximate to the platen 1 of the printer. Platen 1 is supported on a platen shaft 3 which also supports a platen gear 2 which co-rotates with shaft 3 and platen 1. Platen 1 is rotated by a paper feeding motor 4 which transmits clockwise and counterclockwise rotation as viewed in FIG. 1 to platen gear 2 through an intermediate gear 5. By clockwise and counterclockwise rotation of paper feeding motor 4, platen 1 can be rotated either forward or backward (clockwise or counterclockwise). In normal use of the printer, paper is advanced by forward (clockwise in FIG. 1), rotation of the platen which advances paper around the platen and between platen 1 and paper advancing rollers 6 on a spring supported shaft 7 in a conventional manner.
Paper feeding apparatus 100 includes a transmission gear pulley 103 rotatably coupled to side frame 101. Transmission gear pulley 103 has an outer gear 103a and an inner pulley 103b. When paper feeding apparatus 100 is placed in its operating position on top of the printer, transmission gear 103a engages with platen gear 2. In this way, any rotation of platen gear 2 is transmitted to transmission gear pulley 103. The motor power transmitted from platen gear 2 to transmission gear pulley 103 is then transmitted to a gear pulley 105, having a gear 105a and a pulley 105b, by a timing belt 104 wound around pulley 103b and pulley 105b. This transmitted power is then further conveyed from gear pulley 105 to a second gear pulley 113 via a timing belt 112 wound around pulleys 105b and 113b. In this way, both gear pulley 105 and gear pulley 113 are driven by platen gear 2 through gear pulley 103 and timing belts 104 and 112.
Paper feeding apparatus 100 also includes two separate paper tray assemblics generally indicated as 130 and 140, respectively. Paper feeding assembly 130 includes a paper feeding roller shaft 131 with paper feeding rollers 132. Paper feeding roller shaft 131 extends from side wall 102 through side frame 101 terminating in a paper feeding roller gear 107. It also includes a shaft 133 extending from side wall 102 to side wall 101, extending through side wall 101 and terminating in a reset shaft 114. Two paper tray elements or guide elements 134, 135 are slidably supported on shafts 131 and 133. Elements 134 and 135 can be adjusted by sliding to an appropriate width for the paper and a plurality of sheets can be placed on elements 134 and 135. The paper feeding rollers 132 rest against the top sheet. The paper is maintained in contact with rollers 132 by a biasing member such as a spring 136. This allows for varying amounts of paper to be reliably held.
Paper holding member 140 likewise includes a shaft 141 with paper feeding rollers 142. Shaft 141 extends from side member 102 through side member 101 terminating in a paper feeding roller gear 147. Paper feeding member 140 also includes a second shaft 143 extending from side member 102 through side member 101 and terminating in a reset shaft 148. There are two paper tray elements 144, 145. Paper tray elements 144 and 145 are slidably mounted on shafts 141 and 143 to adjust the distance between them for varying widths of paper. A biasing member such as a spring 136' is utilized to maintain pressure by the top sheet of paper against paper feeding rollers 142.
Paper feeding roller gears 107 and 147 are close to pulley or sun gears 105a and 113a but do not engage or mesh with them.
As best seen in FIG. 2B, a selector planet lever 110 is rotatably coupled to side wall 101 having a flucrum point of rotation at the center of sun gear 105. Selector planet lever 110 has a first arm 110a and a second arm 110b separated by an acute angle. A planet gear 106 is rotatably mounted at the end of arm 110b. Planet gear 106 is located so as to engage or mesh with sun gear 105a. As a result, rotation of gear 105a, due to movement of platen gear 2, causes the relative rotation of selector planet lever 110 about its fulcrum point. Arm 110a of selector planet lever 110 has a selector lever 111 attached proximate the end of arm 110a. Selector lever 111 is attached to selector planet lever 110 so that it rotates, and when no rotation is imparted to sun gear 105, selector lever 111 maintains a constant angle with selector planet lever 110. This is achieved by means of a selector lever spring 117 (FIGS. 2A and 3B).
Selector lever 111 has a protrusion 111a at the end opposite the rotatable connection with arm 110a. Side wall 101 has fixed to it a camming member 116. Camming member 116 has separate camming surfaces 116a and 116b. In various orientations of selector lever 111, protrusion 111a contacts and is directed by camming surfaces 116a and 116b as described below.
A second selector planet lever 110 with arms 110a and 110b is rotatably mounted with a fulcrum point at the center of sun gear 113, with a similar selector lever 111 coupled to the end of arm 110a. Likewise, a planet gear 146 is rotatably coupled to the end of arm 110b and meshes with sun gear 113. As a result, rotation of sun gear 113, due to rotation of platen gear 2, causes relative rotation of selector planet lever 110 about sun gear 113. A camming member 115 is coupled to the outside of side member 101 below sun gear 113. Camming member 115 has camming surfaces 115a and 115b designed to interrupt and direct the movement of selector lever 111 through contact with protrusion 111a.
Reference is next made to FIG. 2B. Platen gear 2 of the printer provides motive power through platen transmission gear pulley 103 to pulley or sun gear 105 by a timing belt 104 and the transmission power is further conveyed from gear 105 to a pulley or sun gear 113 by a timing belt 112 as described above. When planet gear 106, attached to arm 110b of selector planet lever 110, is rotated counterclockwise, it meshes with paper feeding roller shaft gear 107 as shown in FIG. 2B, and the transmitted power is conveyed to paper feeding rollers 132 via shaft 131. This has the effect of causing the top sheet of paper in paper compartment 130 to be advanced downward toward platen 1.
This movement is further enabled by a shaft 170 extending from side panel 102 through side panel 101 and terminating in a gear 172 which engages with transmission gear 103. Shaft 170 has intermediate rollers 171 which rotate with shaft 170. As a result, the movement of the paper is assisted by rollers 171 which are rotated by the power generated from gear 103.
The protrusions 111a on selector levers 111 are shaped so as to engage with selector cam members 115 and 116. Only when selector levers 111 pass by selector cams 115 or 116 in the proper way, as a result of a combination of clockwise and counterclockwise rotation of paper feeding motor 4 of the printer, do planet gears 106 and 146 engage with paper feeding roller shaft gears 7 and 147, respectively. The selector cams 115 and 116 have differently shaped camming surfaces 115a and 115b, and 116a, and 116b, respectively, so that different combinations of clockwise and counterclockwise rotation of paper feeding motor 4 as (as viewed in FIG. 1) are required to allow the selector levers 111 to reach an engaging position. Accordingly, selection of one of the paper feeding rollers 132, 142 is possible by appropriate control of clockwise and counterclockwise rotation of paper feeding motor 4.
Reference is next made to FIG. 3A wherein the manner in which protrusion 111a and camming surfaces 115a and 115a interact is depicted. Selector planet lever 110 is shown in FIG. 3A with arm 110b having planet gear 146 removed for clarity of explanation. When platen 1 rotates in a counterclockwise direction (FIG. 1), selector planet lever 110 is rotated in a clockwise direction (FIGS. 1 and 3A), until it touches reset shaft 148 and then stops (shown in solid lines as position A). Since pulleys 105b and 113b are connected by timing belt 112, counterclockwise rotation of platen 1 by more than a predetermined amount places selector planet lever 110 in position A.
Position A is a known reset position in which all selector planet levers 110 and selector levers 111 are in the position shown in FIG. 3A. Reset shaft 148 (or reset shaft 114) prevent further clockwise rotation of 110. Then, when platen 1 rotates in a clockwise direction, protrusion 111a is forced along the bottom surface of camming surface 115a, as is shown in FIG. 3a as position B in dotted lines. To engage planet gear 146 and paper feeding roller gear 147, pivot arm must be rotated in the clockwise direction to the position shown as C. Then, platen 1 must be rotated counterclockwise by the appropriate amount so that selector lever 11 moves from position C to position D. At position D protrusion 111a disengages from camming member 115b, causing selector lever 111 to return to its neutral angled position with respect to arm 110a. Finally, when platen 1 is again rotated clockwise by the appropriate amount, selector lever 111 moves from position D to position E. Selector planet gear 146 engages with paper feeding roller gear 147 (as shown in FIG. 1) in position E, and the top sheet in tray element 140 is separated by separating pawls 120 and fed out of paper feeding apparatus 100.
When the leading edge of the sheet fed out of the paper feeding apparatus contacts the region between platen 1 and paper advancing roller 6 adjacent to platen 1, the leading edge of the sheet deflects during the continuing clockwise rotation of platen 1. When the proper deflection has been achieved, platen 1 is reversed and turned counterclockwise so that the sheet is wound around platen 1 between paper advancing roller 6. This feeds the paper into the printing mechanism in preparation for printing by a printing head (not shown) or other print mechanism.
Thus, after the paper is advanced against platen 1 and platen 1 is then rotated counterclockwise to draw the paper in, selector planet levers 110 rotate clockwise so that selector planet gears 106 and 146 disengage from paper feeding roller gears 107 or 147 (depending upon which paper tray has been selected), and paper feeding roller 132 or 142 can freely rotate as the paper is pulled down between platen 1 and paper advancing roller 19. By allowing the free rotation of rollers 132 and 142 when the printer is printing, the feeder ceases to affect the paper's movement. Finally, selector planet levers 110 return to the reset position shwon as position A in FIG. 3A. As a result, by repetition of this process a continuous stream of single sheets from a plurality of trays can be fed into the printer.
It is critical that only one of the paper feeding rollers (132 or 142) is enabled at a time to assure that only a single sheet of paper is transmitted to the printer. Thus, reference is made to FIG. 3A to show the movement of selector lever 111 when engagement of planet lever 146 and paper feeding roller gear 147 is not desired.
When selector lever 111 is located in position C, if platen 1 is rotated forward in a clockwise position, rather than reversing the rotation of the platen to a counterclockwise direction, selector lever 111 continues on to position F where protrusion 111a is locked within camming surface 115b. In position F selector planet gear 146 does not engage with paper feeding roller gear 147. During this time, the other selector lever 111 can be in a position comparable to position E causing engagement of planet gear 106 and paper feeding roller gear 107 to allow rotation of paper feeding shaft 131 and rollers 132.
Reference is next made to FIGS. 4A-4E wherein the manner in which paper feeding apparatus 100 selects and feeds a sheet of paper from paper tray assembly 130 (front cut sheet feeder).
In response to rotational power generated by motor 4, platen gear 2 drives gear pulley 105 through timing belt 104 and gear pulley 105 in turn rotates gear pulley 113 through timing belt 112. Motor 4 rotates gear pulleys 105, 113 clockwise until selector planet levers 110 have rotated counterclockwise until they are stopped by engagement with reset shafts 114 and 148 as shown in FIG. 4A. As noted above, this is a reset position from which paper tray selection can be initiated based on the known starting point.
To select the front cut sheet feeder assembly 130, gear pulleys 105 and 113 are rotated clockwise (as shown by the arrows in FIG. 4B) which causes selector planet levers 110 to rotate counterclockwise. FIG. 4B shows selector levers 111 rotated counterclockwise to a position B , with protrusions 111a in contact with the left side of camming surfaces 115a and 116a of selector cams 115 and 116, respectively.
Next, as shown in FIG. 4C, gear pulleys 105 and 113 continue to rotate counterclockwise, as shown by the arrows in gear pulleys 105 and 113, to positions C . In position C , protrusion 116a of the selector mechanism for the front cut sheet feeder 130 has slid into contact with camming surface 116b of selector cam 116. On the other hand, protrusion 111a for the back cut sheet feeder 140 slides entirely into camming surface 115b.
Next, when the rotational direction of gear pulleys 105, 113 are reversed to a clockwise direction selector levers 110 move to position D (FIG. 4D). In position D the protrusion 111a for cut sheet feeder 140 is still prevented from moving by camming surface 115b. However, protrusion 111a for the front cut sheet feeder 130 is free of camming surfaces 116a, 116b and freely moves upward to position E under the power of selector lever spring 117. In each of positions A - E of both protrusions 111a there is no engagement of gears 107 and 106 or gears 147 and 146.
Finally, gear pulleys 105 and 113 are again rotated in a counterclockwise direction. Projection 111a of the rear cut sheet feeder 140 again locks within camming surface 115b, maintaining gears 146 and 147 out of engagement so that no power is transmitted to shaft 141. On the other hand, projection 111a of the front cut sheet feeder 130 advances to a position G which causes the engagement of selector planet gear 106 and paper feeding roller gear 107 so that a sheet of paper on the front cut sheet feeder 130 is advanced to platen 1 by paper feeding rollers 132.
In this way paper is fed out of cut sheet feeder 130 while assuring that no paper is fed out of cut sheet feeder 140.
Reference is next made to FIGS. 5A, 5B and 5C wherein the manner in which paper feeding apparatus 100 selects and feeds a sheet of paper from paper tray assembly 140 (back cut sheet feeder).
The starting position for feeding a sheet of paper from the back cut sheet feeder 140 is the same as for feeding a sheet of paper from the front cut sheet feeder 130. This position is shown in FIG. 4A.
Selector levers 111 are rotated in the same way as described above with respect to FIGS. 4A-4E in a clockwise manner so that projections 111a above the front and back cut sheet feeders 130, 140 move to position J and H , respectively. Selector level 111 rotates from position H to position I as a result of protrusion 111a being free of camming surface 115a. The rotation is caused by selector lever spring 117 and terminates when protrusion 111a contact camming surface 115b.
As shown in FIG. 5B, gear pulleys 105 and 113 are rotated in a clockwise manner to move selector levels 111 and protrusions 111a from positions I and J to positions K and M , respectively. Selector lever 111a of the back cut sheet feeder 140 rotates from position K to position L due to the force exerted by selector lever spring 117 as a result of protrusion 111a being out of engagment with both of camming surfaces 115a and 115b. Selector planet gears 146, 106 and paper feeding rollers 147 are not engaged. Accordingly, no paper is fed from the cut sheet feeder up to this point.
As gear pulleys 105 and 113 are again rotated in a counterclockwise direction as shown in FIG. 5C, projection 111a rotates freely in a counterclockwise manner to position P causing selector planet gear 146 to mesh with paper feeding roller 147. As a result, the back cut sheet feeder 140 is driven causing paper feeding roller 132 to advance a single sheet of paper to platen 1. Selector level 111 and projection 111a associated with the front cut sheet feeder 130 moves from position N to position O under the force of selector lever spring 117. As a result, selector planet gear 106 and paper feeding roller 107 are maintained out of engagement so that no paper is fed from the front cut sheet feeder when the back cut sheet feeder 140 is selected.
In this way it is possible to select one of plurality of paper feeding shafts and to rotate the shafts in accordance with the shapes of the appropriate camming members. By combining appropriate counterclockwise and clockwise rotation of the platen, which corresponds to counterclockwise and clockwise rotation of the printer's paper feeding motor, selection of paper from various trays is allowed. This control can be implemented by software for driving the printer.
The paper feeding apparatus is shown as two separate tray areas for holding paper. By extension of the principles shown, a paper feeding apparatus with three or more separate trays for feeding paper can be utilized. It is only necessary for different camming members with differently shaped camming surfaces to provide the ability to select one of a number of different paper feeding trays controlled solely by the clockwise and counterclockwise rotation of the platen. In this way, the paper can be selected by a software driven approach which controls the movement of the platen.
Other mechanical structures are available in accordance with the invention including the use of a gear instead of a timing belt for power transmission.
Accordingly, a paper feeding apparatus in which a cut sheet is selected from among a plurality of paper trays by use of selector cams, selector levers and planet gears is provided. In accordance with the above structure it is possible to provide a paper feeding apparatus having a plurality of paper trays which are separately addressable by software for driving the printer motor. Furthermore, this paper feeding apparatus produces these benefits at low cost without the need for high priced parts such as a one-way clutch.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made in the above construction without departing from the spirit and 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.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
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A paper feeding apparatus for a printer. There are at least two mounting members, each of which is adapted to contain sheets of paper. A paper feeding assembly is associated with each of the mounting members and contacts the paper in the mounting member for feeding single sheets of paper. A paper feed gear is operatively coupled to each of the paper feeding assemblies for co-rotation therewith. A sun gear is present proximate each of the paper feeding gears and each is rotatable about a center point. A transmission mechanism transmits rotational power in first and second directions from a paper feed motor in the printer to each of the sun gears. The first and second directions are opposite to one another. A selector member is associated with each of the paper feed assemblies and has a planet gear on a first arm and a protrusion on a second arm. The selector member is rotatable about the center point of the corresponding sun gear. The planet gear engages with the corresponding sun gear. A selective camming assembly is associated with each of the paper feeding assemblies for controlling the rotation of the corresponding selector member by interaction with the protrusion on the corresponding selector member. This causes the selective engagement of the corresponding planet gear and paper feed gear so that rotational power from the paper feed motor is transmitted to the paper feeding assembly when the paper feed motor rotates in the proper combination of the first and second directions. As a result, a single sheet of paper is fed to the printer from a selected mounting member which is determined by the sequence of rotations of the paper feed motor in the first and second directions.
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FIELD OF THE INVENTION
The present invention relates to packaging films for encapsulating hot melt adhesives. The packaging films are readily miscible with the hot melt adhesive during the adhesive melting stage without deleteriously affecting the adhesive properties, making the packaging film particularly well suited for packaging hot melt adhesives in a pillow, cylinder, pouch, block, cartridge and the like.
BACKGROUND OF THE INVENTION
Hot melt adhesives are solid at room temperature while generally being applied in the molten or liquid state. Typically, these adhesives are provided in the form of blocks and because of their tacky nature, the solid adhesive blocks not only stick to each other or adhere to mechanical handling devices, but also pick up dirt and other contaminants during transport. Additionally, certain applications that require high tack formulations result in blocks that will deform or cold flow unless supported during shipment.
Various methods of packaging hot melt adhesives have been developed to address the above concerns. In one method, non-tacky powders are applied onto the hot melt adhesives, and the contents are bagged in packaging films. In some applications, the packaging films must be removed before melting the hot melt adhesives. In other methods, and as taught in U.S. Pat. No. 5,373,682 and U.S. Pat. No. 7,350,644, the packaging film is a part of the hot melt adhesive, and the packaging film is dissolved with the adhesive during the melting stage. While these films may not deleteriously affect the adhesive properties, for they are in minor quantities (typically less than 5 wt % of the total weight), the films may not readily blend into the molten hot melt adhesives during the heating and application stage. The immiscible portion of the packaging film separates from the hot melt adhesive as a distinct and separate layer by floating on the surface of the melt and/or adhering to the walls of the melt tank, and over time, can cause mechanical problems for the adhesive melt tanks. Because there are numerous types of hot melt adhesives based on various chemistries, the packaging films must be selected to ensure good miscibility with the chosen hot melt adhesive.
There continues to be a need in the art for hot melt adhesive packaging films that allows for wider applicability of hot melt adhesives. The current invention fulfills this need.
BRIEF SUMMARY OF THE INVENTION
The invention provides integral packaging films for various hot melt adhesives. Removal of the integral packaging film is not necessary because the integral packaging film is readily miscible with the hot melt adhesive during the adhesive melting stage without negatively affecting the adhesive properties.
Applicants have discovered that a specific combination of packaging film's chemistry, melt viscosity, melt strength, peak melt temperature, offset melt temperature, and storage modulus are critical in forming a chemically compatible, miscible, film in the integral hot melt adhesive package that is suitable for various hot melt adhesive chemistries.
In one embodiment, the integral packaging film comprises a polymer blend, comprising at least 70 wt % of propylene content; and the packaging film has (a) a viscosity range of about 200,000 to 3,000,000 cps at 200° C.; (b) a melting peak temperature range of about 90 to 140° C. (c) a Tm offset temperature below 149° C.; and (d) a storage modulus (G′) at 100° C. of about 1×10 6 to 1×10 8 Pascal.
Another embodiment is directed to an article that is a hot melt adhesive encapsulated by an integral packaging film. The integral packaging film is completely miscible in the hot melt adhesive without any agitation at 149° C. or higher when the packaging film is present up to 2% of the total weight of the article. The hot melt adhesive comprises poly-alpha-olefins, rubbers, styrenic block-copolymers, ethylene-vinyl acetates, ethylene-butyl acetates, and/or mixtures thereof. The integral packaging film comprises a polymer blend, comprising at least 70 wt % of propylene content; and the packaging film has (a) a viscosity range of about 200,000 to 3,000,000 cps at 200° C.; (b) a melting peak temperature range of about 90 to 140° C. (c) a Tm offset temperature below 149° C.; and (d) a storage modulus (G′) at 100° C. of about 1×10 6 to 1×10 8 Pascal.
Yet another embodiment is directed to the method of packaging a hot melt adhesive with the packaging film to form an integral hot melt adhesive package. The process comprises the step of: (1) preparing the integral packaging film as an encapsulating vessel; (2) pumping or pouring the hot melt adhesive in a molten state into the integral packaging film, and the integral packaging film is in direct contact with a heat sink; (3) sealing the integral packaging film; and (4) cooling the sealed package. The integral packaging film comprises a polymer blend comprising (a) from about 70 to about 99 wt % of propylene content and (b) from about 1 to about 30 wt % of butene and/or ethylene content. The integral hot melt adhesive package is a sealed, non-tacky package that resists dirt and other contaminant during transport.
DETAILED DESCRIPTION OF THE INVENTION
The term “ olefin hot melt adhesive” is used herein generically to refer to all polyolefin based hot melt adhesives, including but not limiting to hot melt adhesives made from amorphous olefin, polyethylene, polypropylene, polybutene and their copolymers.
The terms “wrapped,” “encapsulated” and “packaged” are used interchangeable herein and mean that blocks of hot melt adhesives are encased within a layer of film. The film is a tackless or non-blocking layer and further serves to protect the adhesive from contamination, serves to allow easy shipping and handling.
The term “integral package film” is used herein as package film that surrounds blocks of hot melt adhesive and can be processed (melted and applied onto substrates) without the removal of the film during the heating and application of the adhesive. Similar to packaged films, the integral package film is also non-blocking and protects the adhesives from contaminations.
The integral packaging film comprises a polymer blend. The polymer blend comprises at least two thermoplastic polymers, and the blend has a propylene content of at least about 70 wt %, and up to about 99 wt %, based on the total weight of the polymer blend. Examples of propylene rich copolymers are LMPP 400 and LMPP 600 from Idemitsu Kosan Co., Ltd; Linxar 127, Vistamaxx 6202, Vistamaxx 6102, Vistamaxx 3980, Vistamaxx 3020, Vistamaxx 3000 from ExxonMobile Corp; and the like.
In one embodiment, the other thermoplastic polymer(s) is a butene and/or ethylene comonomers. The other thermoplastic polymers may account from about 1 wt % to about 30 wt %, based on the total weight of the polymer blend. Ethylenes may be accountable up to 15 wt %, preferably below 10 wt %, based on the total weight of the polymer blend. Suitable commercial butene rich polymers include Vestoplast 308, Vestoplast 408, Vestoplast 508, Vestoplast 520, Vestoplast 608, Vestoplast 703 from Evonik Industries, and the like. Suitable commercial ethylene rich polymers include Affinity GA1950 from Dow Chemicals, and the like.
At least one thermoplastic polymer is a metallocene catalyzed polymer. Suitable polymers include metallocene catalyzed polyethylenes, ethylene-butene and ethylene-octane elastomers, plastomers, propylene-butene, propylene-ethylene copolymers.
The films may, if desired, contain antioxidants for enhanced stability as well as other optional components including slip agents such as erucamide, anti-blocking agents such as diatomaceous earth, fatty amides or other processing aids, anti-stats, stabilizers, plasticizers, dyes, perfumes, fillers such as talc or calcium carbonate and the like.
The polymer blends may be blended by any means known in the art. In one embodiment, the polymer blend is processed in a twin screw extruder for mixing and melting. The melted blend is then cast to a film by any means known in the art. The thickness of the film will generally vary from about 0.5 mil to about 5 mil, preferably from about 1 mil to about 3 mil. The thickness of the particular film also varies depending upon the composition and application temperature. The film may be a monolayer or multi-layered film.
It has been discovered that the packaging film must have a specific combination of properties in order to form an integral hot melt adhesive package that is chemically compatible with various hot melt adhesive chemistries while maintaining integrity as a packaging film for the hot melt adhesives. Such packaging film requires (a) a viscosity range of about 200,000 to 3,000,000 cps at 200° C.; (b) a peak melting temperature (Tm) range of about 90 to 140° C. (c) a melting temperature (Tm) offset temperature below 149° C.; and (d) a storage modulus (G′) range of about 1×10 6 to about 1×10 8 Pascal at 100° C.
The peak melting points and offset can be determined by various methods known in the art. The reported peak melting points and Tm offset values reported herein were determined with a DSC (differential scanning calorimetry). Unless otherwise stated, about 5 mg of the film sample was sealed in a crimped alumina pan, cooled the sample to −40° C., and reheated it to 180° C. at a rate of 10° C./min with 2920 DSC TA Instruments. The endothermic melting peak on the second heat up cycle was used to evaluate the peak melting point and heat of fusion, and the end of melting peak was the Tm offset temperature.
The packaging film must encompass all of the above properties in order to form a packaging film, maintain integrity of the film while encapsulating a molten adhesive, result in a non-tacky barrier seal for the molten adhesive and dissolve completely in with the hot melt adhesive upon melting without any agitation. The packaging film is non-blocking at elevated temperatures, temperatures that simulate box car conditions (35-45° C.). The packaging film melts at temperatures above about 149° C. without any agitation or additional energy within 5 hours. The packaging film is meltable together with various and multiple hot melt adhesives and is blendable into the molten hot melt adhesives without deleteriously affecting the properties of the adhesive.
Another embodiment is directed to an article comprising a hot melt adhesive encased with a packing film. The article is an integral hot melt adhesive package formed as a pillow, cylinder, pouch, block, cartridge or chub.
The hot melt adhesive of the integral hot melt adhesive package comprises various thermoplastic polymers. The hot melt adhesives are mainly composed of polymers that include poly-alpha-olefins, rubbers, styrenic block-copolymers, ethylene-vinyl acetates, ethylene-butyl acetates, and/or mixtures thereof. The hot melt adhesives may optionally comprise tackifiers, plasticizer, oils, waxes, and additives.
In one embodiment, the packaging film comprise up to about 2% by weight of the integral hot melt adhesive package, and preferably from about 0.1 to about 1.5%, in order to prevent undue dilution of the adhesive properties. Typically, each packing film has a thickness range of from about 0.5 mil to about 5 mil, preferably from about 1 mil to about 3 mil.
The packaging film of the integral hot melt adhesive package is miscible in various hot melt adhesives without any portions of the film separating from the molten hot melt adhesive by floating on the surface of the hot melt or adhering to the walls of the melt tank.
Typically to form a miscible, chemically compatible and non-separating adhesive, the packaging film is chosen based on the predominant polymer used in the hot melt adhesive. Failure to pick a compatible hot melt adhesive and packaging film results in portions of the films floating on the surface of the hot melt or adhering to the walls of the melt tank. It has been discovered that the instant packaging film is miscible with multiple hot melt adhesive chemistries, e.g., polyolefins, rubbers, ethylene-vinyl acetate copolymers, polyamides, polyesters, polyurethanes, and the like, while forming a non-tacky outer protection.
To package a hot melt adhesive with the packaging film, the hot melt adhesive is melted and pumped or poured into a cylindrical thermoplastic film, where the cylindrical tube being in direct contact with a heat sink, e.g., cooled water or a cooled liquid or gaseous environment. Wrapping and sealing the film can occur either manually or, more preferably, by an automated procedure. The hot melt adhesive being poured or pumped is at a temperature at or above the melting point of the packaging film and the interior of the packaging film becomes melted together with the molten hot melt adhesive and blended into the molten adhesive without deleteriously affecting the properties of the adhesive. The molten hot melt adhesive filled cylinder is sealed and allowed to solidify. Optionally, air is removed with a vacuum during the sealing process, and as a result no gap exists between the film and the hot melt adhesive. The resultant individually integral hot melt adhesive packages can be stored, handled and used without the individual packages sticking together, adhering to other objects, or becoming contaminated even if exposed to increased pressure and/or temperature.
To ultimately utilize the integral hot melt adhesive packages as an adhesive, the package is placed to the melt tank, without removing the film. The strong interface or interphase, between the hot melt adhesive and integral packaging film, requires very little additional energy to melt and blend the film into the adhesive itself.
EXAMPLES
Example 1
Samples 1-7 were formed as packaging film. The propylene (PP) and butane/ethylene comonomer contents are listed in Table 1. Viscosity was measured at 200° C. with a rheometer with near-zero shear. The films were formed by melting the polymer components through a twin-screw extruder, and then casting it on a cold roll at a thickness of 1.5 mil. The miscibility of the film was evaluated by melting approximately 10,000 grams of an amorphous poly alpha-olefin adhesive (DISPOMELT® LITE 300 from Henkel Corporation) in a melt tank with about 0.5 wt % (based on the adhesive) of the film sample at 160° C. The length of time that it took for the film sample to melt into the adhesive, without any agitation, was recorded. For Sample 8, EVA film with 3% VA content blow film was also employed for this study.
TABLE 1
Polymer blend.
Butene/
Ethylene
Viscosity
MFR (ref.)
Film
Propylen
Comonomer
(cps at
g/10 min @
Film
Film
Sample
(%)
(%)
200° C.)
230° C.
Feasibility
Miscibility
1
36.4
63.4
45,000
N/A
Difficult
N/A
2
73.2
26.8
1,000,000
N/A
good
≦3 h
3
91.5
8.5
3,000,000
8.3
good
≦3 h
4
97
3
1,800,000
12
good
≦3 h
5
97
3
680,000
30
good
≦3 h
6
97
3
810,000
N/A
good
≦3 h
7
Non-metallocene-(PP)
2,200,000
12
good
>5 h
based polymer (~97%
PP and 3% comonomer)
8
EVA with 3% VA
5,000,000
2.3
good
>24 h
N/A—not available
Film sample 1, with a low melt viscosity, less than 200,000 at 200° C., could not be converted to a film. All other samples, Film Samples 2-8, were cast as films.
Film samples 2-6 were melted into DISPOMELT® LITE 300, and became a homogeneous mass in less than three hours. Film sample 7 also became homogenous mass, but the non-metallocene based polypropylene copolymer film took greater than five hours to become miscible with the amorphous poly-alpha-olefin type hot melt adhesive. EVA film, Film Sample 8, took more than 24 hours to melt into the adhesive. Moreover, the EVA film gelled and formed hard clusters, and some of the hard clusters floated on the hot melt tank surfaces. Such hard clusters are undesirable for they tend to block the spray or slot nozzles.
Example 2
The melting temperature and melt modulus of the sample films were characterized to assess their melt strength, and the results are shown in Table 2. Melting points were determined with a 2920 DSC (differential scanning calorimetry) TA Instruments. About 5-10 mg of a sample was sealed in a crimped alumina pan, cooled to −40° C., and reheated it to 180° C. at a rate of 10° C./min with 2920 DSC TA Instruments. The second heat up cycle was used to evaluate the peak melting point and Tm offset values.
The storage modulus (G′) of the film at 100° C. was measured by a Rheometric Dynamic Analyzer (RDA III) and TA Orchestrator software version 7.2.0.2. The adhesive sample is loaded into parallel plates 7.9 mm in diameter and separated by a gap of about 2 mm. The sample was then cooled to about −30° C., and the time program was started. The program test increased the temperature at 5° C. intervals followed by a soak time at each temperature of 10 seconds. The convection oven containing the sample was flushed continuously with nitrogen. The frequency is maintained at 10 rad/s. The initial strain at the start of the test was 0.05% (at the outer edge of the plates). An autostrain option in the software was used to maintain an accurately measurable torque throughout the test. The option was configured such that the maximum applied strain allowed by the software was 30%. The autostrain program adjusted the strain at each temperature increment. The shear storage or elastic modulus (G′) was calculated by the software from the torque and strain data.
The film strength of the film sample was evaluated by encapsulating a molten DISPOMELT® LITE Lite 300 with the film samples to form a package. The quality and the strength of the package after cooling were visually evaluated. If the film sample maintained the integrity and formed an encasement of the hot melt adhesive, the film was given a rating of “strong.” If any holes or the hot melt adhesive destroyed the integrity of the film sample, then a rating of “weak” was given to the film.
TABLE 2
Melt strength of films and their application in hot melt capsulation
Melt Strength
Film
Tm Peak
G′ at 100° C.
Film
Sample
(° C.)
(Pascal)
strength
1
104
1.0 × 10 4
Weak
2
82
4.5 × 10 4
Weak
3
80
7.0 × 10 4
Weak
8
106
2.0 × 10 6
Strong
4
123
6.0 × 10 6
Strong
5
138
1.5 × 10 7
Strong
6
123
8.0 × 10 6
Strong
7
147
2.5 × 10 8
Strong
8
106
2 × 10 6
Strong
Samples 1-3 burst during the filling process, resulting in unacceptable packages. Sample 4-8 was strong enough to form acceptable packages without any bursts in the sample film. It was discovered that peak Tm ranges of about 90 to 140° C. and a storage modulus of about 1×10 6 to about 1×10 8 Pascal at 100° C. allowed the films to withstand the filling process and result in acceptable quality of packages.
Example 3
Samples 4-8 were tested for their sprayability. About 10,000 g sample of DISPOMELT LITE® Lite 300 adhesive was encapsulated with a sample film having a thickness of about 1.5 mil. The package was loaded into a hot melt tank set for 160° C. for three hours for samples 4-6 (ten hours for sample 7, and 24 hours for sample 8). The molten adhesive was then sprayed through a four-port ITW spray head (Nordson) and the number of stray globs/minute was recorded in Table 3. The Tm offset of each of the sample film are also recorded in Table 3.
TABLE 3
Film/adhesive package's meltdown and sprayability
Film
Stray Sprayability
Tm offset
Sample
(with DISPOMELT ® LITE 300)
(° C.)
4
2 globs/min
134
5
2 globs/min
144
6
2 globs/min
144
7
>10 globs/min
158
8
>400 globs/min
115
Sample 7 had greater than 10 stray globs/minute. In contrast, samples 4-6 had only two stray globs/minute. Unlike sample 7, samples 4-6 have Tm offset values lower than 149° C. It was discovered that packaging films having Tm offset value below149° C. is an important factor to minimize strays in sprayability. While Sample 8 also has a Tm Offset value less than 149° C., immiscibility of the EVA film with the encapsulated adhesive is a limitation resulting in increased strays.
Example 4
Hot melt adhesive packages with various hot melt adhesives (1,000 g) and packaging film (0.5 wt % based on the hot melt adhesive) were formed and are listed in Table 4. Each package was loaded into a hot melt tank and heated at the listed temperature without any agitation. The miscibility of the film in the hot melt adhesives was visually observed. Also, the length of time required to fully dissolve the film sample and become miscible in the adhesive was noted.
TABLE 4
Film Miscibility with Various Hot Melt Adhesive
Hot Melt Adhesive (polymer
Testing
Miscibility
type)
Film
Temperature
Observation
DISPOMELT ® ® LITE 300
Film
160° C.
Completely
from Henkel Corporation
sample 5
Miscible in less
(Amorphous poly-alpha
than 3 hours
olefin adhesive)
DISPOMELT 901B from
Film
160° C.
Completely
Henkel Corporation
sample 5
Miscible in less
(Styrenic block copolymer
than 3 hours
based adhesive
As observed above, the packaging film(1) made with a polypropylene copolymer that comprises at least 70 wt % propylene content; (2) has a viscosity range of about 200,000 to 3,000,000 cps at 200° C.; (3) has a melting peak temperature range of about 90 to 140° C., (4) has an Tm offset temperature below 149° C;(5) has a storage modulus (G′) at 100° C. of about 1×10 6 to 1×10 8 Pascal, is miscible with various and multiple hot melt adhesives formed from various polymers, and may be used as a universal packaging adhesive for integral hot melt adhesive packages.
|
Propylene polymer based packaging films for encapsulating hot melt adhesives are disclosed. The packaging films are readily miscible with the various hot melt adhesive chemistries during the melting stage without deleteriously affecting the adhesive properties, making the packaging film particularly well suited for packaging hot melt adhesives in a pillow, cylinder, pouch, block, cartridge and like forms.
| 2 |
BACKGROUND OF THE INVENTION
Corn harvester headers employing stalk rolls used in separating the ears from corn stalks have been employed in a number of different types of harvester headers heretofore. Representative of such previous devices are the machines described and claimed in the following patents.
______________________________________3,101,579 Karlsson et al Aug. 27, 19633,126,688 Karlsson March 31, 19643,499,272 Looker March 10, 19703,648,443 Sears March 14, 1972______________________________________
As will be seen from the foregoing patents, the rolls employed in the header constructions each include a plurality of blades or flutes which either extend radially from the axis of the rolls or somewhat tangentially therefrom, whereby it is only the outer edges of said blades or flutes which engage opposing sides of the corn stalks which move through slots or passages that extend longitudinally within the header, in the direction of movement thereof while harvesting the crops. In said devices, it is common practice for purposes of increasing the movement of the stalks incident to having the ears snapped or forcibly pulled therefrom to add cut-off blades adjacent the rear ends of the rolls to insure a final separation or pinching action of the ears from the stalks. Such an arrangement in said prior devices also result in substantial stalk breakage and thereby minimizes the efficiency of the machines. Further, it is preferred practice in the operation of corn harvesters of this type to leave the stalks in somewhat standing condition in the fields after stripping the ears therefrom, whereby additional machines may harvest the stalks and chop or cut them into condition for being used as silage and stored in a silo or otherwise handled for desired purposes.
SUMMARY OF THE INVENTION
It is the principal purpose of the present invention to provide an improved form of flute, a plurality of which are preferably detachably connected to the roll members in a row crop corn harvester header, such header, for example, being of the type shown and described in prior U.S. Pat. No. 3,765,157, in the name of Hyman et al., dated Oct. 16, 1973. However, the improved flutes may be utilized in other harvester headers to improved advantage.
It is another object of the invention to form said improved flutes with longitudinally extending rib projecting from one surface of each flute, substantially intermediately between the opposite side edge portions thereof, and said rolls having a geometric configuration in cross section, preferably square, to provide longitudinally extending faces at right angles to each other to which one edge portion of each flute is connected in a manner to dispose the opposite edge portions substantially tangential to the axis of the rolls and the ribs on said flutes extending outward, whereby when a pair of said rolls are rotated respectively in opposite directions to engage a corn stalk, the outermost edges of the outer edge portion of a flute on one roll will be indexed to co-act relative to the outer surface of the rib on a flute on the opposite roll and the space between said co-acting portions of the respective flutes will be substantially less than the diameter of a corn stalk so as to move the stalk downward relative to a stripping slot in the header with a more effective gripping action but subjecting the stalk to less breakage and damage than has resulted in using conventional type flutes on stalk rolls.
It is a further object of the invention to employ transverse dimensions in said aforementioned rolls and flutes so as to dispose the outermost edges of the outer edge portions of successive flutes on a stalk roll substantially within a plane within which the outer surface of the rib of one of said flutes is disposed, whereby when said pair of successive flutes on one roll co-act with the outermost edge of the outer edge portion of a flute on the opposite roll, the stalk will be engaged at threee locations by the flutes on the first mentioned roll incident to being firmly engaged between the rib on said roll and the outermost edge of one of the flutes on the opposite roll, thereby effecting even greater positive engagement of the stalk by the flutes of said rolls than if said arrangement of the flutes on said rolls were not as indicated.
Still another object of the invention is to attach one of the edge portions of the improved flutes flatly against the faces of the roll and secure the same thereto by bolts extending through a longitudinally spaced series of holes in both the one edge portion of said flutes and the roll, said bolts preferably extending entirely through the roll and being received in aligned holes in an opposing pair of flutes, thereby minimizing attaching means.
Ancillary to the foregoing object, it is still another object to form the holes in said one edge portion of each flute in the form of a longitudinally spaced pairs of holes, each pair of holes being spaced longitudinally a shorter distance than the space between successive pairs thereof, whereby corresponding holes of two of said flutes which are respectively disposed on opposite surfaces of the roll may have bolts extended through said holes to connect said opposing pair of flutes to the roll, while the other hole of each pair is employed in a second pair of said flutes to be connected to the transversely disposed pair of flat surfaces on the roll and receive bolts therethrough to fimly attach the second pair of flutes to the roll and, to permit such connection, said rolls are provided with longitudinally spaced pairs of holes complementary to the spacing of the holes in said flutes but, in the rolls, the holes of each pair thereof respectively are at a right angle to each other.
Details of the foregoing objects and of the invention, as well as other objects thereof, are set forth in the following specification and illustrated in the accompanying drawings comprising a part thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an exemplary row crop corn harvester header of the type to which the present invention pertains.
FIG. 2 is a fragmentary vertical section of a portion of the header shown in FIG. 1 as seen along the line 2--2 thereof.
FIG. 3 is a fragmentary bottom plan view taken from the underside of a portion of the header illustrated in FIG. 2, as seen on the line 3--3 thereof.
FIG. 4 is a fragmentary top plan view of a section of the header shown in the preceding figure in which the shield shown therein has been illustrated in phantom for purposes of simplifying the illustration in which a pair of stalk rolls and propelling endless chain means are shown in operative relationship and portions of a similar arrangement are fragmentarily illustrated in the upper part of the figure.
FIG. 5 is a substantially enlarged, fragmentary transverse sectional view showing details of the improved stalk rolls and flutes illustrated in operative relationship relative to a corn stalk, as seen along the line 5--5 of FIG. 4.
FIG. 6 is a plan view of an improved flute for a stalk roll which embodies the principles of the present invention.
DETAILED DESCRIPTION
Referring to FIG. 1, the header 10 is comprised of a base frame member 12 and opposing side members 14 respectively are connected to opposite ends of the base frame 12 in conventional manner. Base frame member 12 also has an opening 16 through which crop material, such as ears of corn, or otherwise, is passed for delivery to appropriate elevating means or otherwise which move the separated material to apparatus for further processing. An auger 18 extends between the side members 14 and, on opposite ends portions thereof, has reversely spiralling flights 20 thereon, the auger 18 being rotated in a direction to effect consolidation of the crop material for passage through the opening 16.
The header 10 also is provided with a plurality of sectional type shields 22 which are similar to each other and enclose mechanism described in detail hereinafter by which corn stalks are positively moved along longitudinal passages 24 between the side edges of adjacent shields 22. Further, the side members 14 terminate forwardly in partial shields 26, the inner edges of which define one side of additional longitudinal passages 24 in conjunction with the next adjacent shields 22. For additional details of said shield construction, attention is directed to prior U.S. Pat. No. 3,765,157 referred to above in view of the fact that said shields per se comprise no novel part of the present invention.
Referring to FIG. 2, it will be seen that the header 10 is provided with a series of similar rearwardly extending plates 28 having openings through which a drive shaft 30 extends. Also, at opposite sides thereof, the header is provided with a supporting channel member 32, best shown in FIG. 2, which engages a transverse member 34, shown in phantom, which is connected to one of a pair of forwardly extending arms on the forage or corn harvester to which the header 10 is to be connected. Said arms are not illustrated but are of conventional type in the harvesters referred to. The forward end of each of the mechanical units disposed in the shields 22 and 26 are provided with guide shoes 36 which are slidably engagable with the surface of a field containing the crops to be harvested. The forward shield portion 38 of each of the shield units 22 and 26 is pivotally connected at its rearward end to a yoke 40 attached to the guide shoes 36, as best shown in FIGS. 2 and 4, whereby the nose portions at the forward ends of the forward shield portions 38 are yieldable in accordance with the surface of the field over which they move.
As the harvester header 10 is moved along a field, such as one in which rows of stalk crops such as corn are growing and harvesting the same is to be undertaken, the shield members 22 are adjusting transversely in accordance with the details, not shown, but illustrated and described in said aforementioned U.S. Pat. No. 3,765,157, in order to arrange the elongated passages 24 in suitable position to correspond to the spacing of the rows of the corn crop or otherwise. Hence, as the header moves along the rows of corn stalks, for example, said stalks individually are received in sequence in the passages 24. To insure that the stalks will move along said passages, there is an endless flexible member comprising a sprocket chain 42 on each side of the passages 24, said chains being supported by sprocket gears 44 respectively supported upon axes perpendicular to the chains 42 relative to certain extensions of the frame 12 of the header. The chains 42 are so mounted that a span of each of the chains which is nearest the passage 24 is parallel thereto and said chains each support a series of stalk-engaging lugs 46, the lugs on said chains being arranged so that lugs on the opposite chains respectively are adjacent each other to engage the stalks and push them along the passages 24 and also push them through a narrow slot 48, which is best shown in FIG. 5, and is defined by the inner edges of a pair of straight members 50 which, specifically, comprise plates supported immediately below the chains 42.
Also mounted above the plane of straight members 50 are inwardly extending flanges 51, the inner edges of which are parallel to each other and to the edges of members 50 which define slot 48 and are spaced apart a distance less than the thickness of stalks 52 and 54 so as to effect an initial separation of the ears 54 from stalks 52. If such separation does not occur, however, the slot 48 positively insures such separation.
As also best shown in FIG. 5, it will be seen that the corn stalk 52 has an ear 54 extending therefrom and is in process of being pulled down to the slot 48. The width of the slot 48 is substantially equal to or only slightly wider than the diameter of the stalk 52, whereby the ear 54 cannot pass through the slot 54 due to the greater diameter of the ear than the stalk, said ear being only fragmentarily shown.
The drive mechanism for the chains 42 is best shown in FIGS. 2 and 3, details of which are as follows. It will be understood that the drive shaft 30 is driven by a suitable power connection directly to the prime mover, not shown, of the corn harvester or other type of forage harvester to which the header 10 may be connected. Said shaft 30 is shown fragmentarily in FIG. 3 and the same has a sprocket gear 56 connected thereto and, through a sprocket chain 58, the sprocket gear 58 drives another larger diameter sprocket gear 60 which, through a slip-clutch unit 62, drives a shaft 64 which is within a housing 66, shown in FIG. 2, that is adjacent the inner ends of the several units within the shields 22. The end of shaft 64 opposite the slip clutch 62 is fixed to a large spur gear 68 and this meshes with and drives a driven spur gear 70 of smaller diameter than gear 68, the gear 70 being connected to one end of a stub shaft 72, the outer end of which is fixed to a bevel gear 74 which meshes with another bevel gear 76 that is fixed to one end of a shaft 78 upon which one of the stalk rolls 80 is mounted and to which it is fixed for rotation thereby. The shaft 78 also has a spur gear 82 connected thereto which meshes with another spur gear 84 that is connected to a second shaft 86 upon which a second stalk roll 88 is mounted and to which it is fixed for rotation thereby.
There is also fixedly connected to shaft 64 a pair of similar spur gears 90 and 92 which mesh with spur gears 94 and 96 of similar diameter to spur gears 90 and 92 respectively, the spur gears 94 and 96 being fixed to short shafts 98 and 100 to which the sprocket gears 44 are connected, as shown in FIG. 4. Due to the arrangement of the spur gears 90 and 92 upon the shaft 64, it will be seen that the same mesh respectively with spur gears 94 and 96 in a manner to drive the adjacent parallel spans of the sprocket chains 42 in the same direction which is inward from the outer ends of the longitudinal passages 24, toward the inner ends therein, said passages being intersected by a transverse edge 102 formed on the inner ends of the straight members 50 which define the inner ends of the longitudinal passages 24.
From the foregoing, it will be seen that the endless flexible members 42 which comprise sprocket chains are driven by the same power means that rotate the shafts 78 and 86 and, correspondingly, the stalk rolls 80 and 88, the latter being rotated in opposite rotary direction as indicated by the directional arrows 104 in FIG. 5 for purposes of pulling the stalk 52 downward in the direction of the directional arrow 106 shown in FIG. 5 in a manner to strip or pop off the ear 54 from the stalk 52 as the butt end of the ear 54 reaches the narrow slot 49.
The principal feature of the present invention comprises details of the flutes 108, the cross sectional shape of which is best shown in FIG. 5 and the same also being shown in plan view in FIG. 6. The function and operation of the improved flutes 108 is best illustrated in FIG. 5, the description of which is as follows. The improved flutes 108 preferably are formed from sheet metal and by suitable stamping or rolling operation, the same are provided with a substantially central rounded rib 110 which, in addition to providing stiffening for the flutes 108 also, even more importantly, provide a gripping function for the stalks 52, described in detail hereinafter.
The ribs 110 also are provided with opposite outer edge portions 112 and 114. The portions 112 are provided with a series of pairs of holes 116 which are for purposes to be described. The opposite outer edge portion 114 of each of the flutes 108 has a gripping outer edge 118 which also is for purposes to be described, as follows.
Referring to FIG. 5, it will be seen in regard to stalk roll 80, which is at the right hand side of FIG. 5, at the left side thereof as illustrated in said figure, the gripping outer edges 118 of two successive flutes 108 are substantially within the same plane as the outer crest of the central rounded rib 110 of one of said flutes. This is of significant advantage with respect to gripping the stalk 52 particularly in one indexed relationship of the flutes 108 on the opposite stalk rolls 80 and 88 which respectively are carried by the mechanism within the shields 22 respectively on opposite sides of the longitudinal passages 24, said relationship being illustrated in FIG. 5. In said figure, it will be seen that the gripping outer edge 118 of the stalk roll 88 is in gripping opposition to the outer crest of the central rounded rib 110 of the flute 108 which is connected to the stalk roll 80. The distance between said crest of the rib 110 and the outer edge 118 of said flute 108 is less than the diameter of the stalk 82, whereby the stalk will be somewhat pinched between the opposing surfaces referred to above to a sufficient extent to effectively grip the stalk and pull the same downwardly in the direction of the arrow 106 and thereby cause the ear 54 to be forceably separated from the stalk 52 when the butt end of the ear 54 reaches the narrow slot 48. Also, as further illustrated in FIG. 5, the particular incidence of the coaction of the two stalk rolls and the flutes thereon as illustrated in said figure, additional gripping of the stalk 52 is effected by virtue of the gripping outer edges 118 engaging the left hand side of the stalk 52 in addition to the pinching action effected by the outer surface of rib 110 of the stalk roll 80 and the outer edge 118 of the particular flute 108 of stalk roll 88 which engages the opposite side of stalk 52. This results in further gripping of the stalk 52 and the overall gripping described immediately above will recur cyclically each time one of the outer edges 118 of the left hand stalk roll 88 is brought into incidence with the outer surface of the rounded rib 110 of a flute 108 on the right hand stalk roll 80 and the same also occurs between rib 110 of the left hand stalk roll and the outer edges 118 of the right hand stalk roll.
It has been found from actual operation that the gripping imparted to the stalk 52 by the rib 110 and gripping outer edge 118 of each of the improved flutes 108 of the present invention provides far more effective gripping of the stalks 108 of corn and the like for purposes of pulling the same downwardly as the lugs 46 on the flexible endless members 42 move the stalk longitudinally within the passages 24 and the narrow slots 48 than is capable of being performed by the relative straight and flat radial and tangential flutes of the current corn and forage harvesters and especially such as illustrated in the aforementioned U.S. patents to Karlsson et al., Karlsson, Looker and Sears. This is due to the fact that the forceable removal of the ears 54 from the stalks 52 by the above-described mechanism and function thereof is sufficiently reliable that it is generally unnecessary for the ears to engage the transverse edges 102 which are disposed at the inner ends of the passages 24, whereas in the previous and currently employed ear separating mechanism associated with stalk rolls of the existing corn harvesters and the like, it is substantially essential that transverse cut-off members be employed to insure complete separation of the ears from the stalks handled by said mechanism. A further improvement and benefit afforded by the present invention however comprises the fact that at least in general, the stalks are subjected to wedging and bending to only a limited degree and this results in reducing the amount of stalk breakage such as occurs in using current and previous stalk rolls in corn harvesters and the like.
A further aspect of the present invention comprises the relatively simple but highly effective mechanism by which the flutes 108 are attached to the central or basic member 120 of the stalk rolls 80 and 88. As clearly shown in FIG. 5, it will be seen that the preferred configuration of the same in cross section, is square, thus providing four relatively flat faces which extend longitudinally along said roll for purposes of having the outer edge portions 112 firmly connected respectively to said surfaces by a series of bolts 122 which extend through one of each of the pairs of holes 116 formed in the outer edge portions 112 of each of the flutes 108. Also, the central member 120 of the rolls 80 and 88 is provided with a longitudinally spaced series of pairs of holes which are spaced correspondingly to the holes 116 along the outer edge portion 112 of the flutes 108. However, in regard to the holes in the central member 120 of each of said rolls, the holes of each pair thereof respectively are disposed at right angles to each other as can be clearly seen from FIG. 5. Accordingly, when the bolts 122 extend through one of the holes 116 of each pair thereof, one opposing pair of the flutes 108 are firmly connected to the central member 120 of each of the rolls, whereas when a bolt 122 is extended through the other hole 116 of each pair thereof, a second pair of the flutes 108 are connected firmly to the central member 120 of each of the rolls, thus minimizing the amount of bolts necessary to connect the flutes to the central members 120 of the rolls 80 and 88.
From the foregoing, it will be seen that the present invention provides an improved means for gripping the stalks 52 to separate ears 54 therefrom in a manner which results in less stalk damage or breakage and, further, improved positive movement of the stalks is accomplished to minimize the necessity of relying upon the transverse edges 102 at the inner ends of passages 24 to effect removal of ears from the stalks.
While the invention has been described and illustrated in its several preferred embodiments, it should be understood that the invention is not to be limited to the precise details herein illustrated and described since the same may be carried out in other ways falling within the scope of the invention as illustrated and described.
|
A corn harvester header attachable to a forage harvester and provided with a plurality of shield units spaced apart to form passage ways to receive corn stalks and including endless flexible means respectively on each side of said passage to positively feed corn stalks along said passage relative to a narrow slot formed by opposed stripping members which accommodate the stalks but prevent the ears from passing therethrough, and a pair of stalk rolls extending longitudinally below said slot at opposite sides thereof and rotated in opposite directions in a manner to pull said stalk, downward through said slot and thereby strip the ears from said stalk. The present invention concerns the shape of elongated flutes which are attached to the stalk rolls for improved engagement of the stalks thereby.
| 0 |
TECHNICAL FIELD
[0001] The present invention relates to a supporter for protecting or mending the neck, a wrist, an ankle, the lumbar region, a joint, and the like of a human body by being placed thereon. Specific examples include the following items.
[0002] (1) A supporter for a neck guard that is a part of a strap that is to be used by being worn on the neck in order to support a musical instrument, a camera, binoculars, and the like, and that is to be used for distributing load on the neck
[0003] (2) A supporter for a wrist guard for preventing injuries that may be caused due to a wrist being bent backwards abnormally in various types of sports or from a sudden action.
[0004] (3) A supporter for an ankle guard for preventing injuries that may be caused due to an ankle being bent abnormally in various types of sports or from a sudden action.
[0005] (4) A supporter for a joint protector that has a warping preventing lip, suppresses a large movement of a joint that is excessive, and assists the improvement of competitive ability in various types of sports.
[0006] (5) A supporter for a lumbar region belt that is to be used for prevention and treatment of lumbar pain.
BACKGROUND ART
[0007] Various types of supporters such as a medical splint and an elastic cloth for covering have been known. The medical splint is used for immobilizing an affected area, and thus usually it is assumed that the medical splint doesn't move. With the elastic cloth for covering, it is not possible to prevent a specific area of a human body from bending abnormally in various types of sports or from a sudden action.
[0008] In reality, there are cases in which complete immobilization is not desired, but easy displacement is not favorable. There is a demand for a supporter that is moderately immobilized and has a degree of freedom to some extent
[0009] For example, because a musical instrument such as a saxophone or a guitar is quite heavy, in order to lessen a burden, the musical instrument is connected to a strap and the strap is worn on the neck of a player when playing the musical instrument. However, if the player plays the musical instrument for a long period of time, a string-like strap is likely to dig into the neck and cause a pain in the neck Accordingly, wearing such a strap often results in problems such as difficulties in breathing while the player is playing the musical instrument
[0010] In order to improve this, inventions and ideas in which the strap is provided with a neck guard and lies on the neck in a planar manner instead of a linear manner are known. Examples thereof include Japanese Patent No. 4296228 (Patent Document 1), JP 2008-268737A (Patent Document 2), and the like.
[0011] It is important for this type of neck guard to distribute the load evenly so pressure is acceptable. In order to achieve this, a neck guard whose flexibility is too small or too large is not acceptable. If the flexibility is significantly small, the contact area with the neck is reduced, and thus the load is likely to be linear, whereas if the flexibility is significantly large, the neck guard is excessively bent, and thus the load is not distributed even if the contact area with the neck increases.
[0012] In other words, there is a demand for a supporter that can be moderately immobilized and has a degree of freedom to some extent
[0013] There is a similar demand for a wrist supporter, ankle supporter, lumbar region supporter, and joint supporter.
CITATION LIST
Patent Document
[0000]
Patent Document 1: Japanese Patent No. 4296228
Patent Document 2: JP 2008-268737A
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0016] The present invention has been made in view of issues of the above-described conventional techniques, and an object of the present invention is to provide a supporter that has a function of providing appropriate flexibility and of suppressing excessive bending.
Means for Solving the Problem
[0017] The present invention is a supporter for a human body, and the supporter includes a base, a plurality of grooves that are provided in a width direction of the base, fillers that can be respectively inserted into the grooves, and disconnection preventing lips for the fillers.
[0018] Preferably, the fillers each have a small protrusion that extends downward, the base has a through hole or a depression in each of the grooves, and the small protrusion and the through hole can be fitted to each other and freely move to such an extent that they do not separate from each other.
[0019] Preferably, the disconnection preventing lips are extending portions that each extend from two sides of an upper end of a groove toward the groove.
[0020] Preferably, the fillers each have a shape complementary to the grooves and can be inserted therein in a sliding manner in the lateral direction.
[0021] The supporter of the present invention can be used as a neck supporter, a wrist supporter, an ankle supporter, a lumbar region supporter, and a joint supporter.
Effects of the Invention
[0022] According to the present invention, this supporter has gaps between the base and the fillers when in a natural state and thus can be bent. However, if the supporter is excessively bent, the gaps are closed, and if the supporter is excessively bent beyond a fixed range, the supporter is completely inhibited from bending, and thus an appropriate pressure is applied.
[0023] With a preferable embodiment, a small protrusion and a through hole are not closely fixed to each other using an adhesive or the like, and freely move to some extent while maintaining a fitted state without being separated from each other. A base portion and the fillers are not fixed, and thereby it is possible to get an advantage in that the maximum flexibility during bending (the supporter bends in a natural curve) is achieved. Also, because the supporter is not bent in a predetermined curvature or greater, excessive bending can be suppressed.
[0024] Hereinafter, examples of the present invention will be described with reference to accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a perspective view of a supporter according to an example of the present invention in a non-assembled state.
[0026] FIG. 2 is a perspective view of the supporter of FIG. 1 in an assembled state.
[0027] FIG. 3( a ) is a cross-sectional view of the supporter of FIG. 1 in a normal state, and FIG. 3( b ) is a cross-sectional view thereof when load is applied thereto.
[0028] FIGS. 4( a ) and 4 ( b ) are respective enlarged views of circles (a) and (b) shown in FIG. 3 .
[0029] FIG. 5 is a perspective view of a strap having a supporter for a neck guard, which is a first use example of the present invention.
[0030] FIG. 6 is (a) a top view, (b) a bottom view, (c) a cross-sectional view, and (d) a side view of the neck guard of FIG. 5 .
[0031] FIG. 7 is (a) a rear view and (b) a top view of a lumbar region belt having a lumbar region supporter, which is a second use example of the present invention.
[0032] FIG. 8 is a perspective view of a glove having a wrist supporter, which is a third use example of the present invention.
DESCRIPTION OF EMBODIMENTS
[0033] As shown in FIGS. 1 to 4 , a supporter 4 includes a base 41 that is a synthetic resin plate having an elongated ellipse shape (18.5 cm×4 cm) and that has a plurality of grooves 42 (five in this example) on the surface, and strip-like fillers 43 that can be respectively inserted into the grooves 42 . The supporter 4 can be formed by injection molding using a synthetic resin such as nylon that is firm and has elasticity.
[0034] Each groove 42 has a width of approximately 1 cm and the bottom of the groove 42 is formed flat. A disconnection preventing lip 44 is provided so that the inserted filler 43 doesn't disconnect from the groove. The disconnection preventing lip 44 can be an extending portion that extends from two sides of the upper end of the groove 42 toward the groove by approximately 2 mm.
[0035] One through hole 45 is provided at the center in the longitudinal direction and the width direction of each groove.
[0036] The filler 43 has a cross-sectional shape complementary to the groove 42 . In other words, the filler 43 has two layers, namely a base portion 46 corresponding to the groove width of the supporter 4 , and a narrow-width portion 47 due to the disconnection preventing lip. Therefore, if the filler is inserted in a sliding manner into the groove in the direction of arrows shown in FIG. 1 , it closely fits into the groove as shown in FIG. 2 , and the height of the top surface thereof is the same as the supporter.
[0037] The base portion 46 has a small protrusion 49 that has a height of approximately 0.5 to 1 mm and extends downward, and the small protrusion 49 is fitted into the through hole 45 of the groove 42 . The small protrusion 49 and the through hole 45 are not closely fixed using an adhesive or the like, and freely move to some extent while maintaining a fitted state without being separated from each other.
[0038] The base portion 46 and the fillers 43 are not fixed, and thereby it is possible to get an advantage in that the maximum flexibility during bending (the supporter bends in a natural curve) is achieved.
[0039] The supporter 4 is substantially in a linear state in the normal state, as shown in FIG. 3( a ). At this time, as clearly shown in the enlarged view of FIG. 4( a ), gaps 48 are formed between the base 41 and the filler 43 . Because five fillers are used in this example, there are ten gaps 48 (five gaps×two (two sides)). However, if a weight is applied to the supporter 4 , it bends as shown in FIG. 3( b ).
[0040] At this time, as clearly shown in the enlarged view of FIG. 4( b ), the gaps 48 are closed. As a result, because the supporter is not bent in a predetermined curvature or greater, excessive bending can be suppressed.
[0041] This supporter can be used for various purposes as described above.
Use Example 1
[0042] FIG. 5 shows a use example as a strap to which a supporter for a neck guard is attached. A saxophone 1 is worn on the neck of a musician (not shown) via a strap 2 . A neck guard 3 is provided in an area of the strap 2 that is placed on the neck
[0043] As shown in FIG. 6 , the strap 2 passes through and is attached to the neck guard 3 , and thus the neck guard 3 is movable along the strap 2 .
[0044] This neck guard 3 includes right and left end portions 31 and a central portion 32 that constitutes a major area of the neck guard. The central portion 32 includes, from the upper side (outer side of the neck guard, from the wearer's perspective), a surface member 33 , a first cushion layer 34 , the strap 2 , the supporter 4 , a second cushion layer 35 , and a surface member 36 . It is preferable that the surface member 33 is made of a durable material such as a natural leather, an artificial leather, and the like in terms of the durability and appearance. It is preferable that the first and second cushion layers 34 and 35 are made of a soft foamed resin such as polyurethane, polyvinyl chloride, and the like. It should be noted that the feature of the present invention is the above-described supporter 4 , and the number of cushion layers and the material are arbitrarily determined.
[0045] The main purpose of the right and left end portions 31 is for providing an opening 37 for the strap 2 , and for fixing the position of the supporter 4 at the central portion 32 . The configuration thereof is the same as that of the central portion 32 , except that the supporter 4 is not included. Spaces between the right and left end portions 31 and the central portion 32 are closed using a string 38 , and the position of the supporter 4 is fixed.
[0046] If the strap for a neck guard in which the supporter of the present invention is utilized is used, the strap is unlikely to dig into the neck and pain is reduced even if the musician plays the saxophone for a long period of time. As a result, it has been verified that the player can breathe significantly easily while he or she is playing a musical instrument
Use Example 2
[0047] FIG. 7 shows a use example as a lumbar region belt 5 to which a supporter is attached.
[0048] This lumbar region belt 5 includes a wide-width central portion 51 that is to be wrapped around the lumbar region or the gluteal region, tip portions 52 and 53 that respectively extend from the wide-width central portion 51 toward left and right, a touch fastener (not shown) of one tip portion, and a touch fastener attachment portion of the other tip portion. Two supporters 4 are attached into the cloth of a back portion of the lumbar region belt 5 in the vertical direction.
[0049] If the lumbar region belt 5 is used, the lumbar region is stably supported while maintaining the degree of freedom to some extent
Use Example 3
[0050] FIG. 8 shows a use example as a glove 6 to which a supporter is attached. One supporter 4 is attached into the cloth on the back side of a hand of a user. If the user wears a catcher's mitt 61 and catches a ball in this state, for example, even if the pitcher throws the ball very fast, it is possible to prevent the wrist of the user from being bent abnormally.
Use Example 4
[0051] Although not shown, it is possible to protect ankles using socks to which these supporters are attached. Also, similarly, it is possible to protect a joint using a joint protector to which this supporter is attached.
DESCRIPTIONS OF REFERENCE NUMERALS
[0000]
1 Saxophone
2 Strap
3 Neck guard
31 Right and left end portions
32 Central portion
33 Surface member
34 Cushion layer
35 Cushion layer
36 Surface member
37 Opening
38 String
4 Supporter
41 Base
42 Groove
43 Filler
45 Through hole
46 Base portion
47 Narrow-width portion
48 Gap
49 Small protrusion
5 Lumbar region belt
51 Wide-width central portion
52 Tip portion
6 Glove
61 Catcher's mitt
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Provided is a supporter that has an appropriate bending property and is inhibited from excessively bending A supporter ( 4 ) includes a base ( 41 ), a plurality of grooves ( 42 ) that are provided in the width direction of the base ( 41 ), fillers ( 43 ) that can be respectively inserted into the grooves ( 42 ), and disconnection preventing lips ( 44 ) for the fillers ( 43 ). The fillers ( 43 ) each have a small protrusion ( 49 ) that extends downward, the base ( 41 ) has a through hole ( 45 ) or a depression in each of the grooves ( 42 ) , and the small protrusion ( 49 ) and the through hole ( 45 ) can be fitted to each other and freely move to such an extent that they do not separate from each other.
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TECHNICAL FIELD OF THE INVENTION
[0001] This invention relates to a suspension for vehicles. More particularly, it relates to a trailing arm suspension for a pair of axles on a trailer. This invention claims priority from U.S. provisional patent applications 61/058,503 filed Jun. 3, 2008 and 61/110,114 filed Oct. 31, 2008. The contents of that priority documents are adopted herein in their entirety.
BACKGROUND TO THE INVENTION
[0002] This invention applies to vehicle suspensions for free rolling axles (non-driving axles). More specifically this suspension may be preferably used with axles that are arranged in multiple axle clusters. These clusters can have two axle assemblies mounted laterally displaced from each other across the width of the vehicle, and one or more (typically 2, 3, or 4) lines of such axles mounted along the length of the vehicle. In most cases the vehicle is a trailer, but may also be a powered vehicle with auxiliary free rolling axles.
[0003] Similar art in the field is listed as follows.
References US Patents
[0004] U.S. Pat. No. 4,166,640—Van Denberg—Turner suspension with “Tri-Functional” pivot bushing.
U.S. Pat. No. 4,732,407—Oyama—Fuji use of variable rate bushing.
U.S. Pat. No. 5,037,126—Gottschalk—Boler (Hendrickson) trailing arm construction.
U.S. Pat. No. 5,996,981—Dilling—Boler (Hendrickson) narrow bushing.
U.S. Pat. No. 7,108,270—Smith—Cantilever axle suspension, non roll linked.
U.S. Pat. No. 6,142,496—Bartel—Cantilever axle suspension, roll linked.
U.S. Pat. No. 6,286,857—Reese, et al—Trunnion axle suspension.
U.S. Pat. No. 7,077,410—Gregg, et al—Trunnion axle suspension
[0005] In preferred applications, this type of suspension utilizes “air springs” to support the load carried by the trailer chassis frame with pneumatic pressure. The air springs also deflect to absorb bumps and uneven road surfaces. Air springs bring the advantage that their spring schedule may be adjusted, allowing for customization of clearance and reaction characteristics. Interconnecting the air springs for groups of axles with pneumatic hose or pipe allows equal pressure to be applied to groups of axles, permitting the load on each axle within the connected group to carry a relatively equal portion of the total load (axle equalization). Alternative types of resilient cushioning members may be used in place of the air springs. These could include, but are not limited to, hydraulic cylinders, hydraulic cylinders with gas charged accumulators, elastomeric cushions, steel springs, or combinations of spring types.
[0006] This invention particularly and preferably relates to multiwheel axles carried by a trailing arm suspension that permits an axle to rotate to a limited degree about the longitudinal axis of the trailing arm. This is desirable in order to maintain ground contact and equal wheel loading for the wheels on both ends of the individual axle. A trailing arm of such a suspension is also pivotally attached to the vehicle chassis frame such that the pivot joint allows the trailing arm to rotate in a vertical plane, thus allowing the wheel axle to rise and fall according to irregularities in the road surface. The springs positioned between the trailing arm and the chassis frame remote from the trailing arm pivot joint limit the degree of trailing arm rotation in the vertical plane as well as providing support to the chassis frame.
[0007] While the ability of the trailing arm to swing in a vertical plane allows the wheel axle to move upward and downward with respect to the vehicle frame, there is a need in such vehicle suspensions to provide resistance to lateral deflections of the trailing arm. Prior art suspensions have used either a heavy duty resilient compound trunnion pivot (Gregg, et al—U.S. Pat. No. 7,077,410), or a sliding guide at the rear end of the trailing arm (Reese, et al—U.S. Pat. No. 6,286,857), or a Panhard Rod to resist lateral deflection. These lateral forces may be significant as they are caused by centrifugal turning forces, the lateral component of gravitational forces when the vehicle is on banked surfaces and, most significantly, the lateral wheel skid force created when a cluster of axles distributed along the length of the vehicle frame is exposed to turning forces. During turning the forward axles in the cluster must skid toward the inside of the turn, while the rear axles skid toward the outside of the turn. These “skid steer” forces are relatively high due to the coefficient of friction of the tires (grip) and irregularities (ruts) in the road surface. Accordingly, there is a need for a trailing arm to resist excessive lateral deflections of such arm, out of alignment with the vehicle longitudinal axis, without necessarily incurring the relative complexity of a resilient trunnion pivot or the increased suspension construction and maintenance costs usually associated with sliding guide and Panhard Rod based designs.
[0008] There is also a need for a suspension to resist lateral roll or sway of the vehicle frame or chassis to which it is mounted. To resist such lateral roll or sway of the chassis, a relatively parallel alignment of the right and left side trailing arms should be maintained. This is the function of a typical anti-sway bar, when employed. However, in many prior art suspensions systems such supplementary anti-roll features are not provided. As a result roll stability is primarily the function of the suspension spring rate (spring stiffness) and lateral trailing arm spacing (stance), thus these suspensions tend to have low roll stability.
[0009] In this context, there is a need for an improved arrangement for limiting undesired deflections in a trailing arm, while permitting the desired degree of flexibility. This invention addresses that objective.
[0010] The invention in its general form will first be described, and then its implementation in terms of specific embodiments will be detailed with reference to the drawings following hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. The invention in its broadest and more specific forms will then be further described, and defined, in each of the individual claims which conclude this Specification.
SUMMARY OF THE INVENTION
[0011] According to one aspect of the invention a pair of trailing arms connected to the underside of a vehicle frame through respective preferably compliant pivoting couplings is provided with a connecting member which rigidly links a right side trailing arm (with its own axle and wheel set) to a laterally located and generally aligned left side trailing arm (with its axle and wheel set). This connecting member, in linking the right and left trailing arms of a trailing arm suspension, communicates a resisting force to one rotating trailing arm when the other tends to move, effectively forming a substantially unitary duplex trailing arm assembly.
[0012] According to a further aspect of the invention, a vehicle chassis suspension for free rolling axles is provided by:
[0000] a) first and second trailing arms, each pivotally mounted to a vehicle chassis through a pivot mount having a pivot axis that is aligned generally horizontally and perpendicularly to the vehicle centerline, such trailing arm being connected to the vehicle chassis at the root end of the trailing arm, the respective trailing arms each being displaced laterally from one another on a respective side of the vehicle centerline;
b) a resilient cushioning member connected between the underside of the vehicle chassis and each trailing arm for the support of the vehicle frame and the filtering of shock energy transmitted from the trailing arm to the chassis.
c) a pair of wheel axles respectively pivotally mounted to the first and second trailing arms at a point remote from the trailing arm pivot mount, the pivot axes of the axles about the trailing arms being aligned longitudinally with the length of each respective trailing arm;
d) one or more road wheels rotatably connected at each end of each axle, and
e) a connecting member attached to both the first and second trailing arms
whereby, upon rotation of a trailing arm about its trailing arm pivot axis, the connecting member communicates a resisting moment to said rotating trailing arm originating from the other trailing arm.
[0013] Preferably, the connecting member is rigidly fixed to the respective trailing arms and more preferably is formed as a unitary element with respect to the trailing arms.
[0014] According to one variant, the connecting member may connect to the respective trailing arms by being fastened laterally to the side of the trailing arms close to the pivot joint or laterally in line with the pivot axis of the trailing arm. According to another variant, the connecting member may connect to the respective two trailing arms at the forward end of the trailing arms, forwardly of the pivot joint. According to still another variant, the connecting member may connect to the respective two trailing arms towards or at the trailing end of the trailing arms. In appropriate cases the respective trailing arms and the connecting member may be formed in one piece, preferably, of bent tubing.
[0015] This connecting member performs several functions. The connecting member of the invention resists lateral deflection of the right and left trailing arms that would be caused by the lateral forces imposed on the axles by relaying these forces to couples that are opposed by the pivot bearings. Due to the connection between the connecting member and the respective trailing arms, any tendency for a single trailing arm to be displaced laterally will be resisted by the lateral stiffness of the pivot bearings of both trailing arms. This reduces the stress on the respective pivot bearings.
[0016] Such a connecting member also serves to resist any tendency for rotation of the right and left trailing arms about their respective longitudinal axes. Such a tendency may arise from the rotation of the axles about a trailing arm longitudinal axis due to an irregular road surface and from rotational resistance within the axle seat bearing members. Any tendency for such a longitudinal rotation to occur within one trailing arm is met and opposed by the pivot bearings of both trailing arms through the coupling of the connecting member. This also reduces the stress on the respective pivot bearings.
[0017] The connecting member further provides anti-roll stiffness to the vehicle chassis as the elevation of one trailing arm axle relative to the vehicle chassis will tend to create a substantially similar elevation of the laterally adjacent trailing arm axle relative to the vehicle chassis, thus maintaining the axles of each side of the vehicle in relative level alignment with the vehicle chassis, and thus restricting the tendency of the vehicle to cant sideways due to differential lateral suspension deflection.
[0018] According to the invention, the connecting member, while resilient, is of sufficient strength and stiffness to resist the bending and torsional loads imposed on it and to distribute these forces in the form of a couple that is applied to the respective suspension pivot mounts. A significant benefit of this design over previous designs arises from its inherent anti-roll properties together with its efficient resistance to lateral axle movement using fewer active components, such as pivot trunnions or sliding arm guides.
[0019] According to a preferred variant, the pivot bearing components for each trailing arm include one or more pivot shafts within pivot hangers that are attached to the vehicle frame with a rotating pivot bearing housing fixed to the end of the trailing arm. Alternate designs may, at the discretion of the designer, have the pivot bearing components reversed from the preferred embodiment. In this case the bearing housings may be attached to the vehicle chassis with rotating pivot shafts attached to the associated trailing arms. The pivot bearing may also be in the form of trunnions carried by a trailing arm that engage with seats carried on the underside of the vehicle chassis.
[0020] According to a further variant of the invention, the connecting member is connected to the trailing arm remotely from the trailing arm pivot, on the other side of the air springs or similar resilient means from the trailing arm pivot, beyond or at the point of connection of the air springs with the trailing arm. The connecting member in such case may be a continuous extension of the respective trailing arms on both sides of the vehicle chassis, or maybe an independent piece which is joined to each respective trailing arm. The air springs in such cases may either bear directly on each respective trailing arm or on a portion of the connecting member. Additionally, or as a further alternative, in place of the usual two air springs bearing on the trailing arms, a single larger capacity spring or multiple springs may be connected between the connecting member and the vehicle chassis whereby the spring forces are communicated by the connecting member to the trailing arms in equal proportion.
[0021] The foregoing summarizes the principal features of the invention and some of its optional aspects. The invention may be further understood by the description of the preferred embodiments, in conjunction with the drawings, which now follow.
[0022] Wherever ranges of values are referenced within this specification, sub-ranges therein are intended to be included within the scope of the invention unless otherwise indicated. Where characteristics are attributed to one or another variant of the invention, unless otherwise indicated, such characteristics are intended to apply to all other variants of the invention where such characteristics are appropriate or compatible with such other variants.
[0023] Wherever features are disclosed which can function concurrently, in cooperation with or synergistically with other features to provide a useful effect, such combinations may also be adopted as variations on the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The drawings which are attached depict the following:
[0025] FIG. 1 is a pictorial depiction of a duplex trailing arm suspension assembly with air springs according to the invention, with one set of wheels present on a first axle, and with wheels removed for better view on the second axle.
[0026] FIG. 2 is a plan view of the suspension of FIG. 1 .
[0027] FIG. 3 is an end view of the suspension of FIG. 1 looking along the longitudinal axis of a vehicle chassis.
[0028] FIG. 4 is a side view of the suspension of FIG. 1 taken from the side with wheels removed.
[0029] FIG. 5 is a pictorial depiction of the variant of FIG. 1 with all axles and wheels removed, showing the connecting member in bent form.
[0030] FIG. 6 is a pictorial depiction as in FIG. 1 of a variant wherein the connecting member couples to the respective trailing arms along the longitudinal axis of the respective trailing arms and is then bent transversely to provide a common pivot for both trailing arms.
[0031] FIG. 7 is a plan view of the suspension of FIG. 6 .
[0032] FIG. 8 is an end view of the suspension of FIG. 6 looking along the longitudinal axis of a vehicle chassis.
[0033] FIG. 9 is a side view of the suspension of FIG. 6 taken from the side with wheels removed.
[0034] FIG. 10 is a perspective view of two connecting members for two sets of pairs of laterally aligned, multi-wheel axles wherein the connecting members are each a continuous extension of the respective trailing arms on both sides of the vehicle chassis and the air springs bear on the trailing arm at the points of connection with the connecting member.
[0035] FIGS. 10A , 10 B, and 10 C are respectively plan, end and side views of the trailer suspension configuration of FIG. 10 .
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0036] As shown in FIGS. 1-5 a pair of trailing arms 13 , 13 A are respectively connected to the underside of a vehicle frame (not shown) at their root ends through respective, generally compliant pivot mounts 5 and pivot hangers 1 . Each pivot mount 5 has a pivot axis that is aligned generally horizontally and perpendicularly to the vehicle centerline.
[0037] These pivot mounts 5 each preferably include an elastomeric bushing which allows rotational movement of the connected trailing arm 13 , 13 A in a vertical plane about the pivot axis of the pivot mount 5 , while allowing a small degree of rotational movement about other axes perpendicular to the pivot axis. The compliance provided by these elastomeric bushings only permits small radial movements of the trailing arms 13 , 13 A relative to the pivot axis of the pivot mounts 5 within the elastic limits of the bearing material.
[0038] The respective trailing arms 13 , 13 A are each displaced laterally from one another on a respective side of the vehicle centerline with their respective pivot axes in alignment. Air springs 7 are positioned between the respective trailing arms 13 , 13 A and the vehicle chassis. The air springs 7 rest on air spring support pads 25 which form part of the trailing arm 13 , 13 A.
[0039] Each of the wheel axles 14 , 14 A is respectively mounted to the first and second trailing arms 13 , 13 A at points remote from the trailing arm pivot mounts 5 through an axle coupling 3 that allows a limited degree of rotation of the wheel axles 14 , 14 A about the longitudinal axes of the trailing arms 13 , 13 A. Optionally, the trailing arm to axle coupling 3 may comprise elastomeric material in the form of a bushing whereby limited amounts of pivotal, radial and axial movements of the trailing arms 13 , 13 A are accommodated by deflection of the elastomeric material, and in this case it is preferable that such elastomeric material present a greater resistance to lateral motion of the attached axles than to vertical teetering motions. These rotational axes are aligned with the longitudinal lengths of the respective trailing arms 13 , 13 A, and very generally, longitudinally and parallel to the centerline of the vehicle.
[0040] A connecting member 23 rigidly links a right side trailing arm 13 A (with its own axle 14 A and wheel set 27 ) to a laterally located and generally aligned left side trailing arm 13 (with its own axle 14 and wheel set—not shown). This connecting member 23 in linking the right and left trailing arms 13 , 13 A of a trailing arm suspension effectively forms a substantially unitary duplex trailing arm assembly.
[0041] The connecting member 23 acts so that, upon a tendency for rotation of one trailing arm 13 , 13 A about its pivot mount 5 and trailing arm pivoting axis, the connecting member 23 , being connected to the other trailing arm 13 , 13 A, communicates a resisting moment to such 1st rotating trailing arm 13 , 13 A, which resists its tendency to rotate. This resisting moment originates from the other trailing arm 13 , 13 A. This transferred moment reduces the tendency of the vehicle chassis and associated load to roll with respect to the wheel sets.
[0042] The connecting member 23 is rigidly fixed to the respective trailing arms 13 , 13 A at any point along the lengths of such trailing arms 13 , 13 A. The preferred connection between the connecting member 23 and the trailing arms 13 , 13 A is substantially rigid, a unitary design being desirable, followed by a welded, bolted, dowelled, clamped etc. connection. The respective trailing arms 13 , 13 A and the connecting member 23 are preferably respectively formed of bent tubing but may be made of any structurally adequate material, preferably steel.
[0043] The connecting member 23 may connect to the respective trailing arms 13 , 13 A by being fastened laterally to the side of the trailing arms 13 , 13 A close to the pivot mount 5 , and even laterally in line with the pivot axis of the pivot mount 5 provided that a sufficiently rigid connection is effected. The connecting member 23 may connect to the respective two trailing arms 13 , 13 A at the trailing end of the trailing arms 13 , 13 A, as shown in FIGS. 10-10C , being bent so as to be routed around intervening components such as an air spring 7 .
[0044] The connecting member 23 may alternately connect to the respective two trailing arms 13 , 13 A at the forward end of the trailing arms, forwardly of the pivot mount 5 . While such a connection may be affected laterally, the connecting member 23 may connect initially as a forward longitudinal extension of the trailing arms 13 , 13 A. This alternative is shown FIGS. 6-9 . In this case, the respective trailing arms 13 , 13 A and the connecting member 23 may be conveniently, respectively formed of a single, unitary bent tubing as depicted in FIGS. 6-9 .
[0045] While not depicted, a single larger capacity spring may be connected to the center of the connecting member 23 in the configuration as shown FIGS. 6-9 . This single spring may be supplemental to or may serve in place of the two separate air springs 7 . Such a central spring can be positioned to ensure that the spring forces it generates are communicated by the connecting member 23 to the trailing arms 13 , 13 A in equal proportion. As an alternative to a single central spring, multiple springs 7 may be placed in the alternate position between the connecting member 23 and the vehicle chassis.
[0046] As shown in FIGS. 6-9 the connecting member 23 may serve as part of an alternate pivot mount 5 A for supporting the respective trailing arms 13 , 13 A. In this case the pivot mounts 5 A are fitted into pivot hangers 1 that are attached to the underside of the vehicle chassis permitting the respective trailing arms 13 , 13 A to pivot about the co-aligned pivot axes of the pivot mounts 5 A.
[0047] The connecting member 23 can be straight or bent or any shape as long as it creates sufficient structural stiffness to communicate the suspension forces from one trailing arm 13 , 13 A to the other and thus from one pivot connection 5 , 5 A to the other. In particular the connecting member 23 is shown as being bent in FIGS. 1 , 3 in a form to facilitate clearance for removal of the inboard wheels on multiple axle groups where the wheels must be removed towards the front or rear of the vehicle, e.g. trailer, chassis. The connecting member 23 may also be bent or formed to extend the length of material comprising it, in order to achieve a specifically desired degree of resistance to deflection and control the characteristics of force transfer between the trailing arms 13 and 13 A.
[0048] In FIGS. 10 , 10 A, 10 B, and 10 C a first pair of aligned multiwheel axles 14 , 14 A are depicted as being carried on respective trailing arm portions 13 , 13 A joined by a first connecting member 23 . Additionally, a second connecting member 23 A (only) is depicted as following the first in the location where it would be present on a multiwheel vehicle chassis. In these figures the connecting member 23 is a continuous extension of the respective trailing arms 13 , 13 A on both sides of the vehicle chassis. As such, the connecting member portion 23 is connected to each respective trailing arm 13 , 13 A remotely from the respective trailing arm pivot mount 5 at a point at or beyond where the respective air springs 7 positioned against the vehicle chassis bear on each trailing arm 13 , 13 A. A connecting member 23 , 23 A as it traverses between the respective trailing arms 13 , 13 A may be optionally bent upwardly or otherwise to provide ground clearance, to accommodate the shape of the vehicle chassis or for the convenience of access as described earlier.
[0049] While not depicted, a single larger capacity spring may be connected to the center of the connecting member 23 in place of the two separate air springs 7 . Such a central spring can be positioned to ensure that the spring forces it generates are communicated by the connecting member 23 to the trailing arms 13 , 13 A in equal proportion. As an alternative to a single central spring, multiple springs may be placed between the connecting member 23 and the vehicle chassis.
[0050] The presence of the connecting member 23 provides anti-roll stiffness while maintaining alignment of the axles 14 , 14 A with the vehicle chassis without the need for additional pivot connections, bumpers or guides. This reduces the number of functional components. The degree of anti-roll stiffness may be adjusted through the selection of the cross-section of connecting member 23 to control its stiffness as well as selection of resilient pivot mounts 5 , 5 A for varying degrees of compliance.
CONCLUSION
[0051] The foregoing has constituted a description of specific embodiments showing how the invention may be applied and put into use. These embodiments are only exemplary. The invention in its broadest, and more specific aspects, is further described and defined in the claims which now follow.
[0052] These claims, and the language used therein, are to be understood in terms of the variants of the invention which have been described. They are not to be restricted to such variants, but are to be read as covering the full scope of the invention as is implicit with the invention and the disclosure that has been provided herein.
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A duplex trailing arm chassis support system has two longitudinal trailing arm members disposed on respective sides of the vehicle chassis and a structurally connecting cross member joining the two trailing arms to couple the movement of the two respective arms. Resilient cushioning members extend between each of the trailing arms and the underside of the vehicle chassis or between the connecting member and the vehicle chassis to provide resilient support to the vehicle chassis. Each trailing arm carries a wheel axle having wheels on both ends of the axle, each of the wheel axles being pivotally mounted to its respective trailing arm for rotational movement about the longitudinal axis of the trailing arm, allowing the axles to rock from side to side.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a perfection of Provisional Patent Application Ser. No. 61/916,267, filed on Dec. 15, 2013, the disclosure of which is fully incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to an emergency descent system, or “EDS” for use by anyone in a business context, including but not limited to those working in construction, utility operations, etc. The Federal Occupation Safety & Health Administration (or “OSHA”) requires that anyone working at a minimum height of 6 feet in any type of business wear a fall arrest system (or “FAS”). This harness will be worn in that setting. More particularly, this invention relates to an EDS that can be worn as a normal safety harness over clothing. Alternately, it can be integrated into a worker's clothing and/or coveralls, etc.
[0004] 2. Relevant Art
[0005] Descent control devices have been developed with the objective of lowering individuals (or objects) from a higher to lower elevation. Such devices have taken many forms and have utilized a variety of elements. Some are capable of providing a mechanical braking mechanism, such as a dead-man or panic control feature, when the device would be used for descent, escape, or rescue purposes.
[0006] Concerns with occupational safety have led to the development of mechanisms that enable a worker to lower himself from an elevated position such as a scaffold, crane, lift truck or platform in the event of an emergency. That equipment is, in some respects, similar to known fire escape devices, mountain climbing equipment, and military equipment.
[0007] One descent control device with a dead-man brake, in the form of a vertical cylindrical drum or capstan about which a rope is wound and a tapered slot through the drum for receiving and releasably gripping the rope, is shown in Varner et al. U.S. Pat. No. 4,883,146. That device includes plates on each end of a vertical cylindrical drum or capstan with apertures on each end plate through which the rope is threaded, then wound in two or more turns around the drum.
[0008] Tapered slots are well known for releasably fastening ropes, lines and cables. The use of cylindrical capstans for holding and providing a mechanical advantage for tightening ropes is also known. Likewise, a variety of fire escape devices utilize rope wound around a cylinder. See, for example, Budd U.S. Pat. No. 386,237; FitzGerald U.S. Pat. No. 536,866; Howe U.S. Pat. No. 771,251; Thuemer U.S. Pat. No. 946,588; Smith U.S. Pat. No. 1,115,603; Steffen U.S. Pat. No. 4,311,218; and Forrest U.S. Pat. Nos. 4,508,193 and 4,550,801.
[0009] In addition, there are known but clearly distinguishable teachings in Hobbs U.S. Pat. No. 3,678,543; Arancio U.S. Pat. No. 3,738,449; Wagner U.S. Pat. No. 4,019,609; Bell et al. U.S. Pat. No. 4,714,135; Varner et al. U.S. Pat. Nos. 5,038,888 and 5,131,491; Bassett U.S. Pat. No. 6,131,697; Harbers Jr. U.S. Pat. No. 6,585,082; Metz U.S. Pat. No. 6,817,443; Henson U.S. Pat. No. 6,823,966; and Halevy U.S. Pat. No. 7,357,224. See also, Ador Published U.S. App. No. 20020112916; Price Published U.S. App. No. 20020158098; Gelman Published U.S. App. No. 20030159887; Richardson Published U.S. App. No. 20040140152; Fischer et al. Published U.S. App. No. 20060011415; Harris Jr. Published U.S. App. Nos. 20060113147 and 20100122874; Moon et al Published U.S. App. No. 20070158139; and Botti Published U.S. App. No. 200702460298.
SUMMARY OF THE INVENTION
[0010] It is the principal object of the present invention to provide an improved controlled descent system that can provide full body protection to any and all workers operating at high levels in an industrial (commercial, construction, utility or other service) setting. While primarily intended as an outerwear item, it is understood that alternative embodiments may be BUILT INTO the clothing/coveralls, etc. worn by many service personnel.
[0011] A related object is to provide an industrial EDS-type harness (to be worn over an individual/wearer's chest and upper legs) for enabling that industrial user to affect a fail-safe descent from most any elevated working level in an emergency.
[0012] There are several key distinct differences/improvement of this harness over its original patent pending harness predecessors. Most notably:
[0013] 1—A Brake Pin Guide and SHORTENED Brake Pin have been moved to the left side of the EDS Rack for this latest generation harness. This solves several problems. Particularly, it removes the pin from being atop the wearer's right shoulder when pulled. In the original harness designs, that location caused the pin to pull very hard and possibly stick in a sharp turn area of the shoulder strap while a person is suspended. That, in turn, caused the Brake Strap underneath in the Brake Plate Tunnel to be pinched and not move as freely. Moving the Brake Pin Guide from the end of the Brake Plate to the Brake Pin Grommet Strap on the left side of the EDS Rack allows for not only relocating the Brake Pin but also shortening its length. Now when the Brake Strap is pulled, the Brake Pin is pulled to underneath the EDS Rack and not up into the Right Shoulder Strap eliminating the possibility of Brake Strap jamming.
[0014] 2—A serpentine Kevlar® Lined Brake and Limiter have been removed. This type of brake cannot be used on smaller diameter line, such as the 3/16″ line described herein. There is not enough surface area to allow the “earlier version” of brake to work. It puts a large amount of “twist” in the line that might cause it to jam within the EDS rack.
[0015] 3—A Kevlar® Delta Cross Brake is used.
[0016] A—This brake is specifically designed for the smaller diameter lines like the preferred 3/16″ soft Aramid® lines described below.
[0017] B—It has a Brake Line Guide that prevents twists being made in the Line.
[0018] C—When the Kevlar® Delta Cross Brake is pulled on, it not only keeps the Line from twisting but it also applies frictional pressure from two different directions at the same time.
[0019] D—It causes the Line to bend, exerting even more frictional pressure.
[0020] E—This Brake is also OFFSET with the Left Arm longer than the Right and the Brake Anchor Strap is attached in such a way to allow for the Brake to PIVOT. When the Brake Strap is pulled, it applies pressure to the Brake and all of the stopping qualities are used. When pressure is reduced on that Brake Strap, the Kevlar® Delta Cross Brake relaxes. That causes it to straighten out and Pivot to the left or counter clockwise thereby allowing for the Line to more freely transverse through the Kevlar® Delta Cross Brake and up through the EDS Rack while the wearer descends.
[0021] When this new Brake Strap is pulled, it causes the Kevlar® Delta Brake Strap to do all of the following at the same time:
[0022] i—Rotate Clockwise;
[0023] ii—Start bending into a U configuration;
[0024] iii—Apply pressure to the Line from two different directions; and
[0025] iv—Squeeze Line over its complete 360° surface area over a 3 ″ long section.
[0026] F—the new Brake Line Guide prevents the Line from twisting during braking
[0027] All of these qualities are vital to insure proper braking when using such a small diameter soft Line.
[0028] 4—a new size/shape of EDS Rack can now be used which is 50% smaller than the CDS Rack used in the original harness. This can be reduced in size for the smaller diameter Line used, 3/16″ line compared to the 11 mm (½″) line used in the Original Rescue One CDS Harness. This makes the harness lighter weight, less bulky and more compactable all of which results in greater comfort to the harness wearer of this invention.
[0029] 5—Smaller Diameter Line, 3/16″ Aramid® Line. This new technology allows for a very small diameter, very lightweight (1.3 pounds per 100 feet), very strong (over 5000 pound tensile) very soft braided, compactable descent line that is also cut and burn resistant. All of these qualities result in a very light, compactable, comfortable harness with even greater line length carrying capacity, even greater descending ability and far better rescue potential for a greater number of industrial job applications including but not limited to the greater heights required of radio and microwave tower workers and those performing elevated wind turbine servicing.
[0030] Wind turbines are close to 300 feet in elevation. The amount of 11 mm line used in current rescue equipment to allow a worker to descend this distance will weigh in excess of 20 pounds and take up the space of a medium sized duffle bag. The amount of a 3/16″ Aramid Line needed to descend 300 feet weighs 3.9 pounds and can fit in a standard oatmeal box or small rope bag.
[0031] To recap: the Kevlar® Delta Cross Brake is key. It allows for the use of a smaller diameter line. With the smaller line, the size of EDS Rack can be correspondingly reduced. The technology of lines has improved to where a very small diameter line is also strong enough to be used in critical emergency escape and rescue applications. With the smaller and lighter components, it allows for the harness to be lighter, less bulky, and more comfortable. All of these qualities ensure that a worker will find less to dislike about the new harness, more to like and more of a reason to wear it which means more use, greater safety and more lives saved.
[0032] Lastly, the movement of the Brake Pin Guide and Brake Pin allows for the harness to operate more effectively.
SUMMARY OF THE DRAWINGS
[0033] Further features, objects and advantages will become clearer when reviewing the detailed description made with reference to the accompanying drawings in which:
[0034] FIG. 1 is a top plan view of one embodiment of a finished waist belt according to this invention;
[0035] FIG. 2 is a top plan view of the suspension relief strap (SRS) and waist belt sewn thereto;
[0036] FIG. 3 is a close up view of the right side to an elastic support panel showing the line support loops joined adjacent one another;
[0037] FIG. 4 is a top plan view showing both angled side support panels between the side and center panels directly above the top edge of the waist belt;
[0038] FIG. 5 is a top plan view showing the Kevlar EDS Rack, and its top support straps glued to the middle Y brace;
[0039] FIG. 6 shows the same arrangement from FIG. 5 but with the Right Shoulder Strap affixed thereto;
[0040] FIG. 7 is a top plan view showing (dimensionally with a tape measure added) one embodiment of brake strap component;
[0041] FIG. 8 is a top plan schematic view for a Kevlar Delta Cross Brake according to this invention;
[0042] FIG. 9 is a top view showing the folded and sewn brake guide for the Kevlar Delta Cross Brake (KDCB);
[0043] FIG. 10 is a top plan view showing the Brake Anchor Strap folded over the Brake and Brake Guide Kevlar Delta Cross Brake;
[0044] FIGS. 11-13 show, sequentially, the Brake Guide Ends being folded backward and then hot melt glued to the Brake Anchor Strap;
[0045] FIG. 14 is a top view showing the lower section of the Brake Anchor Strap being folded up and over an upper section of that same Brake Anchor Strap;
[0046] FIG. 15 is a top view showing the Center Sewn area being centered on the Brake Anchor Strap fold;
[0047] FIG. 16 is a top plan view of a finished (fully assembled) Kevlar Delta Cross Brake (KDCB);
[0048] FIGS. 17 and 18 show the top ( 17 ) and bottom ( 18 ) views of the Brake Strap extending down to the top of the Delta opening;
[0049] FIG. 19 shows the tip of the Kevlar Delta Cross Brake pointed towards the center of the Brake Plate Opening;
[0050] FIG. 20 is a close up view showing the Kevlar Brake Pin Grommet Strap facing down next to and parallel with a left edge of the harness;
[0051] FIG. 21 is a top view showing the Brake Strap pulled through the Brake Plate Tunnel;
[0052] FIG. 22 is a top view showing the EDSRAS placed through the large bottom hole of the EDS Rack with a folded edge toward the middle of that EDS Rack;
[0053] FIGS. 23 and 24 show the front ( 23 ) and rear ( 24 views of one embodiment of brake strap cover (BSC) according to this invention;
[0054] FIG. 25 is a top plan view of one embodiment of brake pin for use with the present invention;
[0055] FIG. 26 is a top plan view showing one matching safety buckle and metal slider adjusting buckle for a leg strap component of this harness;
[0056] FIG. 27 is a top view showing the Tri Glide Adjusters of both Shoulder Straps placed through the same side of a Waist Belt Loop;
[0057] FIG. 28 shows a loop of Technora® line threaded through an Anchor Strap Loop then through itself;
[0058] FIG. 29 is a top view showing the Technora® line threaded back and forth between the elastic line holders, then the Kevlar Delta Cross Brake and EDS Rack;
[0059] FIG. 30 shows a template for cutting out a Tear-Away D-Ring Cover (TADRC) according to one embodiment of this invention;
[0060] FIG. 31 shows, in side view, a D-Ring Strap hot melt glued through a D-Ring according to this invention;
[0061] FIG. 32 is a top view showing Line 5″ End Loop fed through a D-Ring Strap Loop and the complete TADRSC, then secured to the D-R Strap Loop;
[0062] FIG. 33 is a close up view showing the SRS folded back and forth before being stored in its elastic storage panels in order to be deployed from the top layer down if/when needed;
[0063] FIG. 34 is a top plan view showing one preferred embodiment of line threading through a secured EDS Rack according to the invention;
[0064] FIG. 35 is a top view showing a Brake Strap Loop folded down onto its own Velcro component;
[0065] FIG. 36 shows the folded Brake Strap Loop of FIG. 35 stored its own Brake Strap Cover;
[0066] FIG. 37 is a close up view showing Line pulled up through the Kevlar Line Loop Guide and D-Ring;
[0067] FIG. 38 is a close up showing how during line installation, two loops are made on each side of the D-Ring with line coming from the Elastic Storage Loops;
[0068] FIG. 39 shows a pair of scissors holding the “spot” through which the Brake Pin will be insert in the direction of the scissors with the lower line loop coming over the top of the D-Ring and on the inside of the upper loop;
[0069] FIG. 40 is a close up view showing the Brake Pin inserted first through the Brake Pin Guide, next through the two created loops in the same direction as the scissors/place holder in FIG. 39 , and then through the Kevlar Brake Pin Grommet Strap;
[0070] FIG. 41 is a close up showing the pin shoved through the 1″ D-Ring as far as it will go;
[0071] FIG. 42 is a top view showing the remaining Brake Pin Strap folded onto the Brake Plate near the EDS Rack;
[0072] FIGS. 43 and 44 are close up views showing the Brake Pin Strap Cover folded over the Brake Pin Strap and attached with its Velcro, its notched section going under the EDS Rack and attaching to its Brake Pin Strap Cover Security Strip;
[0073] FIGS. 45 and 46 are top views showing the harness before ( 45 ) and after ( 46 ) the Back Cover and Tear-Away D-Ring Cover are fully situated in place; and
[0074] FIG. 47 is a top plan, rear view of a fully assembled harness according to the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0075] With reference to the accompanying drawings, there is shown a first preferred embodiment of Industrial EDS Harness. Also, When referring to any numerical length, width or other number range herein, it should be noted that all such numbers are mostly representative of just one embodiment of Industrial EDS harness (mostly as shown). Furthermore, any such range of numbers should expressly include each and every fraction or decimal between its stated minimum and maximum. For instance, any one component (strap, etc.) measuring from 1 to 3 inches in length should also specifically cover any strap measuring 1.1, 1.25 and 1.5 inches . . . and so on, up to about 2.75, 2.8 and 2.99 inches. The same applies for every other quantitative range herein.
[0076] The basic single layer harness will contain 44 feet of line as measured to a typical wearer's waist. Most people have another 3 feet of legs and with a tether of 4 to 6 feet for enabling easily descents of about 50 feet. In alternative versions, the line can be double or triple stacked with each additional layer increasing descent capability another 44 feet, all beneath a harness cover.
[0077] Still other variations employ an external line storage bag that can be attached to the rear of a harness for its wearer to descend several hundred feet if working on a Wind Turbine or other high elevation locale. When an external line storage bag is used, there will be no need to store a first section of line in elastic storage loops. All the line will be in the external storage bag and the line fed through an opening in the back of the harness and then transitioning through the Delta Cross Brake and up through the EDS Rack.
[0078] Note the following example for a working Industrial EDS Harness prototype:
Components for Industrial EDS Harness
[0000]
A—1⅞″ 6000 lb. nylon webbing (can be changed depending on application), approx. 40′.
1—72″ Right Shoulder Strap (RSS) 1—71″ Left Shoulder Strap (LSS) (Right will shorten due to sewing on Brake Plate later) 2—Left 8″ and Right-26″ Chest Straps (CS) 2—14½″ Line Loop Braces (LLB) 2—14½″ Elastic Loop Braces (ELB) 2—5″ Elastic Loop Brace Bridge Strap (ELBBS) 1—6⅛×4⅛″ Y Brace (YB) 1—30″ total, fold top down 9¾″ Spine Plate (SP) 1—Start with 110″ of webbing, Waist Belt (WB). 2—57″ Leg Straps 1—7″ Guide Strap 1—19″ Brake Plate, start with 19″ of webbing, mark 1⅛″ from both ends and fold to that mark and HMG (hot melt glue). Will end with 17½″ Brake Plate.
B—2¼″ Nylon Webbing
2—9⅜″ Elastic Line Storage Loop Bases, Outside Edges 2—6″ Elastic Line Support Bases, Sides, cut at ½″ angle both ends, final length 5½″. 1—8″ Elastic Line Support Base, Center 1—15½″ D-Ring Anchor Strap
C—3″ Nylon Webbing
2—14″ Face Support Panels
D—1″ 2500 lb. Black nylon webbing, approx. 18″.
2—7″ EDS Rack Side Support Straps 1—4½″ Brake Pin Guide (BPG), folded with double ¼″ grommets 1—3″ Brake Pin D-Ring Strap with 1″ Stainless Steel D-Ring. Fold over and HMG
E—1″ 2500 lb. Red nylon webbing Suspension Relief Strap (SRS), 9′.
1—9′ with 1¾″ of 1″ Hook Velcro sewn in place at a point beginning 5½″ from one end. (Between marks 5½″ and 7¼″ from one end).
F—1″ Kevlar 3500 lb. webbing, Offray #1781, appox 5′.
Delta Cross Brake, three pieces of 1″ Kevlar webbing. 1—8¾″ Brake 1—7½″ Brake Anchor Strap 1—8¼″ Brake Guide 2—10″ Top EDS Rack Supports 1—2¼″ Line Loop Guide 1—9½″ EDS Rack Attachment Strap (EDSRAS), folded at center and sewn. 1—6½″ Brake Pin Grommet Strap (BPGS), folded Kevlar strap with double grommets on the left side of the EDS Rack, end with 3¼″ after folded.
G—⅝″ 2800 lb. Red nylon webbing, must be high quality, tightly woven.
1—64″Brake Strap, Weaver Leather #4058-Rd.
H—1″ 800 lb. Polypro webbing, approx. 3′
2—17½″Clearance Strips, folded in half lengthwise and sewn, start with 17¾″ (will shrink when sewn ¼″).
I—EDS Rack—Forged Aluminum A356 T61, 40000 lb. tensile.
J—¼″ Stainless steel ss304 cold finish 3¾″ long pin total with polished 2⅝″ stem, ½″ ID welded eye.
K—¼″ Steel Spur Grommets, 4.
L— 3/16″ Tech 12 Sampson Technora® Line, 5,600 tensile, 44 feet finished line length with a 5″ loop on both ends (loops measured by extended length, not diameter).
M—330D Cordura material for Brake Pin Strap Cover, Brake Handle Cover and Back Cover, approx ½ yard of material.
N—Poly/Cotton material for Face Cover, 18½″ triangle with top point cut to leave 1½″ cut surface, both bottom corners cut to leave 2″ cut surface, approx. ¼ yard of material.
O—Velcro in 2″, 1″ and ⅝″ widths.
1—2″×38½″×37½″ Left Face/Right Shoulder Loop Velcro, top end square cut, bottom corner is cut at 1″ angle (37½″ on outside edge). 1—2″×20″×22″, Right Face Loop Velcro, the inside edge is longer than the outside edge, both ends cut at 1″ angle. 1—2″ 16″×16″ Bottom Face Loop Velcro, both ends square cut (placed on first before left and right sides). 1—2″×3″ Loop Velcro, center top of Y Brace over Top EDS Rack Supports. 1—2″×3″ Loop Velcro, Cut at an angle on one end, Top Left Spine Plate. 1—1″×1¾″ Hook Velcro, Suspension Relief Strap (SRS). 1—1″×6″ Hook Velcro, Brake Plate. 2—1″ Loop Velcro cut 2¼″×3⅜″, both ends angle cut, for bottom back outside corners. 1—1″×3¼″ Hook Velcro, Brake Strap Cover Pin Flap Security Strip. 1—⅝″×5″ Loop Velcro, Brake Strap. 1—⅝″×1″ Loop Velcro, Brake Strap. 1—⅝″×1″ Hook Velcro, Brake Strap.
P—3″ wide black heavy elastic material for 2-2¼″×3″ Elastic Storage Panels to hold the Suspension Relief Strap.
Q—1½″ wide black heavy elastic material (used for the Elastic Storage Loops and Elastic Support Panels that hold the line), approx. 5′.
2—20⅝″ Elastic Storage Loops, Outside Edges. 1—9⅜″ Elastic Support Loops, Center. 2—5¾″ Elastic Support Loops, Sides, ¼″ angle cut on both ends, final length 5½″.
R—2 sets of Metal Safety Buckles for Leg Straps, Niagara Safety Products #350
S—2 sets of Metal Flat Buckles, for Waist and Chest Straps, Aluminum, ESS Design
T—4 Metal Slider Adjusting Buckles, for webbing adjustment on Legs and Shoulder Straps.
U—1-1″ Stainless Steel D-Ring
V—Tear Away D-Ring Cover, materials listed here for clarity;
A—Cordura® Cover cut from template. B—1⅞″ webbing in the following lengths, 2-7″, 11½″, 11¾″, 1-12″×10½″(¾″ angle cut on both ends of one side. C—2-1″×5½″ webbing. D—Hook Velcro in the following lengths, 4-2″×3″, 2-2″×7″. E—Loop Velcro, 2-2″×3″ F—D-Ring Anchor Strap, 15½″×2¼″ webbing. G—D-Ring, Yoke, 2¼″ throat.
W—13″×5″ Warning Label for Brake Handle Cover, Poly material.
X—3×2″ Rescue One EDS logo embroidered on Center of Lower back cover.
Harness Assembly Steps
[0156] Heavy Sew with 270 Bonded Poly thread, WW Tacker 135 Bonded Poly thread, Kevlar 138 Bonded Natural Thread
1—Assemble Suspension Relief Strap, 9 feet of 1″ 2500 lb Red Nylon Webbing. Sew 1¾″ of 1″ Hook Velcro 5½″ from one end. 2—Assemble the Waist Belt, Start with 110″ of webbing.
A—Place the 57″ Left Leg Straps at approx. 60 degree angle at a point 15½″ from the stop which will be the left end of the waist strap. B—Place Waist Strap over the Leg Strap end and Hot Melt Glue (HMG). C—Place Female Flat Buckle over the end of the Waist Strap and fold end back to a point 16″ from the stop. D—Fold down Leg Strap at an angle over the Waist Strap and HMG. E—Make marks at 1¾″ and 3½″ from folded left end of webbing in the Female Buckle. This will be where the WW tacker will sew between the marks. F—Mark 21½″ and 53″ from left folded webbing end. These two marks will be the Lineman's Loops Center Marks of the Left (21½″) and Right (53″). G—Mark at 4½″ from left folded webbing end. H—Fold webbing in half at the 21½″ mark and place it on the 4½″ mark forming the Left Lineman's Loop. HMG both layers to the RIGHT of the Leg Strap ONLY. I—Place Right Leg Strap 49½″ from the left folded webbing end stop and HMG Waist strap over the Right Leg Strap. J—HMG 7″ Guide Strap on Waist Strap between 48″ and 55″ from left Waist Strap stop. K—Fold Right Leg Strap down and over Waist Strap at an angle and HMG. L—Mark at 52½″ from Left Folded Webbing End on the Guide Strap. M—Fold the 53″ Right Lineman's Loop Center mark in half and pull it back to the 52½″ mark forming the Right Lineman's Loop, HMG. N—Mark 3″ from RIGHT Waist Strap end. O—Finished Waist Belt. FIG. 1 —In order listed below, lay all parts in jig as stated and Hot Melt Glue (HMG) in place. Basic harness structure is 18″ triangle measured from the center of all three corners.
4—Add Y Brace to top of harness, top edge of Y Brace will be 3¾″ above top center crossing. Add Elastic Loop Brace Bridge Straps (ELBBS) 4½″ above the center of lower corners, parallel with and half way over the shoulder strap locations. 5—Add Left Shoulder Strap, Right Shoulder Strap will overlap the left, both shoulder strap bottoms will extend 11″ below the waist belt lower edge, measured along the inside edge of shoulder straps (these extensions become the short Male Buckle Leg Straps. 6—Add Line Loop Braces, lowest corners will be 2¾″ from inside edge of Shoulder Strap measured along bottom edge of waist belt location and highest corners will be 13½″ from bottom center corners, bottom edges even with lower edge of Waist Belt line. 7—Add Elastic Loop Braces along side of Shoulder Straps. 8—Add Spine Plate, with 9.5″ fold underneath and top even with top of Y Brace. 9—Add Right Shoulder Strap overlapping Spine Plate. 10—Waist Belt over harness back. 11—Showing 18″ from Center of left bottom harness crossing to Center of right bottom harness crossing. 12—Showing 18″ from Top Center Crossing to Center of right bottom crossing. 13—Left Lineman's Loop. 14—HMG the SRS end over the Waist Belt, centered and with the left lower end corner of the SRS even with the inside edge of the Right Leg Strap, Hook Velcro facing up. 15—WW sew all parts, there are 31 WW Tack. FIG. 2 16—Heavy sew the Right Lineman's Loop with sewing centered and parallel with the Long Leg Strap and then the SRS, sewing in a V, see the next two photos. The sew over the SRS will be parallel to the Short Right Leg Strap. Then sew the Left Lineman's Loop. 17—HMG both 14″×3″ Webbing Face Support Panels on the Face side of the harness, WW Sew with 12 sews on each panel. 18—HMG face cover on same side as Support Panels with narrow cut end at top. 19—HMG 2″ loop Velcro around all edges over Face Cover EXCEPT ABOVE TOP CENTER CROSSING, NEED TO SEW CDS RACK TOP SUPPORTS BEFORE FINAL SEWING OF VELCRO. Place the 16″×16″ Bottom Face Loop Velcro on FIRST between the Short Leg Straps over the Waist Belt. Second place the 20″×22″ Right Face Velcro (left side facing up). Last place the 38½″×37½″ Left Face/Right Shoulder Velcro on, it will overlap the right side. 20—HMG 2¼″×3¼″×1″ loop Velcro on bottom of right and left rear lower BACK corners. 21—HMG top and bottom edge of 3″w×1⅞″h Elastic SRS Securing Panels to bottom of harness back. Both start ¼″ on each side of spine plate. 22—HMG 2¼″×1″ Kevlar Line Loop Guide (KLLG) on the left upper side of the BACK, 3½″ below Top Center Crossing, HMG only the ends to each side of the left side webbing forming a loop. 23—Sew all around inside and outside edges of harness outside edge webbing with Face Down. SEW ON THE SIDE OF THE WEBBING AND NOT VELCRO. Do not sew above top center crossing. When sewing, double sew across the KLLG ends. 24—Form Elastic Line Loop Storage Panels:
A—Cut 2 Bases 9⅜″×2¼″ webbing, mark every ½″ leaving 3/16″ on each end. B—1½″ wide Elastic×20⅝″, mark every 1⅛″, leaving 3/16″ on each end.
25—Sew Elastic to Base forming 18 loops, aligning marks. 26—Form Elastic Line Support Panels:
A—Center Base, 8″×2¼″, mark every 1¼″, leaving ¼″ on each end. B—Center Elastic, 1½″×9⅜″, mark every 1½″, leaving 3/16″ on each end. C—Side Bases 2-5½″×2¼″, cut top and bottom at ½″ angle, start with 6″. D—Side Elastic 2-1½″×5½″, cut top and bottom at ¼″ angle, start with 5¾″. E—Sew Center Panel at markings, forming 6 loops. F—Sew Side Panels at top, middle and bottom, forming 2 loops each. Side panels will be opposites. FIG. 3
27—HMG Elastic Line Loop Storage Panels as follows;
A—Place Right Panel left lower corner ½″ below top edge of waist belt, with Right side of loops ½″ inside of Right Harness edge. B—Place Left Elastic Loop Line Storage Panel right lower corner ½″ below top edge of Waist Belt, with Left Side of Loops ⅜″ inside of Left Harness edge.
28—HMG the Elastic Line Support Panels as follows;
A—Place Center Support Panel over Spine Plate with bottom edge extending ¼″ below top edge of Waist Belt. B—Place both Angled Side Support Panels between the Side and Center Panels with both bottom edges extending ¼″ below top edge of Waist Belt. Both Lateral Sides of the Angled Side Support Panels will extend ½″ past the Lateral edge of each SRS Elastic Storage Panels. FIG. 4
29—Heavy sew all Elastic Storage and Support Panels around the outside edges. 30—Assemble the EDS Rack as follows;
A—Assemble the Left EDS Rack Support Strap as follows;
a—Punch two holes in the 6½″×1″ Kevlar Brake Pin Grommet Strap, one hole will be 2⅜″ from one end and the other hole will be 2½″ from the opposite end. The holes will be 1½″ from each other's center. b—Press ¼″ Stainless Steel Gommets into both Kevlar Brake Pin Grommet Strap holes, make sure Grommets are facing opposite directions. c—Punch two holes in the 4½″×1″ Brake Pin Guide, one hole will be 1⅜″ from one end and the other hole will be 1½″ from the opposite end. The holes will be 1½″ from each other's center. d—Press ¼″ Stainless Steel Gommets into both Brake Pin Guide holes, make sure Grommets are facing opposite directions.
B—Fold in half the Kevlar Brake Pin Grommet Strap (3¼″) and the Brake Pin Guide (2 3/16″) and HMG, the grommet WASHERS will be pointing up and will be offset so you can see the bottom edge of the underneath grommet washer thru the top grommet's hole. This allows the holes to line up when the straps are bent to insert the Brake Pin. C—HMG the Brake Pin Guide onto the Kevlar Brake Pin Grommet Strap with the WASHERS pointing up creating the Combined Grommet Straps. D—HMG 7″ EDS Rack Side Support Strap over the Combined Grommet Straps at 90 degree angle and Combined Grommet Straps pointing down, there will be 1½″ space left on the right end of the EDS Rack Support Strap. E—Place the Left EDS Rack Support Strap up thru the Left Side Slot on the EDS Rack and HMG the ends together. The Kevlar Brake Pin Grommet Strap will be on top and the Combined Grommet Straps will be pointing towards the bottom of the EDS Rack. There will be ⅜″ space between the EDS Rack and the Combined Grommet Straps. F—Heavy sew the Combined Grommet Straps to the Left EDS Rack Side Support Strap. G—Place the two 10″ Kevlar EDS Rack Top Support Straps and the 7″ Right EDS Rack Side Support Strap in their slots on the EDS Rack. Sew across the Right EDS Rack Side Support Strap next to the EDS Rack.
31—HMG Kevlar® EDS Rack Top Support Straps to middle of Y Brace. Extend Top Supports down so they are even with bottom of Y Brace on harness face. The Combined Grommet Straps will be on the Right and pointing up. Heavy Sew Top Supports to Y Brace and Harness. FIG. 5 32—Assemble the Brake Pin Strap Cover as follows:
A—Cut Cordura material 14″×6½″ B—Fold Left long side 1″ and HMG C—Fold both top and bottom edges ¾″ and HMG D—HMG 12½″ Hook Velcro over long folded side E—HMG 1¾″ Loop Velcro along bottom edge adjoining the Hook Velcro F—Cut a V Notch into the Hook Velcro beginning at 2″ below the top edge and along the left edge of the Hook Velcro. The bottom opening of the notch will be 4¼″ down from the top edge along the left edge of the Hook Velcro. The bottom of the V of the notch will be 2⅞″ down from the top edge and along the right edge of the Hook Velcro. The lower edge of the V Notch will be longer than the upper edge of the V Notch. G—Sew along the outside and inside edges of the folded sides, sewing along inside of the Hook Velcro and V Notch.
33—HMG and Sew 1″×3¼″ Hook Velcro on BPSC with 1½″ overlap aligned with top right point. 34—HMG Brake Pin Strap Cover (BPSC) to underside of the beginning of the right shoulder strap. Start at right outside edge of the Top Center Crossing and place long cut edge 1″ onto the right shoulder strap. The notched side of the BPSC will be to the outside with the Hook Velcro down. 35—HMG 3″×2″ Loop Velcro at the center top of the Y Brace over the CDS Rack Supports. The 3″ side will be even with the top of the Y Brace. 36—HMG the remaining 2″ loop Velcro up to top of Y Brace on Left and down Right Shoulder Strap above crossing, over the BPSC edge and down the right shoulder strap. FIG. 6 37—HMG 2×2×3″ loop Velcro with top edge cut at an angle on Top Left of Spine Plate on back of harness. 38—Sew loop Velcro on Top Left Face and Center over the EDS Top Support Straps ONLY. Do this by sewing the Inside edge of the Right Shoulder Strap Loop Velcro from the Top Center Crossing to the top of the Y Brace and then over the Center Loop Velcro and finally the remainder of the Left Shoulder Strap Loop Velcro. Sew 2×3″ loop Velcro on Top Left Spine Plate also at this time. DO NOT SEW PAST TOP OF Y BRACE ON THE RIGHT SHOULDER LOOP VELCRO. DO NOT SEW OUTSIDE EDGE OF RIGHT SHOULDER STRAP LOOP VELCRO. DO NOT SEW DOWN RIGHT SHOULDER STRAP. This section of Loop Velcro will be sewn when the Brake Plate is sewn to the Right Shoulder Strap. Sew in a triangular C-shaped pattern. 39—Sew the Inside, Outside and Bottom Edges of the last 4″ of loop Velcro extended down the right shoulder strap. 40—Assemble Brake Plate as follows:
A—Start with 19″ of 1⅞″ webbing, mark 1⅛″ from both ends. Fold both ends to these marks and HMG, will end up with 17½″. B—HMG and SEW 6″×1″ Hook Velcro centered on one end and adjoining the cut end of the fold. C—HMG on both 17½″Clearance Strips (CS), (folded in half 800 lb polypro and sewn) to the underside outside edges of the Brake Plate. Make sure rounded/fold edge of CS is towards center of Brake Plate.
41—HMG the Assembled Brake Plate onto the Right Shoulder Strap. Start at Top Center Crossing on the back aligning with the bottom edge of the BPSC on the face and go down the right shoulder strap. Heavy Sew the Brake Plate along both outside edges, sewing thru the Clearance Strips and double tacking the ends securely. 42—Assemble 64″×⅝″ Red Brake Strap as follows, sew with 138 Kevlar Thread:
A—Mark from one end 22¼″, 27¼″, 28″, 28½″, 40″, 40½″. B—On the opposite side, mark 22¼″, 23¼″, 28″, 28½″, 32¼″, 33¼″, 59½″. C—HMG 5″ of ⅝″ LOOP Velcro between the 22¼″ and 27¼″ marks. D—On the opposite side HMG 1″ of LOOP Velcro between 22¼″ and 23½″ marks. E—HMG 1″ of HOOK Velcro between the 32¼″ and 33¼″ marks on the same side. F—Sew all Velcro to Brake Strap. G—Fold Brake Strap to align the 28″ and 28½″ marks to the 40″ and 40½″ marks. H—Sew between the 28″ and 28½″ marks creating the Handle Loop. There are two free ends created. The top free strap with no Velcro is the Brake Pin Strap. The bottom strap with the attached Velcro is the Brake Strap. FIG. 7
43—Create the Kevlar Delta Cross Brake (KDCB) as follows: FIG. 8
A—7½″ Brake Anchor Strap (BAS) is vertical with center being 3½″ from top. B—8¾″ Brake Strap is laid across BAS at a 45 degree angle and centered. C—8¼″ Brake Guide is laid across the Brake Strap at a 90 degree angle to the BAS. D—Mark ½″ down from top of BAS E—Sew 1″ across the Brake Guide center. F—Fold Brake Guide up lengthwise along the sewing line. FIG. 9 G—Fold Brake left bottom end up over the Brake Guide and fold the right upper end down over the Brake Guide pulling the ends together towards the back side of the Brake Anchor Strap and HMG aligning both outside top corners. The Brake Anchor Strap is folded over the Brake and Brake Guide, HMG the ends together, pointing down. FIG. 10 H—Fold both Brake Guide Ends backwards and HMG to BAS with top edges even with the ½″ line on the BAS. FIGS. 11-13 I—Fold lower section of BAS up and over the upper section of BAS. The lower Section is ½″ longer than the upper section and will extend above the upper section ½″. FIG. 14 J—The Center Sewn area will be Centered on the BAS fold. FIG. 15 K—Fold the ½″ longer BAS strap over the shorter one and HMG. L—Finished Kevlar Delta Cross Brake. FIG. 16
44—Sew KDCB as shown with 138 Kevlar thread. 45—Trim the non-overlapped edges and HMG the Kevlar Delta Cross Brake on top of the end of the Brake Strap on the SAME side as the 5″ Loop Velcro and heavy sew trimmed edges and Brake Strap. Brake Strap end will extend down to the top of the Delta opening. FIGS. 17-18 46—Attach the Kevlar Delta Cross Brake to the back of the harness as follows:
A—HMG the Brake Anchor Strap bottom edge 8¼″ down from the Top Center Crossing and 3″ from the Left harness edge. The tip of the Kevlar Delta Cross Brake will be pointed towards the center of the Brake Plate Opening. FIG. 19
47—Heavy sew the Bottom 2″ of the Brake Anchor Strap. 48—HMG the Left EDS Rack Side Support Strap to the harness by laying the Left Side Support across the left edge of the harness with the top edge of the Left Side Support even with the Top Center Crossing. The Kevlar Brake Pin Grommet Strap will be facing down next to and parallel with the left edge of the harness. FIG. 20 49—HMG the 1″ D-Ring and 3″ Folded Strap next to the Left EDS Rack Side Support Strap with the cut ends of the D-Ring Strap against the Left EDS Rack Side Support Strap with the inside edge of the D-Ring Strap even with the cut ends of the Left EDS Rack Side Support Strap. Heavy sew across the Left Side Support ¼″ from the edge of the harness, sew over 1″ area. Sew close to the D-Ring and over a 1″ area. 50—Pull the Brake Strap thru the Brake Plate Tunnel. FIG. 21 51—HMG and Heavy Sew the Right EDS Rack Side Support along Right edge of harness with the end of the Right Side Support extending 1½″ down past the Top Center Crossing, next to and parallel with the right edge of the harness. Begin Heavy Sewing ¼″ below Top Center Crossing and sew over 1″ area. 52—Form the EDS Rack Attachment Strap (EDSRAS) as follows:
A—Fold in half long ways the 9½″×1″ Kevlar strap and sew with 138 Kevlar Thread across at 4¾″.
53—Place EDSRAS thru the EDS Rack large bottom hole with the folded edge towards the middle of the EDS Rack. HMG the EDSRAS so it extends 5¼″ below the Top Center Crossing and 1½″ from the Right Harness edge and parallel to the Right Harness edge. Heavy Sew the bottom 2 inches of the EDSRAS. FIG. 22 54—Assemble and attach the Brake Strap Cover as follows:
A—Start with 7¼″×9⅛″ Cordura® Material. Measure from top and bottom 1½″, fold to this mark and HMG. B—HMG 1″×1″ Loop Velcro, 2″ down from top and centered on the face. C—HMG 6″ of 1″ Hook Velcro along both long top sides, starting at the bottom. D—Fold both Velcro covered sides long ways and underneath, and HMG. E—Create Pull Tab with 6″ of 1″ webbing. HMG and sew 1″ Hook Velcro 2″ from one end. HMG and sew 1″ Hook Velcro on the same side far end. F—Fold Pull Tab in half, HMG and sew the two ends to the Top of the BSC with the Hook Velcro on the end on top. This will align the Hook Velcro on the underneath side of the Pull Tab with the Loop Velcro on the Brake Strap Cover face. G—Sew around all edges of the BSC and the center 1″ Loop Velcro on the face. H—HMG and sew the Emergency Instructions bottom right edge to the underside of the BSC, directly opposite the center Loop Velcro on the face. DO NOT SEW THRU THE PULL TAB END.
55—HMG bottom edge of Brake Strap Cover (BSC) to Right Shoulder Strap 1″ below farend of Brake Plate (15″ below the Y Brace). The BSC with be able to extend up and over the Brake Plate. The warning label is already connected to the BSC. Sew BSC only ACROSS bottom edge that is overlapping right shoulder webbing. FIGS. 23-24 56—Insert the end of the Brake Pin Strap up through the eye hole of the ¼″×3¾″ Brake Pin. Fold strap back to the 59½″ mark, HMG and Sew end securely over 1″ area. The cut end of the Brake Pin Strap will be ON TOP. FIG. 25 57—Attach Adhesive Warning Labels and Rope Threading Diagram. Mark 16″ down on both shoulder straps from the inside edge measured from the Y Brace. Mark 6″ from the ends of both Shoulder Straps and all Leg Straps, this mark will be on the Face Side. 58—Place on all remaining Safety Buckles and Metal Slider Adjusting Buckles on Leg Straps. Fold over 3″ and WW Sew on all terminal ends. The Male Safety Buckle will be on the Short Leg Strap. FIG. 26 59—Place the Tri Glide Adjusters on both Shoulder Straps and place both straps through the same side Waist Belt Loops. Take both cut ends and place around Center Tri Glide post, overlap 3″, HMG and Sew. FIG. 27 60—HMG and Sew Chest Straps on. Sew both with the top edges 16″ from Y brace measuring along inside edge of each shoulder strap. The underside of Left Female Chest Strap, 8″ strap is folded back 3″ to secure the Flat Female Buckle and WW Sewn. HMG to the underside of the Left Chest Strap 2″ and WW Sewn. 61—HMG and Heavy Sew the folded 5″×1″ Line Anchor Strap to the Left side Waist Belt half way between the Left Line Storage Loop Panel and the Left Line Support Panel. The folded end will be pointing towards the top of the harness and the two cut ends will be even with the bottom of the Waist Belt, Heavy Sew the bottom 1¼″ leaving an upper loop. 62—Place loop of the Technora® line thru the Anchor Strap Loop and thread it thru itself. FIG. 28 63—Place the remainder of the line into the Storage and Support Panels starting at the bottom of the harness and work your way up. 64—Thread the line thru the Kevlar® Delta Cross Brake and EDS Rack. FIG. 29 65—Create the Tear-Away D-Ring Cover (TADRC) as follows;
A—Mark out the Cordura material with the Pattern Template and cut. FIG. 30 B—HMG the webbing onto the TADRC as shown. 11½″ is vertical, 12″×10½″ is horizontal middle, 11¾″ is horizontal bottom, 2-7⅛″ are bottom side verticals with 1″×5½″ next to them. C—HMG the Hook Velcro over the Webbing and the Loop Velcro on the opposite side. D—Trim, cut and sew. Both 7″ Leg Sections Top Edge must be cut to the 1″ webbing. E—Assemble D-Ring Strap. Mark at 8″ on the 15½″×2¼″ webbing. Sew in Thirds at this mark. HMG D-Ring Strap to D-Ring as shown, strap will be 4½″ long. FIG. 31 F—HMG and Heavy Sew D-Ring Strap to TADRC. Top of D-Ring will be even with the bottom of the cover and cut end of D-Ring Strap will be against cover. The top of the D-Ring Strap forms a Loop to attach the Line.
66—Place the Line 5″ End Loop thru the D-Ring Strap Loop and place the complete TADRSC thru the Loop so the Line is secured to the D-R Strap Loop as shown. FIG. 32 67—Fold SRS back and forth and place in Elastic Storage Panels so SRS deploys from top layer down. FIG. 33 68—Set Brake, Brake Pin as follows: FIG. 34
A—Pull Brake Strap Loop until Brake is tight and approx. ½″ of red strap is showing between the Loop Velcro and the end of the Brake Plate. Fold Brake Strap onto the Brake Plate and attach to Velcro. B—Fold Brake Strap Loop down to its Velcro and Fold Brake Strap Cover with Emergency Instructions over the Brake Strap Loop and attach to its Velcro. FIGS. 35-36 C—Pull Line up through the Kevlar Line Loop Guide and 1″ D-Ring. FIG. 37 D—Make two loops as shown on each side of the 1″ D-Ring with the line coming from the Elastic Storage Loops. FIG. 38 E—Brake Pin will insert in the direction of the instrument shown. The lower loop will come over the top of the 1″ D-Ring and will be on the inside of the upper loop. FIG. 39 F—Insert the Brake Pin through the Brake Pin Guide First, then through the two created loops in the same direction as the instrument was and then through the Kevlar Brake Pin Grommet Strap. FIG. 40 G—Finally shove the pin through the 1″ D-ring as far as it will go. FIG. 41 H—Fold the remaining Brake Pin Strap onto the Brake Plate near the EDS Rack. FIG. 42 I—Fold the Brake Pin Strap Cover over the Brake Pin Strap and attach with its Velcro. The notched section goes under the EDS Rack and attaches to its Velcro and the Brake Pin Strap Cover Security Strip Hook Velcro rolls over the edge and attaches to the face. FIGS. 43-44
69—Create Back Cover; Height is 18″×22″ at the widest point. The Top edge is 13″ wide and the bottom edge from center of each outside curve is 13½″. Loop Velcro on the Top Outside Edge is 7½″×2″. 2″ Loop Velcro is around inside edge except along the top. Long Outside Edge is 12½″, Short Outside Edge is 7″. 70—Place Back Cover and Tear-Away D-Ring Cover on harness and attach all Velcro. Industrial EDS Harness is complete. FIGS. 45-47
[0319] While certain illustrative embodiments have been shown in the drawings and described above in considerable detail, it should be understood that there is no intention to limit the invention to the specific forms disclosed.
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An industrial safety harness for allowing a distressed worker to lower him or herself from a distance at least six feet above ground. The harness comprises adjustable belt sections for the worker's upper chest, waist and upper thighs. In a grommet strap on the left shoulder of this harness, there is stored a brake pin guide and shortened brake pin and secondary brake strap. A triangular shaped panel for the worker's back holds a smaller diameter, lighter weight safety line, at least about 40 feet in length. One preferred line, made from Aramid®, passes through a modified delta cross brake that includes a Kevlar® component with a brake line guide that prevents line twisting. The improved brake applies frictional pressure from different directions at the same time.
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BRIEF SUMMARY OF THE INVENTION
This invention relates to novel organic compounds, particularly novel benzospiran derivatives embraced by the formula ##SPC2##
Wherein the sum of A and B is at least the integer 2; A is selected from the group consisting of --(CH 2 ) n - wherein n is 1 through 5 and --(C n H 2n -- 2 XY)-- wherein X is selected from the group consisting of hydroxy, acetoxy, amino and acetamido and Y is hydrogen, and X when taken together with Y is selected from the group consisting of =0 and =CR 3 R 4 wherein R 3 and R 4 are selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; B is absent or --(CH 2 ) n - wherein n is 1 through 3; R 1 is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R 2 is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, ##EQU2## WHEREIN N IS 2 THROUGH 5 AND Ar is phenyl having zero through three substituents selected from the group consisting of lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms; bromine, chlorine and fluorine; R 1 and R 2 taken together with --N< is a saturated heterocyclic amino radical selected from the group consisting of unsubstituted and substituted pyrrolidino, piperidino, and hexamethylenimino; Z is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms, nitro, amino, monoalkylamino of 1 through 3 carbon atoms, acylamido of 1 through 4 carbon atoms, bromine, chlorine and fluorine; and pharmacologically acceptable acid addition salts thereof.
The preferred compounds of this invention embraced by Formula I, immediately above, are those having the formula ##SPC3##
which are inclusive of those represented by the formulae ##SPC4##
wherein A, B, Ar, n, R 1 and Z have the same meaning as above and R 5 is selected from the group consisting of hydrogen, hydroxy and methylene; and a pharmacologically acceptable acid addition salt thereof.
Examples of Ar are phenyl, m-chlorophenyl, p-fluorophenyl, m-ethylphenyl, o-methylphenyl, 3,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2-bromo-5-ethylphenyl, 2-chloro-3,5-dipropylphenyl and 2,4,6-trichlorophenyl. Examples of lower alkyl of 1 through 3 carbon atoms are methyl, ethyl, propyl and isopropyl. Examples of lower alkoxy of 1 through 3 carbon atoms are methoxy, ethoxy, propoxy, and isopropoxy. Examples of unsubstituted and substituted pyrrolidino, piperidino and hexamethylenimino are pyrrolidino, 2-methylpyrrolidino, piperidino, 2-ethylpiperidino, hexamethylenimino, 3-methoxyhexamethylenimino and 2-ethyl-4-methylhexamethylenimino. Examples of ##EQU3## is phenyl having from zero through three substituents selected from the group consisting of fluorine, chlorine, bromine, lower alkyl of 1 through 3 three carbon atoms and lower alkoxy of 1 through 3 carbon atoms, are: 4-oxo-4-(p-fluorophenyl)-butyl, 4-oxo-4-(2-chloro-1-methylphenyl)butyl, 4-oxo-4-phenylbutyl, 4-oxo-4-(p-tolyl)butyl, 4-oxo-4-(p-methoxyphenyl)butyl, 4-oxo-4-(p-chlorophenyl)butyl, 4-oxo-(2-bromo-4-chlorophenyl)butyl, 3-oxo-3-(p-bromophenyl)propyl, 5-oxo-4-(o-ethoxyphenyl)pentyl, and the isomeric forms thereof. Examples of monoalkylamino of 1 through 3 carbon atoms are methylamino, ethylamino, propylamino and isopropylamino. Examples of acylamido of 1 through 4 carbon atoms are formylamido, acetamido, propionamido and isopropionamido.
The novel benzospiran compounds of Formula I exist either in the non-protonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment. They form stable protonates, i.e., acid addition salts, on neutralization of the free base form with suitable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, citric and lactic acids, and the like. Conversely, the free base of the novel compounds of Formula I can be obtained from a salt (e.g., from the hydrochloride or sulfate salts) by neutralization with a base such as sodium hydroxide, extracting with an immiscible solvent, for example chloroform, drying the extract, for example, with anhydrous sodium sulfate, and removing the solvent by evaporation.
The novel compounds of generic Formula I, above, include those of three types, namely, 3',4'-dihydro-spiro[cyclohexane-1,1'(2'H)-naphthalene]s having the general structure ##SPC5##
spiro[cyclohexane-1,2'-indan]s of the general structure ##SPC6##
and spiro[cyclohexane-1,2'-tetralin]s of the general structure ##SPC7##
wherein R 1 , R 2 and Z have the same meaning as above and R 5 is selected from the group consisting of hydrogen, hydroxy and methylene.
The novel compounds of Formula I (a, b and c), above, and intermediates therefor are prepared in accordance with the procedures of Processes A, B and C, respectively, described below.
Process A
The following sequence of formulae illustratively represents procedures for the preparation of compounds of Formula I(a). ##SPC8##
wherein Ar, n and Z have the same meaning as above, R is lower alkyl of 1 through 3 carbon atoms, the symbol --N
represents a saturated heterocyclic amino radical selected from the group consisting of unsubstituted and substituted pyrrolidino, piperidino and hexamethyleneimino and X is selected from the group consisting of chlorine, bromine and an anion of a pharmacologically acceptable acid addition salt.
The compounds embraced by Formula I(a) of the flowsheet designated Process A, above, are prepared by the procedures indicated therein, employing the methods and reactions described below.
1. The first step of the process comprises reducing a known 4-cyano-4-phenylcyclohexanone (a), e.g., with sodium borohydride (in a solvent such as tetrahydrofuran) at low temperature, to yield a corresponding 4-cyano-4-phenylcyclohexanol (b).
2. A thus produced 4-cyano-4-phenylcyclohexanol (b) obtained in step (1) is directly reduced, e.g., with lithium aluminum hydride (in a solvent such as tetrahydrofuran) at elevated (reflux) temperature, to give a corresponding 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c). This compound is also prepared via the tetrahydropyranyl ether of (b).
3. A 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c) produced in step (2) is first converted to its corresponding tetrahydropyranyl ether (d) (e.g., by mixing it will dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid in a solvent such as ether), then the formyl function of said ether (d) alkyllated via the Wittig reaction (e.g., by reacting it with a mixture of a trialkylphosphonoacylate, in a solvent such as tetrahydrofuran, and sodium hydride, followed by heating at reflux) to give a corresponding alkyl-4-hydroxy-1-phenylcyclohexaneacrylate tetrahydropyranyl ether (e), followed by hydrolysis of said compound (e); for example, with an alkanol (such as methanol) acidified with an acid such as hydrochloric acid, to give a corresponding alkyl-4-hydroxy-1-phenylcyclohexaneacrylate (f).
4. An alkyl- 4-hydroxy-1-phenylcyclohexaneacrylate (f) prepared in step (3) is reduced catalytically (e.g., with hydrogen in the presence of palladium on carbon), to give a corresponding alkyl-4-hydroxy-1-phenylcyclohexane-3-propionate (g).
5. An alkyl-4-hydroxy-1-phenylcyclohexane-3-propionate (g) obtained in step (4) is hydrolyzed, e.g., by heating it at reflux with an alkali metal hydroxide (such as sodium hydroxide) in an alkanol (such as methanol), to yield a corresponding 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h).
6. The next step of the process comprises oxidizing the 4-hydroxyl function of a 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h) produced in step (5), e.g., with Jones reagent (chromium trioxide -- sulfuric acid), preferably at ice bath temperature, to yield a corresponding 4-oxo-1-phenylcyclohexane 3-propionic acid (i).
The compounds embraced by intermediate (i) can also be prepared by another method, namely, via alkylene ketals, as follows:
1'. A 4-cyano-4-phenylcyclohexanone (a) is ketalized, e.g., by heating (at reflux) in benzene with an alkylene glycol (in the presence of a catalyst such as p-toluenesulfonic acid), to yield a corresponding 4-cyano-4-phenylcyclohexanone alkylene ketal (j).
2'. A 4-cyano-4-phenylcyclohexanone alkylene ketal (j) produced in step (1') is converted with about 0.5 mole equivalent of lithium aluminum hydride (in a solvent such as tetrahydrofuran) at room temperature to a corresponding imine, followed by its hydrolysis (e.g., in a solvent such as tetrahydrofuran with an acid such as hydrochloric acid), to yield a corresponding 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-alkylene ketal (k).
3'. A 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-alkylene ketal (k) produced in step (2') is alkylated via the Wittig reaction (e.g., by reacting it with a mixture of a trialkylphosphonoacetate, in a solvent such as tetrahydrofuran, and sodium hydride, followed by heating at reflux) to give a corresponding alkyl-4-oxo-1-phenylcyclohexaneacrylate alkylene ketal (l).
4'. An alkyl-4-oxo-1-phenylcyclohexaneacrylate alkylene ketal (l) prepared in step (3') is reduced catalytically (e.g., with hydrogen in the presence of palladium on carbon), to give a corresponding alkyl-4-oxo-1-phenylcyclohane-3-propionate alkylene ketal (m).
5'. An alkyl-4-oxo-1-phenylcyclohexane-3-propionate alkylene ketal (m) obtained in step (4') is hydrolyzed, e.g., by heating it at reflux with an alkali metal hydroxide (such as sodium hydroxide) in an alkanol (such as methanol), to give a corresponding 4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketal (n).
6'. In this step, the alkylene ketol protective group of a 4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketal (n) produced in step (5') is removed by employing conventional reagents and procedures, e.g., by stirring an aforesaid compound with a dilute aqueous acid (e.g., hydrochloric) in acetone at moderate (room) temperature for a long (6 to 60 hour) period, to give a corresponding 4-oxo-1-phenylcyclohexane-3-propionic acid (i), also produced by the method ending with step (6), above.
7. A 4-oxo-1-phenylcyclohexane-3-propionic acid (i) prepared in step (6) or (6') is cyclized, e.g., by allowing it to stand at room temperature for from about 15 to about 80 hours with liquid hydrogen fluoride, to yield a corresponding spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione (o).
8. A spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione (o) prepared in step (7) is monoketalized at the non-conjugated least hindered carbonyl function, e.g., by heating (at reflux) in a solvent such as benzene with an alkylene glycol (in the presence of a catalyst such as p-toluenesulfonic acid), to yield a corresponding spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dialkyltrimethylene ketal) (p).
9. A spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dialkyltrimethylene ketal (p) produced in step (8) is reduced at the 4'-position, e.g., by long (about 12 to about 18 hours) heating (at reflux) with hydrazine hydrate and an alkali metal base such as sodium hydroxide in a solvent such as an alkylene glycol (e.g., ethylene glycol) to give a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one, 2,2-dialkyltrimethylene ketal (g).
10. In this step, a 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one, 2,2-dialkyltrimethylene ketal (q) prepared in step (9) has its ketal protective group removed by hydrolysis, e.g., by mixing it with an acid (such as hydrochloric acid) in a solvent (such as acetone) at moderate (room) temperature for from about 2 to about 10 hours, to yield a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one (r).
11. A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one (r) produced in step (10) has its 4-keto function reduced, e.g., by mixing said compound in a solvent such as ethanol with sodium borohydride at moderate (room) temperature for from about 3 to about 8 hours, to produce a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol (s).
12. Letting stand (preferably at low temperature for from about 3 to about 14 hours) a mixture of a 3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-ol (s) obtained in step (11) in an amine base (e.g., pyridine) and a lower alkyl sulfonyl halide (such as methanesulfonyl chloride), yields a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)naphthalen]-4-ol lower alkyl sulfonate (t).
13. A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol alkyl sulfonate (t) resulting from step (12) and sodium azide in a solvent such as dimethylformamide, on heating (at from about 65° to about 100° C. for from about 4 to about 24 hours), yields a corresponding 3',4'-dihydrospiro[cyclohexane 1,1'(2'H)-1,1'(2'H)-naphthalen]-4-ylazide (u).
14. A 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-1,1'(2'H)-naphthalen]-4-ylazide (u) obtained in step (13) on reduction of its azido function, e.g., by reacting said compound with lithium aluminum hydride in a solvent such as tetrahydrofuran at moderate (room) temperature for from about 3 to about 10 hours, yields a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)] in its free base form. On treating an ether extract of a thus produced compound with an ethereal solution of a suitable (pharmacologically acceptable) acid, its acid addition salt form is obtained.
The free base or acid addition salt forms of the 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamines [I(a)] obtained as in step (14), above, are employed as starting materials for producing a variety of derivatives thereof, for example, in accordance with the methods described in (a) through (e) that follow.
a. Heating (e.g., under reflux for from about 8 to about 24 hours) a 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)] obtained in step (14) with a dihaloalkane, gives a corresponding (1-single ring nitrogen containing heterocyclo)-3',4'-dihydrospiro-(cyclohexane- 1,1'(2'H)-naphthalen)-4-yl [I(a)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid, yields the corresponding acid addition salt. For example, heating a 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)] with 1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiodohexane, yields, respectively a corresponding 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]piperidine [I(a)], a 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl)pyrrolidine [I(a)] or a 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]hexamethyleneimine [I(a)], which can be converted to their acid addition salts in the manner described in the immediately preceding sentence.
b. The production of a compound selected from the group consisting of the free bases and acid addition salts of a 4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]alkanophenone of the formula ##SPC9##
wherein Ar, n and Z have the same meaning as above, comprises reacting (in the presence of an alkali metal iodide and an alkali metal carbonate) a corresponding compound obtained as in step (14) selected from the group consisting of the free bases and acid salts of a compound of the formula ##SPC10##
wherein Z has the same meaning as above, with a corresponding compound of the formula ##SPC11##
wherein Ar, R and n have the same meaning as above and X is selected from the group consisting of chlorine and bromine, followed by hydrolyzing (i.e., deketalizing) a thus produced compound, e.g., with aqueous acid in an alkanol.
c. Reacting a 3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-ylamine [I(a)] obtained as in step (14), in an amine base (such as pyridine) in the cold with a lower alkyl haloformate (e.g., ethyl chloroformate, methylbromoformate or propyl chloroformate), yields a corresponding lower alkyl 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate of the formula ##SPC12##
wherein R and Z have the same meaning as above.
d. A lower alkyl 3',4'-dihydrospiro[cyclohexane1,1'(2'H)-naphthalene]-4-carbamate I(a), prepared as in (c) immediately above, is reduced, for example, by heating it in a solvent such as tetrahydrofuran [e.g., under reflux for from about 8 to about 24 hours] with lithium aluminum hydride, to yield a corresponding 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-lower alkylamine [I(a)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid gives a corresponding acid addition salt thereof.
e. Following the procedure of (b), above, but substituting as starting material the free base or acid addition salt of a 3',4'-dihydrospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-yl-N-lower alkylamine [I(a)], obtained as in (d) immediately above, yields a corresponding 4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-2 through 5-yl-N-lower alkylamino]alkanophenone [I(a)], or an acid addition salt thereof.
Process B
The following sequence of formulae illustratively represents procedures for the preparation of compounds of Formulae I(b). ##SPC13##
wherein Ar, n, -N , R, X and Z have the same meaning as in Process A, above.
The compounds embraced by formula I(b) of the flowsheet designated Process B, above, are prepared by the procedures indicated therein, employing the methods and reactions described below.
1. The first step of the process comprises reducing an alkyl p-hydroxy benzoate [1] (prepared as in Ann. 141, 247), e.g., by hydrogenating it in the presence of a catalyst (such as 5 percent rhodium/aluminum) in a solvent (such as absolute ethanol) at room temperature, to yield a corresponding alkyl-4-hydroxycyclohexane carboxylate [2].
2. An alkyl-4-hydroxycyclohexane carboxylate [2] obtained in step (1) is oxidized at the 4-position, e.g., in acetone with Jones reagent as low temperature (at from about 5° to about 20° C.) to give a corresponding 4-carboalkoxy-1-cyclohexanone [3].
3. A 4-carboalkoxy-1-cyclohexanone [3] prepared in step (2) is ketalized at the 4-position, e.g., by heating (at reflux) in benzene with an alkylene glycol (in the presence of a catalyst such as p-toluenesulfonic acid) for from about 4 to about 8 hours, to yield a corresponding 4-carboalkoxy-1-cyclohexanone alkylene ketal [4].
4. A 4-carboalkoxy-1-cyclohexanone alkylene ketal [4] obtained in step (3) on reaction with lithium diisopropyl amide (prepared by adding butyl lithium in a solvent such as pentane to diisopropylamine in a solvent such as tetrahydrofuran at low temperature) followed by addition of a benzyl halide (such as α-bromotoluene, α-chloro-p-xylene, α-bromo-m-xylene, m-methoxybenzyl chloride, and the like), yields a corresponding 4-benzyl (or substituted benzyl)-4-carboalkoxy-1-cyclohexane alkylene ketal [5].
5. A 4-benzyl (or substituted benzyl)-4-carboalkoxy-1-cyclohexane alkylene ketal [5] obtained in step (4) is saponified, e.g., by heating (at reflux for from about 10 to about 24 hours) in a solvent such as ethylene glycol with an alkali metal hydroxide (such as potassium hydroxide), to give a corresponding 4-benzyl (or substituted benzyl)-4-carboxy-1-cyclohexanone alkylene ketal [6].
6. A 4-benzyl (or substituted benzyl)-4-carboxy-1-cyclohexanone alkylene ketal [6] prepared in step (5) is deketalized, e.g., by stirring it with a dilute aqueous acid (e.g., hydrochloric acid) in acetone at moderate (room) temperature for from about 6 to about 60 hours, to give a corresponding 1-benzyl (or substituted benzyl)-4-cyclohexanone-1-carboxylic acid [7].
7. Reacting a 1-benzyl (or substituted benzyl)-4-cyclohexanone-1-carboxylic acid [7] obtained in step (6) with hydrogen fluoride at room temperature (or with phosphorus pentachloride at reflux temperature, followed by treatment with stannic chloride), gives a corresponding unsubstituted or substituted spiro(cyclohexane-1,2'-indan)-1'4-dione [8].
8. An unsubstituted or substituted spiro(cyclohexane-1,2'-indan)-1'4-dione [8] obtained in step (7) is ketalized at the 4-position, e.g., by heating (at reflux) in benzene with an alkylene glycol (in the presence of a catalyst such as p-toluenesulfonic acid) for from about 3 to 7 hours, to yield a corresponding unsubstituted or substituted spiro(cyclohexane-1,2'-indan)-1',4-dione 4-alkylene ketal [9].
9. A spiro(cyclohexane-1,2'-indan)-1'4-dione 4-alkylene ketal [9] prepared in step (8) on being subjected to Wolff-Kischner reduction, namely, by heating it (at reflux) with hydrazine hydrate and an alkali metal hydroxide (such as potassium hydroxide) in a solvent such as ethylene glycol for from about 8 to about 12 hours, gives a corresponding spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [10].
10. A spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [10] obtained in step (9) is deketalized, e.g., by stirring it with a dilute aqueous acid (such as hydrochloric acid) in acetone for from about 3 to about 8 hours, to give a corresponding spiro(cyclohexane-1,2'-indan)-4-one [11].
11. A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10), on heating at reflux for from about 4 to about 8 hours with an acid addition salt of hydroxylamine and an alkali metal hydroxide such as sodium hydroxide, yields a corresponding spiro(cyclohexane-1,2'-indan)-4-one oxime [12].
12. A spiro(cyclohexane-1,2'-indan)-4-one oxime [12] prepared in step (11), on standing in a solvent such as tetrahydrofuran with an anhydride of a hydrocarbon carboxylic acid in the presence of an esterification catalyst (e.g., pyridine) at moderate (room) temperature for from about 4 to about 8 hours, yields a corresponding spiro(cyclohexane-1,2'-indan)-4-one oxime acylate [13].
13. A spiro(cyclohexane-1,2'-indan)-4-one oxime acylate [13] produced in step (12), on reducing its oxime function, e.g., by reacting said compound with diborane in a solvent such as tetrahydrofuran (preferably at low temperature), yields a corresponding spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form, which on extracting with ether and treating said extract with an ethereal solution of a suitable (pharmacologically acceptable) acid, gives the corresponding acid addition salt form.
The compounds embraced by the spiro(cyclohexane-1,2'-indan)-4-amines and their acid addition salts [I(b)], immediately above, can be prepared by another method, as follows:
11'. A spiro(cyclohexane-1,2'-indan)-4-one [11] obtained in step (10) has its 4-keto function reduced, e.g., by mixing said compound in ethanol with sodium borohydride at moderate (room) temperature for from about 3 to about 8 hours, to produce a corresponding spiro(cyclohexane-1,2'-indan)-4-ol [14].
12'. Letting stand (preferably at low temperature for from about 3 to about 18 hours) a mixture of a spiro(cyclohexane-1,2'-indan)-4-ol [14] obtained in step (11') in an amine base (e.g., pyridine) and a lower alkyl sulfonyl halide (such as methanesulfonyl chloride), yields a corresponding spiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate [15].
13'. A spiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate [15] obtained in step (12') and sodium azide in a solvent such as dimethylformamide, on heating (at from 65° to about 100° C. for from about 4 to about 20 hours), yields a corresponding spiro(cyclohexane-1,2'-indan)-4-ylazide [16]; on reduction of the azido function of a thus produced compound [16], e.g., by reacting said compound with lithium aluminum hydride in a solvent such as tetrahydrofuran at moderate (room) temperature for from about 3 to about 10 hours, yields a corresponding spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form, which on extracting with ether and treating said extract with an ethereal solution of a suitable acid, gives the corresponding acid addition salt form.
The free base or acid addition salt forms of the spiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained as in step (13) or (13'), above, are employed as starting materials for preparing a variety of derivatives thereof, for example, in accordance with the methods set forth in (a) through (e) that follow.
a. Heating (e.g., under reflux for from about 8 to about 24 hours) a spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step (13) or (13') with a dihaloalkane, yields a corresponding (1-single ring nitrogen containing heterocyclo)-spiro(cyclohexane-1,2'-indan)-4-yl [I(b)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid, gives the corresponding acid addition salt thereof. For example, heating a spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] with 1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiodohexane, yields, respectively, an acid addition salt of a corresponding 1-[spiro(cyclohexane-1,2'-indane)-4-yl]piperidine [I(b)], a 1-[spiro(cyclohexane-1,2'-indane)-4-yl]pyrrolidine [I(b)] or a 1-spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine [I(b)], which can be converted to their acid addition salts in the manner described in the immediately preceding sentence.
b. The production of a compound selected from the group consisting of the free bases and acid addition salts of a 4-[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]alkanophenone of the formula ##SPC14##
wherein Ar, n and Z have the same meaning as above, comprises reacting (in the presence of an alkali metal iodide and an alkali metal carbonate) a corresponding compound obtained in step (13) or (13') selected from the group consisting of the free bases or acid addition salts of a compound of the formula ##SPC15##
wherein Z has the same meaning as above, with a corresponding compound of the formula ##SPC16##
wherein Ar, R and n have the same meaning as above and X is selected from the group consisting of chlorine and bromine, followed by hydrolyzing (i.e., deketalizing) a thus produced compound, e.g., with aqueous acid in an alkanol.
c. Reacting a spiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step (13) or (13'), haloformate (e.g., ethyl chloroformate, methyl bromoformate or propyl chloroformate) yields a corresponding lower alkyl spiro(cyclohexane-1,2'-indane)-4-carbamate having the formula ##SPC17##
wherein R and Z have the same meaning as above.
d. A lower alkyl spiro(cyclohexane-1,2'-indane)4-carbamate [I(b)], prepared as in (c) immediately above, is reduced, e.g., by heating it (under reflux) in a solvent such as tetrahydrofuran (for from about 8 to about 24 hours) with lithium aluminum hydride, to yield a corresponding spiro(cyclohexane-1,2'-indane)-4-yl-N-methylamine [I(b)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid gives a corresponding acid addition salt thereof.
e. Following the procedure of (b), above, but substituting the free base or acid addition salt of a spiro(cyclohexane-1,2'-indane)-4-yl-N-methylamine [I(b)] obtained as in (d) immediately above as starting material, yields a corresponding [spiro[cyclohexane-1,2'-indan]-2 through 5-yl-N-lower alkylamino]alkanophenone [I(b)], or an acid addition salt thereof.
The unsubstituted and substituted spiro(cyclohexane-1,2'-indan)-1'4-dione alkylene ketals [9] prepared in step (8) of Process B can be employed as starting materials for producing a variety of 1'-hydroxyspiro(cyclohexane-1,2'-indan) compounds [I(b)] by the procedures that follow.
1. A spiro(cyclohexane-1,2'-indan)-1'4-dione alkylene ketal [9] has its 1'-keto function reduced, e.g., by reacting said compound with lithium aluminum hydride in a solvent such as tetrahydrofuran at moderate (room) temperature for from about 3 to about 10 hours, yields a corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17].
2. A 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17] produced in step (1) has its ketal protective group removed by hydrolysis, e.g., by allowing said compound to stand for from about 4 to about 20 hours with an acid (such as hydrochloric acid) in a solvent such as acetone) at room temperature, to yield a corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one [18].
3. A 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one [18] prepared in step (2), on standing at room temperature for from about 5 to about 10 hours in a solvent such as tetrahydrofuran with an anhydride of a hydrocarbon carboxylic acid in the presence of an esterification catalyst (e.g., pyridine), yields a corresponding 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-one [19].
4. A 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-one [19] produced in step (3) has its 4-keto function reduced, e.g., by stirring said compound (in a solvent such as isopropanol) with sodium borohydride at moderate (room) temperature for from about 1/2 to about 4 hours, to give a corresponding 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol [20].
5. Letting stand (preferably in the cold for from about 4 to about 20 hours) a mixture of a 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol [20] obtained in step (4) in an amine base (e.g., pyridine and a lower alkyl sulfonyl halide (e.g., methanesulfonyl chloride), yield a corresponding 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate [21].
6. A 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate [21] obtained in step (5) and sodium azide in a solvent such as dimethylformamide, on heating (at from about 65° to about 100° C. for from about 4 to about 20 hours), yields a corresponding 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ylazide [22], which on reduction, e.g., by reaction with lithium aluminum hydride in a solvent such as tetrahydrofuran at room temperature for from 8 to about 16 hours, yields a corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form, which on extracting with ether and treating the extract with an ethereal solution of a suitable acid, (e.g., hydrochloric), gives the corresponding acid addition salt form.
The free base or acid addition salt forms of the 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained in step (6) immediately above, are employed as starting materials for preparing a variety of derivatives thereof, for example, in accordance with the methods set forth in (a) through (e) that follow.
a. Heating (e.g., under reflux for from about 8 to about 24 hours) a 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step (6) with a dihaloalkane, yields a corresponding (1-single ring nitrogen containing heterocyclo)-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl [I(b)], which on dissolving in ether and treating with an appropriate acid, gives the corresponding acid addition salt thereof. For example, heating a 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] with 1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiodohexane, yields, respectively, a corresponding 1'-hydroxy-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)], a 1'-hydroxy-1-[spiro(cyclohexane-1,2'-indane)-4-yl]pyrrolidine [I(b)] or a 1'-hydroxy-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine [I(b)], which are converted to their acid addition salts in the manner described in the immediately preceding sentence.
b. The production of a compound selected from the group consisting of the free bases and acid addition salts of a 4-[(1'-hydrospiro[cyclohexane-1,2'-indan]-4-yl)amino]alkanophenone [I(b)] comprises: reacting (in the presence of an alkali metal iodide and an alkali metal carbonate) a corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine [I(b)] obtained in step (6) with a corresponding 2,2-dialkyl-1,3-propanediol ketal of a ω-haloalkanophenyl ketone, followed by hydrolyzing a thus produced compound.
c. Reacting a 1'-hydroxy-4-[[spiro[cyclohexane-1,2'-4-amine [I(b)] obtained in step (6) in pyridine in the cold with a lower alkyl haloformate, yields a corresponding lower alkyl-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)].
d. A lower alkyl-1'-hydroxy-spiro(cyclohexane-1,2'-indane)-4-carbamate [I(b)], prepared as in (c) immediately above, is reduced by heating with lithium aluminum hydride, to yield a corresponding 1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamine [I(b)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid give a corresponding acid addition salt thereof.
e. Following the procedure of (b), above, but substituting the free base or acid addition salt of a 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkyl-amine [I(b)] obtained as in (d) immediately above as starting material, yields a corresponding 4-[1'-hydroxyspiro[cyclohexane-1,2'-indan]-2 through 5-yl-N-lower alkylamino]-alkanophenone [I(b)], or an acid addition salt thereof.
The unsubstituted and substituted 1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketals [17] prepared in step (1) of the process set forth immediately above, can be used as starting materials for producing a variety 1'-acetamido-spiro(cyclohexane-1,2'-indan) compounds by the procedures that follow.
1. A 1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [17] in a solvent such as tetrahydrofuran is treated in the cold with butyl lithium in a solvent such as pentane and a lower alkyl sulfonyl halide (such as methanesulfonyl chloride) in a solvent (e.g., tetrahydrofuran), to give a corresponding 1'-halospiro(cyclohexan-1,2'-indan)-4-one alkylene ketal [23].
2. A 1'-halospiro(cyclohexan-1,2'-indan)-4-one alkylene ketal [23] produced in step (1) is heated with sodium azide in a solvent such as dimethylformamide at from about 80° to about 100° C. for from about 15 to about 24 hours and the resulting azido intermediate recovered by conventional procedures and then reduced (e.g., with lithium aluminum hydride in a solvent such as tetrahydrofuran), to give a corresponding 1'-aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [24].
3. A 1'-aminospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [24] prepared in step (2) is acylated, e.g., by treating it with an anhydride of a hydrocarbon carboxylic acid (such as acetic anhydride) in the presence of a catalyst (such as pyridine), to give a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [25].
4. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [25] produced in step (3), is hydrolyzed, e.g., by standing at room temperature for from about 5 to about 20 hours with an acid such as hydrochloric acid in a solvent such as acetone, to give a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [26].
5. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [26] obtained in step (4) has its 4-keto function reduced, e.g., by reacting said compound with sodium borohydride in a solvent such as isopropanol at moderate (room) temperature for from about 3 to about 10 hours, to give a mixture of 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols [27], which are separated into their two isomers by conventional procedures, e.g., chromatography or fractional crystallization.
6. Letting either of the isomers of the 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols [27] obtained in step (5) stand for from about 3 to about 10 hours in an amine base (e.g., piperidine) with a lower alkyl sulfonyl halide (e.g., methanesulfonyl chloride, yields a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate [28].
7. A 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate [28] obtained in step (6) and sodium azide in a solvent such as dimethylformamide, on heating (at from about 65° to about 100° C. for from about 4 to about 20 hours), yields a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ylazide, which on reduction, e.g., by reaction with lithium aluminum hydride in a solvent such as tetrahydrofuran at room temperature for from about 8 to about 16 hours, yields a corresponding 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form, which on extracting with ether and treating said extract with an ethereal solution of a suitable acid (e.g., hydrochloric) gives the corresponding acid addition salt form.
The free base or acid addition salt forms of the 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained in step (7) immediately above, are employed as starting materials for preparing a variety of derivatives thereof, in the same manner as described above using the corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines [I(b)] as starting compounds set forth in (a) through (e) following step (6) of the synthesis of said 1'-hydroxyspiro compounds [I(b)]. By utilizing the aforesaid procedures, compounds such as the following are obtained:
a. 1'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidines [I(b)], 1'-acylamido-1-[spiro(cyclohexane)-1,2'-indan)-4-yl]pyrrolidines [I(b)] and 1'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimines [I(b)];
b. 4-[(1'-acylamidospiro[cyclohexane-1,2'-indan]-4-yl)aminoalkanophenones [I(b)] and acid addition salts thereof;
c. lower alkyl-1'-acylamidospiro(cyclohexane-1,2'-indane)-4-carbamates [I(b)];
d. 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamines [I(b)]; and
e. 4-[1'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamino]alkanophenones [I(b)], and acid addition salts thereof.
The free base or acid addition salt of a 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine [I(b)], also named an N-[4-aminospiro[cyclohexane-1,2'-indan]-5'-yl]acylamide [I(b)], is prepared from a spiro(cyclohexane-1,2'-indan)-4-one [11] starting compound, by employing the procedures that follow.
1. A spiro(cyclohexane-1,2'-indan)-4-one [11] [prepared as above in step (10) of the first process for producing the compounds of Process B] in the cold (at about 0° C.) in trifluoroacetic acid, has nitric acid added thereto and the low temperature maintained for from about 1 to about 4 hours, to yield a corresponding 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29] .
2. A 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one [29] produced in step (1) is catalytically reduced (e.g., with hydrogen in the presence of palladium on carbon, in a solvent such as ethyl acetate), to give a corresponding 5'-aminospiro(cyclohexane-1,2'-indan)-4-one [30] .
3. A 5'-aminospiro(cyclohexane-1,2'-indan)-4-one [30] prepared in step (2) is treated in the cold (at about 0° C.) with an amine base such as pyridine and the anhydride of a hydrocarbon carboxylic acid (e.g., acetic anhydride) for from about 3 to about 8 hours, to give a corresponding 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [31] .
4. A 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-one [31] prepared in step (3) has its 4-keto function reduced, e.g., by reacting said compound with sodium borohydride in a solvent such as isopropanol at moderate (room) temperature for from about 3 to about 10 hours, to give a corresponding 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol [32] .
Using a thus produced 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol [32] as starting material and employing the procedures described in steps (6) and (7) and (a) through (e), above, for preparing the corresponding 1'acylamido compounds, yields 5'-acylamido counterparts such as
6. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonates [33] ;
7. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ylazides [34] and 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines [I(b)] (as free base or acid addition salt);
a. 5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidines [I(b)], 5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidines [I(b)] and 5'-acylamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimines [I(b)];
b. 4-[[5'-acylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]alkanophenones [I(b)] and acid addition salts thereof;
c. lower alkyl-5'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates [I(b)];
d. 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamines [I(b)]; and
e. 4-[5'-acylamidospiro[cyclohexane-1,2'-indan)-4-yl-N-lower alkylamino]alkanophenones [I(b)], and acid addition salts thereof.
The unsubstituted or substituted spiro(cyclohexane-1,2'-indan)-1'4-dione alkylene ketals [9][prepared as in step (8) of the first process for producing the compounds of Process B] can be employed as starting materials for preparing a variety of 1'-exomethylenespiro(cyclohexane-1,2'-indan) compounds by the procedures that follow.
1. A spiro(cyclohexane-1,2'-indan)-1'4-dione-4-alkylene ketal (9) in a solvent such as tetrahydrofuran, on addition to a methyl magnesium halide (such as methyl magnesium bromide) in a solvent such as ether, after standing at moderate (room) temperature for from about 6 to about 24 hours, gives a corresponding 1'-hydroxy-1'-methyl-spiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [40] .
2. A 1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one alkylene ketal [40] produced in step (1), on stirring with an acid (such as hydrochloric) in a solvent (such as acetone) at room temperature for from about 4 to about 20 hours, yields a corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41 .
3. A 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41] prepared in step (2) has its 4-keto function reduced, e.g., by stirring said compound (in a solvent such as isopropanol with sodium borohydride at moderate (room) temperature for from about 2 to about 10 hours, to give a corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42] .
4. Letting stand (preferably in the cold for from about 4 to about 20 hours) a mixture of a 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol [42] obtained in step (3) in an amine base (such as pyridine) and a lower alkyl sulfonyl halide (such as methanesulfonyl chloride), yields a corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol lower alkyl sulfonate [43] .
5. A 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonate [43] obtained in step (4) and sodium azide in a solvent such as dimethylformamide, on heating at from about 65° to about 100°C. for from about 4 to about 20 hours, gives a corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ylazide [44], which on reduction, e.g., with lithium aluminum hydride in a solvent such as tetrahydrofuran at room temperature for from about 4 to about 16 hours, yields a corresponding 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine [I(b)] in its free base form, which on extracting with ether and treating said extract with an ethereal solution of a suitable acid (e.g., hydrochloric), gives the corresponding acid addition salt form.
The free base or acid addition salt forms of 1'-exo methylenespiro(cyclohexane-1,2'-indan)-4-amines [I(b)] obtained in step (5) immediately above, are employed as starting materials for preparing a variety of derivatives thereof, in the same manner as described above using the corresponding 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines [I(b)] as starting compounds set forth in (a) through (e) following step (6) of the synthesis of said 1'-hydroxyspiro compounds [I(b)]. By following the aforesaid procedures, there are obtained 1'-exo-methylene counterparts such as
a. 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-piperidines [I(b)], 1'-exo-methylenespiro(cyclohexane-1,2'-indan)pyrrolidines [I(b) ] and 1'-exo-methylenespiro(cyclohexane-1,2'-indan)hexamethyleneimines [I(b)];
b. alkanophenones of 1'-exo-methylenespiro(cyclohexane-1,2'-indan-4-amine [I(b)], also names 4-[[1'-methylenespiro(cyclohexan-1,2'-indan)-4-yl]amino]alkanophenones [I(b)], and acid additon salts thereof;
c. lower alkyl 1'-exo-methylenespiro(cyclohexane-1,2'-indane)-4-carbamates [I(b)];
d. 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamines [I(b)]; and
e. 4-[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl-N-lower alkylamino]alkanophenones [I(b)] and acid addition salts thereof.
Process C
The following sequence of formulae illustratively represents procedures for the preparation of compounds of Formula I(c). ##SPC18##
wherein Ar, n, --N , R, X and Z have the same meaning as in Process A, above.
The compounds embraced by Formula I(c) of the flow-sheet designated Process C, above, are prepared by the procedures indicated therein, employing the methods and reactions described below.
1. The first step of the process comprises reducing a 4-benzyl (or substituted benzyl)-4-carboalkoxy-1-cyclohexanone alkylene ketal [5] [prepared as above in step (4) of the first process for producing the compounds of Process B], for example, by reacting it in a solvent such as tetrahydrofuran with lithium aluminum hydride and heating the reaction mixture (at reflux) for from about 3 to about 8 hours, to give a corresponding 4-benzyl (or substituted benzyl)-4-hydroxymethylcyclohexan-1-one alkylene ketal (1).
2. A 4-benzyl (or substituted benzyl)-4-hydroxymethyl-cyclohexan-1-one alkylene ketal (1) obtained in step (1) in an amine base (such as pyridine) on standing in the cold with a lower alkyl sulfonyl halide (such as methanesulfonyl chloride), yields a corresponding 4-benzyl (or substituted benzyl)-4-hydroxymethylcyclohexan-1-one, alkylene ketal, lower alkyl sulfonate (2).
3. A 4-benzyl (or substituted benzyl)-4-hydroxymethylcyclohexan-1-one, alkylene ketal lower alkyl sulfonate (2) prepared in step (2) on heating for from about 10 to about 18 hours at from about 100° to about 165° C. with potassium cyanide in a solvent such as hexamethylphosphoramide, yields a corresponding 4-benzyl-4-cyanomethylcyclohexan-1-one alkylene ketal (3).
4. A thus produced 4-benzyl-4-cyanomethylcyclohexan-1-one alkylene ketal (3) obtained in step (3) on saponification, e.g., by heating it with an alkali metal hydroxide (such as potassium hydroxide) in a solvent such as an alkalene glycol (e.g., ethylene glycol) for from about 8 to about 18 hours, gives a corresponding 4-benzylcyclohexan-4-acetic acid-1-one alkylene ketal (4).
5. A 4-benzylcyclohexane-4-acetic acid-1-one alkylene ketal (4) prepared in step (4) is deketalized, e.g., by stirring it with a dilute aqueous acid (e.g., hydrochloric) in acetone at moderate (room) temperature for from about 36 to about 72 hours, to give a corresponding 4-benzylcyclohexan-4-acetic acid-1-one (5).
6. A 4-benzylcyclohexane-4-acetic acid-1-one (5) prepared in step (5) is cyclized, e.g., by allowing it to stand at moderate (room) temperature for from about 15 to about 80 hours with liquid hydrogen fluoride, to yield a corresponding 3',4'-dihydroxpiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6).
7. A 3', 4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4', 4-dione (6) obtained in step (6) is monoketalized at the non-conjugated least hindered carbonyl function, e.g., by heating (at reflux) in a solvent such as benzene with an alkylene glycol (in the presence of a catalyst such as p-toluenesulfonic acid), to yield a corresponding 3', 4', -dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4 -dione, 4-(ethylene ketal) (7).
8. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4 -dione, 4-(ethylene ketal) (7) prepared in step (7) is reduced at the 1'-position, e.g., by heating (at reflux) for from about 1/2 to about 3 hours with hydrazine hydrate and a base (e.g., potassium hydroxide) in a solvent such as an alkylene glycol (e.g., ethylene glycol), to give a corresponding 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal (8).
9. In this step, a 3',4'4'-dihydrospiro[cyclohexane-1,2'-(1'H)-naphthalen]-4-one, ethylene ketal (8) obtained in step (8) has its ketal protective group removed by hydrolysis, e.g., by heating it (at reflux) for from about 8 to about 20 hours with an acid (such as hydrochloric) in a solvent (such as acetone), to yield a corresponding 3',4'4'-dihydrospiro[cyclohexane-1,2'(1'H)-napththalen]-4-one (9).
10. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one produced, e.g., by mixing said compound in a solvent such as isopropanol with sodium borohydride at moderate (room) temperature, to give a corresponding 3' ,4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10).
11. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol obtained in step (10) on standing in the cold (at about 0° C.) for from about 3 to about 6 hours in an amine base (e.g., pyridine) with a lower alkyl sulfonyl halide (e.g., methanesulfonyl chloride), gives a corresponding 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol lower alkyl sulfonate (11).
12. A 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol lower alkyl sulfonate prepared in step (11) and sodium azide in a solvent such as dimethylformamide, on heating (at from about 65° to about 100° C. for from about 4 to about 20 hours); yields a corresponding 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylazide, which on reaction with lithium aluminum hydride in a solvent such as tetrahydrofuran at moderate (room) temperature for from about3 to about 10 hours, yields a corresponding 3',4 '-dihydrospiro(cyclohexane-1,2'(1'H)-naphthalen)-4-ylamine [I(c)] in its free base form. On treating an ether extract of a thus produced compound with an ethereal solution of a suitable (pharmacologically acceptable) acid, its acid addition salt form is obtained.
The free base or acid addition salt forms of the 3',4 '-dihydrospirol[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamines [I(c)] obtained as in step (12), above, are employed as starting materials for producing a variety of derivatives thereof, for example, in accordance with the methods described in (a) through (e) that follow.
a. Heating (e.g., under reflux for from about 8 to about 24 hours) a 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] obtained in step (12) with a dihaloalkane, gives a corresponding (1-single ring nitrogen containing heterocyclo)-3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl [I(c)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid, yields the corresponding acid addition salt. For example, heating a 3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c) ] with 1,5-diiodopentane, 1,4-dibromobutane or 1,6-diiododhexane, yields, respectively, a corresponding 1-[3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)], a 1-[3',4 '-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]pyrrolidine [I(c)] or a 1-[3',4 '-dihydrospiro(cyclohexane-1,2'(1'H)-naphthalen)-4-yl[hexamethyleneimine [I(c)], which can be converted to their acid addition salts in the manner described in the immediately preceding sentence.
b. The production of a compound selected from the group consisting of the free bases and acid addition salts of a 4-[(3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl)amino]alkanophenone of the formula ##SPC19##
wherein Ar, n and Z have the same meaning as above, comprises reacting (in the presence of an alkali metal iodide and an alkali metal carbonate) a corresponding compound obtained as in step (12) selected from the group consisting of the free bases and acid addition salts of a compound of the formula ##SPC20##
wherein Z has the same meaning as above, with the corresponding compound of the formula ##SPC21##
wherein Ar, R and n have the same meaning as above and X is selected from the group consisting of chlorine and bromine, followed by hydrolyzing (i.e., deketalizing) a thus produced compound, e.g., with aqueous acid in an alkanol.
c. Reacting a 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] obtained as in step (12), in pyridine in the cold with a lower alkyl haloformate (e.g., ethyl chloroformate, methyl bromoformate, propyl chloroformate or isopropyl bromoformate), yields a corresponding lower alkyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate of the formula ##SPC22##
wherein R and Z have the same meaning as above.
d. A lower alkyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)], prepared as in (c) immediately above, is reduced, e.g., by heating it in a solvent such as tetrahydrofuran (under reflux for from about 6 to about 24 hours) with lithium aluminum hydride, to yield a corresponding 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine [I(c)], which on dissolving in ether and treating with an ethereal solution of an appropriate acid gives a corresponding acid addition salt thereof.
e. Following the procedure of (b), above, but substituting as starting material the free base or acid addition salt of a 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino [I(c)], obtained as in (d) immediately above, yields a corresponding 4-[(3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-2 through 5-yl-N-methylamino]alkanophenone [I(c)], or an acid addition salt thereof.
All of the compounds included within Formula I (a, b and c) of the flow-sheets, above, can be isolated from their respective reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water rand separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the products can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as, methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like.
The free bases and acid addition salts of the novel compounds of Formula I are useful as central nervous system (CNS) depressants when administered to humans and animals. They possess tranquilizing activity and are consequently useful in humans for controlling anxiety and schizophrenia; in animals the aforesaid compounds are useful for their calming effects and can be given to reduce aggressive behavior. These compounds have been shown to possess CNS depressing activity (especially tranquilizing activity) via the loss of righting reflex, traction, chimney, dish and pedestal tests carried out in the manner described by Boissier et al. in Medicina Experimentalis 4, 145 (1961).
Tranquilizing effects of compounds of this invention are shown by the following tests in mice:
Chimney test: [Med. Exp. 4, 145 (1961)]: The test determines the ability of mice to back up and out of a verticle glass cylinder within 30 seconds. At the effective dosage, 50 percent of the mice failed doing it.
Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicates tranquilization. ED 50 equals the dose of test compound at which 50 percent of the mice remain in the dish.
Pedestal test: The untreated mouse leaves a standard pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute.
Nicotine antagonism test: Mice in a group of 6 are injected with the test compound. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death.
The following compounds typical of this invention have (by intraperitoneal injection) ED 50 as shown in the table below.
______________________________________ ED.sub.50 (in mg./kg.)COMPOUND Ch D P Ni______________________________________4'-fluoro-4-[(3',4'-dihydro-spiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl)amino]butyro-phenone hydrochloride [I(a)] 25 10 16 54'-fluoro-4-[methyl(spiro-[cyclohexane-1,2'-indan)-4-yl)amino] butyrophenone hydro-chloride [I(b)] 16 3.6 9 44'-fluoro-4-[(3',4'-dihydro-spiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl)amino]butyro-phenone hydrochloride [I(c)] 9.9 9.9 12.5 7______________________________________ Ch = chimney test D = dish test P = pedestal test Ni = nicotine antagonism (3) test
As tranquilizers, the compounds of Formula I (a, b and c) and their pharmacologically acceptable acid addition salts can be prepared and administered to humans, mammals, birds and animals in a wide variety of oral or parenteral dosage forms, singly or in admixture with other coacting compounds, in doses of from about 10 mg. to about 100 mg./kg., depending on the severity of the condition being treated and the recipient's response to the medication.
The free bases and pharmacologically acceptable acid addition salts of the compounds of Formula I (a, b and c) are also useful in lowering blood pressure when administered to humans and animals. This activity makes them useful in the treatment of essential hypertension. These compounds have been shown to possess hypotensive activity when tested in the manner described by Weeks and Jones, in Proc. Soc. Exp. Biol. and Med. 104, 646 (1960). The following compounds typical of this invention have (by oral administration to rats) MED 100 (minimal effective dose) as shown in the table below.
______________________________________COMPOUND MED.sub.100 (in mg./kg.)______________________________________4'-fluoro-4-[(spiro[cyclohexane1,2'-indan]-4-yl)amino]butyro-phenone hydrochloride [I(b)] 504'-fluoro-4-[[1'-hydroxyspiro-[cyclohexane-1,2'-indan]-4-yl]-amino]butyrophenone hydrochloride[I(b)] 50______________________________________
As hypotensives, the compounds of Formula I (a, b and c) and their pharmacologically acceptable acid addition salts can be prepared and administered to humans, mammals, birds and animals in a wide variety of oral or parenteral dosage forms, singly or in admixture with other coacting compounds in doses of from about 10 mg. to about 100 mg./kg., depending on the severity of the condition being treated and the recipient's response to the medication.
The compounds of Formula I (a, b and c) (used as tranquilizers and/or hypotensives) can be administered with a pharmaceutical carrier which can be solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups, or elixirs.
DETAILED DESCRIPTION
The following examples are illustrative of the manner of making and using the invention and set forth the best mode comtemplated by the inventor of carrying out his invention, but are not to be construed as limiting the scope thereof, as obvious modifications and equivalents will be apparent to those skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.
EXAMPLE 1A
4-Cyano-4-phenylcyclohexano(b)
To an ice and methanol cooled solution of 4 g. (0.0205 M) of 4-cyano-4-phenylcyclohexanone (a) (prepared as in J. Chem. Soc. 1959, 1446) in 150 ml. of tetrahydrofuran, a suspension of 1 g. of sodium borohydride in 50 ml. of tetrahydrofuran is added in 5 ml. portions in the course of about 10 minutes. The mixture is stirred for about 30 minutes and allowed to stand in the cold for about 18 hours. The bulk of the solvent is removed under vacuum and the residue treated with water. The precipitate is extracted with ether and the organic fraction washed successively with 2.5 N hydrochloric acid solution, saturated aqueous sodium bicarbonate, water and brine and then evaporated to dryness. The residue is recrystallized with benzene to give 1.81 g. (43.8% yield) of 4-cyano-4-phenylcyclohexanol (b) melting at 103° to 111° C.
Anal. Calcd. for C 13 H 15 NO: C, 77.58; H, 7.51; N, 6.96
Found: C, 77.98; H, 7.34; N, 6.58.
Following the procedure of Example 1A but substituting other 4-cyano-4-phenylcyclohexanones (a) as starting materials, such as
1. 4-cyano-4-(4-bromophenyl)cyclohexanone(a),
2. 4-cyano-4-(3-fluorophenyl)cyclohexanone(a),
3. 4-cyano-4-(3-methylphenyl)cyclohexanone(a),
4. 4-cyano-4-(2-propylphenyl)cyclohexanone(a),
5. 4-cyano-4-(4-ethoxyphenyl)cyclohexanone(a),
6. 4-cyano-4-(3-aminophenyl)cyclohexanone(a),
7. 4-cyano-4-(4-methylaminophenyl)cyclohexanone(a),
8. 4-cyano-4-(5-ethylaminophenyl)cyclohexanone(a),
9. 4-cyano-4-(2-aceylamidophenyl)cyclohexanone(a), and the like,
yields, respectively,
1. 4-cyano-4-(4-bromophenyl)cyclohexanol(b),
2. 4-cyano-4-(3-fluorophenyl)cyclohexanol(b),
3. 4-cyano-4-(3-methylphenyl)cyclohexanol(b),
4. 4-cyano-4-(2-propylphenyl)cyclohexanol(b),
5. 4-cyano-4-(4-ethoxyphenyl)cyclohexanol(b),
6. 4-cyano-4-(3-aminophenyl)cyclohexanol(b),
7. 4-cyano-4-(4-methylaminophenyl)cyclohexanol(b),
8. 4-cyano-4-(5-ethylaminophenyl)cyclohexanol(b),
9. 4-cyano-4-(2-acetylamidophenyl)cyclohexanol(b), and the like.
EXAMPLE 2A
4-Hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c)
A solution of 2 g. (0.01 M) of 2 g. of 4-cyano-4-phenylcyclohexanol(b) (obtained as in Example 1A) in tetrahydrofuran is added to a suspension of 0.52 g. (0.015 M) of lithium aluminum hydride in 10 ml. of tetrahydrofuran. The mixture is stirred at room temperature for about 15 minutes, at reflux for about 1 hours, and then cooled in an ice bath. To it is added successively 0.52 ml. of water, 0.52 ml. of 15% aqueous sodium hydroxide solution and 1.56 ml. of water. The precipitated inorganic gel is collected on a filter, washed twice with ether and the combined filtrates evaporated to dryness. The residue is treated with 20 ml. of 1:1 acetic acid:water and 2 drops of concentrated sulfuric acid and heated on a steam bath for about 30 minutes. The mixture is cooled to room temperature, extracted thoroughly with methylene chloride, the combined extracts washed successively with water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residual product, 1.37 g. (66% yield) of 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c) has a melting point of 74° to 76° C.
Anal. Calcd. for C 13 H 16 O 2 : C, 76.44; H, 7.90. l.
Found: C, 76.06; H, 7.84.
Following the procedure of Example 2A but substituting other 4-cyano-4-phenylcyclohexanols(b) as starting materials, such as
1. 4-cyano-4-(5-chlorophenyl)cyclohexanol(b),
2. 4-cyano-4-(4-ethylphenyl)cyclohexanol(b),
3. 4-cyano-4-(3-propoxyphenyl)cyclohexanol(b),
4. 4-cyano-4-(5-isopropylaminophenyl)cyclohexanol(b),
5. 4-cyano-4-(4-propionylamidophenyl)cyclohexanol(b), and the like,
yields, respectively,
1. 4-hydroxy-1-(5-chlorophenyl)-1-cyclohexanecarboxaldehyde(c),
2. 4-hydroxy-1-(4-ethylphenyl)-1-cyclohexanecarboxaldehyde(c),
3. 4-hydroxy-1-(3-propoxyphenyl)-1-cyclohexanecarboxaldehyde(c),
4. 4-hydroxy-1-(5-isopropylaminophenyl)-1-cyclohexanecarboxaldehyde(c),
5. 4-hydroxy-1-(4-propionylamidophenyl-1-cyclohexanecarboxaldehyde(c),
and the like.
EXAMPLE 3A
Ethyl-4-hydroxy-1-phenylcyclohexaneacrylate(f)
1. To a partial solution of 3.51 g. (0.017 M) of 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde(c) (obtained as in Example 2A) in 35 ml. of ether, 2 g. of dihydropyan and 0.11 g. of p- toluenesulfonic acid is added. After stirring for a short time at room temperature, complete solution is attained. The reaction mixture after standing at room temperature for about 4 hours is washed first with saturated aqueous sodium bicarbonate solution then with brine and evaporated to dryness. The residue is recrystallized once from petroleum ether to give 4.53 g. of 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde pyranyl ether (d), having a melting point of 43.5° to 54° C.
2. A solution of 3.52 g. (0.158M) of triethyl phosphonacetate in 45 ml. of tetrahydrofuran is prepared and 0.67 g. of 56% sodium hydride added. The mixture is stirred at room temperature for about 30 minutes and a solution of (0.158M) of the 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde pyranyl ether (d) [prepared as in (1), above], in 45 ml. of tetrahydrofuran added. Following about 4 hours of heating at reflux and about 15 hours of standing at room temperature, most of the solvent is removed under vacuum and the residue taken up in ether and water. The organic layer is washed with water and brine and then evaporated to dryness to give methyl-4-hydroxy-1-phenylcyclohexaneacrylate tetrahydropyranyl ether (e).
3. A solution of the methyl-4-hydroxy-1-phenylcyclohexaneacrylate tetrahydropyranyl ether (e) [prepared as in (2), above,] in 75 ml. of methanol and 7.5 ml. of 2.5 N hydrochloric acid is stirred at room temperature for about 1 hour and then most of the methanol removed under vacuum. The residue is dissolved in ether and water and the organic layer washed successively with water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is chromatographed on a column of 500 g. of silica gel (silicic acid) with elution first by 5.5 l. of methylene chloride, then 20% ethyl acetate:methylene chloride. The more polar fractions found similar by thin layer chromatography (TLC) are combined to yield 3.5 g. (80% yield) of ethyl-4-hydroxy-1-phenylcyclohexaneacrylate(f) as a gum.
Following the procedure of Example 3A but substituting other 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehydes(c) as starting materials, such as
1. 4-hydroxy-1-(3-bromophenyl)-1-cyclohexanecarboxaldehyde(c),
2. 4-hydroxy-1-(4-propylphenyl)-1-cyclohexanecarboxaldehyde(c),
3. 4-hydroxy-1-(5-ethoxyphenyl)-1-cyclohexanecarboxaldehyde(c),
4. 4-hydroxy-1-(3-methylaminophenyl)-1-cyclohexanecarboxaldehyde(c),
5. 4-hydroxy-1-(2-formylamidophenyl-1-cyclohexanecarboxaldehyde(c), and the like,
yields, respectively,
1. ethyl-4-hydroxy-1-(3-bromophenyl)cyclohexaneacrylate(f),
2. ethyl-4-hydroxy-1-(4-propylphenyl)cyclohexaneacrylate(f),
3. ethyl-4-hydroxy-1-(5-ethoxyphenyl)cyclohexaneacrylate(f),
4. ethyl-4-hydroxy-1-(3-methylaminophenyl)cyclohexaneacrylate(f),
5. ethyl-4-hydroxy-1-(2-formylamidophenyl)cyclohexaneacrylate(f), and the like.
EXAMPLE 4A
Ethyl-4-hydroxy-1-phenylcyclohexane-3-propionate(g)
A mixture of 3.5 g. (0.0128 M) of ethyl-4-hydroxy- 1-phenylcyclohexaneacrylate(f) (prepared in Example 3A), 150 ml. of ethyl acetate and 0.4 g. of palladium on carbon catalyst is hydrogenated until the theoretical amount of hydrogen is consumed. The catalyst is collected on a filter and the filtrate evaporated to dryness to give 3.36 g. (95% yield) of ethyl-4-hydroxy-1-phenylcyclohexane-3-propionate(g) as a gum.
Following the procedure of Example 4A but substituting other alkyl-4-hydroxy-1-phenylcyclohexaneacrylates(f) as starting materials, such as
1. methyl-4-hydroxy-1-(2-chlorophenyl)cyclohexaneacrylate(f),
2. propyl-4-hydroxy-1-(3-methoxyphenyl)cyclohexaneacrylate(f),
3. methyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexaneacrylate(f),
4. ethyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexaneacrylate(f), and the like,
yields, respectively,
1. methyl-4-hydroxy-1-(2-chlorophenyl)cyclohexane-3-propionate(g),
2. propyl-4-hydroxy-1-(3-methoxyphenyl)cyclohexane-3-propionate(g),
3. methyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionate(g),
4. ethyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionate(g), and the like.
EXAMPLE 5A
4-Hydroxy-1-phenylcyclohexane-3-propionic acid (h)
A solution of 0.68 g. (0.0025 M) of ethyl-4-hydroxy-1-phencyclohexane-3-propionate(g) (obtained in Example 4A) and 1 ml. of 50% sodium hydroxide in 10 ml. of methanol is heated at reflux for about 20 hours. Most of the solvent is removed under vacuum and the residue dissolved in water. The aqueous solution is washed with ether and made acidic with concentrated hydrochloric acid. A solid precipitate is collected on a filter and recrystallized from benzene to give 0.44 g. (71% yield) of 4-hydroxy-1-phenylcyclohexane-3-propionic acid (h) having a melting point of 153.5° to 155° C.
Anal. Calcd. for C 15 H 20 O: C, 72.55; H, 8.12.
Found: C, 72.47; H, 8.05.
Following the procedure of Example 5A but substituting other alkyl-4-hydroxy-1-phenylcyclohexane-3-propionates (g) as starting materials, such as
1. methyl-4-hydroxy-1-(3-fluorophenyl)cyclohexane-3-propionate(g),
2. isopropyl-4-hydroxy-1-(4-ethoxyphenylcyclohexane-3-propionate(g),
3. ethyl-4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionate(g),
4. propyl-4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionate(g), and the like,
yields, respectively,
1. 4-hydroxy-1-(3-fluorophenyl)cyclohexane-3-propionic acid(h),
2. 4-hydroxy-1-(4-ethoxyphenyl)cyclohexane-3-propionic acid(h),
3. 4-hydroxy-1-(5-ethylaminophenyl)cyclohexane-3-propionic acid(h),
4. 4-hydroxy-1-(4-acetylamidophenyl)cyclohexane-3-propionic acid(h), and the like.
EXAMPLE 6A
4-Oxo-1-phenylcyclohexane-3-propionic acid(i)
To a mechanically stirred, ice cooled partial solution of 2.36 g. (0.0095 M) of 4-hydroxy-1-phenylcyclohexane-3-propionic acid(h) (prepared as in Example 5A) in acetone, 5 ml. of Jones reagent (chromium trioxide-sulfuric acid) is added in the course of about 5 minutes. Most of the solvent is removed under vacuum and the residue dissolved in ether and water. The organic layer is washed with water and brine, evaporated to dryness and the residue recrystallized from methylene chloride: Skellysolve B to give 2.13 g. (91.2% yield) of 4-oxo-1-phenylcyclohexane-3-propionic acid(i) having a melting point of 139° to 140.5° C.
Anal. Calcd. for C 15 H 18 O 3 : C, 73.14; H, 7.37.
Found: C, 72.49; H, 7.27.
Following the procedure of Example 6A but substituting other 4-hydroxy-1-phenylcyclohexane-3-propionic acids(h) as starting materals, such as
1. 4-hydroxy-1-(3-bromophenyl) cyclohexane-3-propionic acid(h),
2. 4-hydroxy-1-(3-ethylphenyl)cyclohexane-3-propionic acid(h),
3. 4-hydroxy-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(h), and the like, yields, respectively,
1. 4-oxo-1-(2-bromophenyl)cyclohexane-3-propionic acid(i),
2. 4-oxo-1-(3-ethylphenyl)cyclohexane-3-propionic acid(i),
3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(i), and the like.
EXAMPLE 7A
4-Cyano-4-phenylcyclohexanone, ethylene ketal(j)
A mixture of 10 g. (0.05 M) of 4-cyano-4-cyano-4-phenylcyclohexanone(a), 2.85 ml. [3.16 g. (0.51M)] of ethylene glycol and 0.12 g. of p-toluenesulfonic acid in 90 ml. of benzene is heated at reflux under a Dean-Stark trap for about 6 hours. The solution is allowed to cool and then washed successively with sodium bicarbonate solution, water and brine. The organic layer is evaporated to dryness and the residue recrystallized from cyclohexane to give 11.27 g. (92.7% yield) of 4-cyano-4-phenylcyclohexanone, ethylene ketal(j), having a melting point of 120° to 122.5° C.
Anal. Calcd. for C 15 H 17 NO 2 : C, 74.05; H, 7.04; N, 5.76
Found: C, 74.10; H, 6.98; N, 5.77.
Following the procedure of Example 7A but substituting other 4-cyano-4-phenylcyclohexanones(a) as starting materials, such as
1. 4-cyano-4-(4-chlorophenyl)cyclohexanone(a),
2. 4-cyano-4-(4-methoxyphenyl)cylohexanone(a),
3. 4-cyano-4-(3-ethylaminophenyl)cyclohexanone(a),
4. 4-cyano-4-(2-propionylamidophenyl)cyclohexanone(a), and the like,
yields, respectively,
1. 4-cyano-4-(4-chlorophenyl)cyclohexanone, ethylene ketal(j),
2. 4-cyano-4-(4-methoxyphenyl)cyclohexanone, ethylene ketal(j),
3. 4-cyano-4-(3-ethylaminophenyl)cyclohexanone, ethylene ketal (j),
4. 4-cyano-4-(2-propionylamidophenyl)cyclohexanone, ethylene ketal(j), and the like.
EXAMPLE 8A
4-Oxo-1-phenylcyclohexanecarboxaldehyde, 4-ethylene ketal(k)
To a suspension of 0.16 g. (0.0014 M) of lithium aluminum hydride in 10 ml. of tetrahydrofuran, 2 g. (0.0082 M) of 4-cyano-4-phenylcyclohexanone ethylene ketal(j) (prepared as in Example 7A) in 100 ml. of tetrahydrofuran is added in the course of about 15 minutes. The mixture is stirred at room temperature for about 1.75 hours and then cooled in an ice bath, and then 0.16 ml. of water, 0.16 ml. of 15% aqueous sodium hydroxide solution and 0.48 ml. of water added successively, The inorganic gel is collected on a filter, rinsed with ether and the combined filtrates evaporated to dryness. The residue in 30 ml. of tetrahydrofuran and 3 ml. of 2.5 N hydrochloric acid is stirred at room temperature for about 15 minutes, treated with 1 g. of sodium bicarbonate and then evaporated to dryness under vacuum. Ether is added to the residue, the organic portion separated and evaporated to dryness. The residue is chromatographed on silica gel, eluted with 1% ethyl acetate: methylene chloride and the more polar crystalline fractions combined to yield 0.87 g. (86.4 % of theoretical) of 4-oxo-1-phenylcyclohexanecarboxaldehyde, 4-ethylene ketal(k), having a melting point of 56° to 64° C. and nuclear magnetic resonance (NMR) and infrared (IR) spectra in agreement with the expected structure of the compound.
Following the procedure of Example 8A but substituting other 4-cyano-4-phenylcyclohexane ethylene ketals(j) as starting materials, such as
1. 4-cyano-4-(3-fluorophenyl)cyclohexanone, ethylene ketal(j),
2. 4-cyano-4-(2-ethylphenyl)cyclohexanone, ethylene ketal(j),
3. 4-cyano-4-(4-propylaminophenylcyclohexanone, ethylene ketal(j),
4. 4-cyano-4-(5-acetylamidophenyl)cyclohexanone, ethylene ketal(j), and the like,
yields, respectively,
1. 4-oxo-1-(3-fluorophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),
2. 4-oxo-1-(2-ethylphenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),
3. 4-oxo-1-(4-propylaminophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),
4. 4-oxo-1-(5-acetylamidophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k), and the like.
EXAMPLE 9A
Ethyl -4-oxo-1-phenylcyclohexaneacrylate, ethylene ketal(l)
To a solution of 4.74 g. (0.021 M) of triethyl phosphonoacetate in 60 ml. of tetrahydrofuran, 0.89 g. of 57% sodium hydride is added. Following about 10 minutes of stirring at room temperature a solution of 5.2 g (0.021 M) of 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-ethylene ketal(k) (prepared as in Example 8A) in 60 ml. of tetrahydrofuran is added. The solution is stirred at reflux for about 4 hours and at room temperature for about 18 hours. Most of the solvent is removed under vacuum, and the residue dissolved in ether and water. The organic layer is washed with water and brine and then evaporated to dryness. The residue is chromatographed over a column of 700 ml. of silica gel and eluted, first, with 1,600 ml. of Skellysolve B, then with 4 l. of 5% acetone: Skellysolve B. The ultraviolet absorbing fractions found to be alike by TLC are combined to give 6.38 g. (96% yield) of ethyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketal(l.) as a gum.
Following the procedure of Example 9A but substituting other 4-oxo-1-phenylcyclohexanecarboxaldehyde 4-ethylene ketals(k) as starting materials, such as
1. 4-oxo-1-(2-bromophenyl)cyclohexanecarboxaldehyde, ethylene ketal(k),
2. 4-oxo-1-(3-ethoxyphenyl)cyclohexanecarboxaldehyde, ethylene ketal(k), and the like, yields, respectively,
1. ethyl-4-oxo-1-(2-bromophenyl)cyclohexaneacrylate, ethylene ketal(1),
2. ethyl-4-oxo-1-(3-ethoxyphenyl)cyclohexaneacrylate, ethylene ketal(l), and the like.
EXAMPLE 10A
Ethyl-4-oxo-1-phenylcyclohexane-3-propionate, ethylene ketal(m)
A mixture of 6.38 g. (0.0202 M) of ethyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketal(l) (obtained in Example 9A), 0.63 g. of 10% palladium on carbon catalyst and 150 ml. of ethyl acetate is shaken under an atomsphere of hydrogen until the theoretical amount is consumed. The catalyst is collected on a filter and the filtrate evaporated to dryness to give 6.38 g. (about 100% of theoretical yield) of ethyl-4-oxo-1-phenylcyclohexane-3-propionate, ethylene ketal(m) as a crude oil.
Following the procedure of Example 10A but substituting other alkyl-4-oxo-1-phenylcyclohexaneacrylate ethylene ketals(m) as starting materials, such as
1. ethyl-4-oxo-1-(3-methylphenyl)cyclohexaneacrylate, ethylene ketal(l), and the like,
yields,
1. ethyl-4-oxo-1-(3-methylphenyl)cyclohexane-3-propionate, ethylene ketal(m), and the like.
EXAMPLE 11A
4-Oxo-1-phenylcyclohexane-3-propionic acid, ethylene ketal(n)
A solution of 6.38 g. (0.020 M) of ethyl-4-oxo-1-phenylcyclohexane-3-propionate ethylene ketal(m) (obtained in Example 10A) and 8 ml. of 50% sodium hydroxide solution in 80 ml. of methanol is heated at reflux for about 20 hours. Most of the methanol is removed under vacuum, water added to the residue and the latter washed with ether. The aqueous layer is then made strongly acidic and the material that precipitates is extracted with ether. The combined ether extracts are washed with brine and evaporated to dryness to give 4-oxo-1-phenylcyclohexane-3-propionic acid, ethylene ketal(n).
Following the procedure of Example 11A but substituting other alkyl-4-oxo-1-phenylcyclohexane-3-propionate ethylene ketals(m) as starting materials, such as
1. propyl- 4-oxo-1-(5-ethoxyphenyl)cyclohexane-3-propionate, ethylene ketal(m),
2. methyl-4-oxo-1-(3-acetylamidophenylcyclohexane- 3-propionate, ethylene ketal(m), and the like,
yields, respectively,
1. 4-oxo-1-(5-ethoxyphenyl)cyclohexane-3-propionic acid, ethylene ketal(n),
2. 4-oxo-1-(3-acetylamidophenyl)cyclohexane-3-propionic acid, ethylene ketal(n), and the like.
EXAMPLE 12A
4-Oxo-1-phenylcyclohexane-3-propionic acid(i)
The 4-oxo-1-phenylcyclohexane-3-propionic acid ethylene ketal(n) obtained in Example 11A is dissolved in 50 ml. of acetone and 5 ml. of 2.5 N hydrochloric acid and allowed to stand at room temperature for about 48 hours. The solution is evaporated to near dryness under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized from methylene chloride: Skellysolve B to give 1.7 g. (34.5% yield of 4-oxo-1-phenylcyclohexane-3-propionic acid(i) having a melting point of 143° to 144.5° C. This compound is identical to the compound prepared in Example 6A.
Anal. Calcd. for C 15 H 18 O 3 : C, 73.15; H, 7.37
Found: C, 73.04; H, 7.40.
Following the procedure of Example 12A but substituting other 4-oxo-1-phenylcyclohexane-3-propionic acid alkylene ketals(n) as starting materials, such as
1. 4-oxo-1-(3-chlorophenyl)cyclohexane-3-propionic acid, ethylene ketal(n),
2. 4-oxo-1-(4-isopropylphenyl)cyclohexane-3-propionic acid, ethylene ketal(n),
3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid, ethylene ketal(n), and the like,
yields, respectively,
1. 4-oxo-1-(3-chlorophenyl)cyclohexane-3-propionic acid(i),
2. 4-oxo-1-(4-isopropylphenyl)cyclohexane-3-propionic acid(i),
3. 4-oxo-1-(5-methylaminophenyl)cyclohexane-3-propionic acid(i), and the like.
EXAMPLE 13A
Spiro [cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)dione(o)
To 5 g. (0.0203 M) of 4-oxo-1-phenylcyclohexane-3-propionic acid(i) (prepared as in Examples 6A or 12A), 5 ml. of hydrogen fluoride is distilled and the solution allowed to stand at room temperature for about 20 hours. The residue is dissolved in ether, washed successively with water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from ether to give 0.13 g. (28% of theoretical yield) of spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o) having a melting point of 145.5° to 148° C.
Calcd. for C 15 H 16 O 2 : C, 78.23; H, 7.88
Found: C, 78.39; H, 7.18
Following the procedure of Example 13A but substituting other 4-oxo-1-phenylcyclohexane-3-propionic acids(i) as starting materials, such as
1. 4-oxo-1-(3-propylphenyl)cyclohexane-3-propionic acid(i),
2. 4-oxo-1-(4-ethoxyphenyl)cyclohexane-3-propionic acid(i),
3. 4-oxo-1-(2-ethylaminophenyl)cyclohexane-3-propionic acid(i),
4. 4-oxo-1-(3-acetylamidophenyl)cyclohexane-3-propionic acid(i), and the like,
yields, respectively,
1. 6'-propylspiro[cyclohexane-1,1'(2'H)naphthalene]-4,4'(3'H)-dione(o),
2. 7'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),
3. 5'-ethylaminospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),
4. 6'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o), and the like.
EXAMPLE 14A
Spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal)(p)
A solution of 3.19 g. (0.014 M) of spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o) (prepared as in Example 13A), 1.45 g. (0.014 M) of 2,2-dimethylpropanediol and 0.06 g. of p-toluenesulfonic acid in 57 ml. of benzene is heated under a Dean-Stark trap for about 5.5 hours. The solution is washed with saturated aqueous sodium bicarbonate and brine and then evaporated to dryness. The residue is chromatographed over a column of 400 ml. of Florisil (activated magnesium silicate) and eluted with 7.5% ethyl acetate; Skellysolve B. The crystalline fractions are combined to yield 3.29 g. (75% of theoretical) of spiro[cyclohexane-1,1'(2'H)-naphthalene]4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal) (p) having a melting point of 136° to 138° C.
Anal. Calcd. for C 20 H 26 O 3 : C, 76.40; H, 8.34
Found: C, 76.49; H, 8.38.
Following the procedure of Example 14A but substituting other spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'-(3'H)-diones(o) as starting materials, such as
1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o),
2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione(o), and the like,
yields, respectively,
1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal)(p),
2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal)(p), and the like.
EXAMPLE 15A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q)
A solution of 3.63 g. (0.0115 M) of spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal(p) (prepared as in Example 14A), 1.54 ml. of hydrazine hydrate and 2.23 g. of potassium hydroxide in 28 ml. of ethylene glycol is heated to reflux. Distillate is collected until the pot temperature rises to 200° C. and refluxing is continued for about 18 hours. The mixture is poured into water and a precipitated material is extracted with ether. The combined extracts are washed with water and brine and then evaporated to dryness. The residue is recrystallized from petroleum ether to give 2.39 g. (69.5% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-one, 2,2-dimethyltrimethylene ketal(q) having a melting point of 109° to 111° C.
Anal. Calcd. for C 20 H 28 O 2 : C, 79.95; H, 9.39
Found: C, 79.95; H, 9.51.
Following the procedure of Example 15A but substituting other 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketals) (p) as starting materials, such as
1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal)(p),
2. 6'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione, 4-(2,2-dimethyltrimethylene ketal)(p), and the like, yields, respectively,
1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q),
2. 6'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q), and the like.
EXAMPLE 16A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r)
A mixture of 2.39 g. (0.008 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q) and 2.4 ml. of 2.5 N hydrochloric acid in 24 ml. of acetone is stirred at room temperature for about 6 hours. To the reaction mixture, 15 ml. of water is added and most of the acetone removed under vacuum. Ether is added to the residue, the organic layer washed successively with water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from petroleum ether to give 1.19 g. (70% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r) having a melting point of 115° to 120° C.
Following the procedure of Example 16A but substituting other 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltriethylene ketals(q) as starting materials, such as
1. 2'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q),
2. 3'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q),
3. 4'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one, 2,2-dimethyltrimethylene ketal(q), and the like,
yields, respectively,
1. 2'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),
2. 3'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),
3. 4'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r), and the like.
EXAMPLE 17A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s)
To a partial solution of 5.10 g. (0.038 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen-4-one(r) (prepared as in Example 16A) in 105 ml. of 95% ethanol, 2.59 g. of sodium borohydride is added and the mixture stirred at room temperature for about 4 hours. Most of the solvent is removed under vacuum and water added to the residue. The material that precipitates is extracted with ether and the combined extracts washed with water and brine and evaporated to dryness. The residue is recrystallized once from Skellysolve B and then chromatographed over a column containing 500 ml. of silica gel with elution by 10% acetone:Skellysolve B. On the basis of TLC the less polar fractions are combined and recrystallized from benzene:cyclohexane to give a small amount of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), having a melting point of 144.5° to 146° C., and an NMR spectrum suggesting that the compound has the hydroxy substituent in the axial position.
Anal. Calcd. for C 15 H 20 O: C, 83.28; H, 9.32
Found: C, 83.53; H, 9.61.
On the basis of melting point the more polar fractions are combined and recrystallized from Skellysolve B to give 3.89 g. (75.6% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s) having a melting point of 80° to 83° C., and an NMR spectrum suggesting that the compound has the hydroxy substituent in the equatorial position.
Anal. Calcd. for C 15 H 20 O: C, 83.28; H, 9.32
Found: C, 83.47; H, 9.55.
Following the procedure of Example 17A but substituting other 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ones(r) as starting materials, such as
1. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r),
2. 6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-one(r), and the like,
yields, respectively,
1. trans and cis 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s),
2. trans and cis 6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), and the like.
EXAMPLLE 18A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol, methane sulfonate(t)
To an ice-cooled solution of 3.89 g. (0.018 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4ol (obtained in Example 17A) in 40 ml. of pyridine, 4 ml. of methane sulfonyl chloride is added. The mixture is allowed to stand in the cold for about 6 hours and then diluted with water. The material that precipitates is extracted with ether and the combined extracts washed successively with ice cold 2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from cyclohexane to give 5 g. (94.3% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t), having a melting point of 118° to 120° C.
Anal. Calcd. for C 16 H 22 O 3 S: C, 65.27; H, 7.53; S, 10.89
Found: C, 65.17; H, 7.61; S, 10.70
Following the procedure of Example 18A but substituting other 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ols(s) as starting materials, such as
1. 6'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s),
2. 8'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol(s), and the like,
yields, respectively,
1. 6'-fluorospiro[cyclohexan-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t),
2. 8'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t), and the like.
EXAMPLE 19A A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yiazide(u)
A mixture of 5 g. (0.017 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t) (obtained in Example 18A) and 5 g. of sodium azide in 50 ml. of dimethylformamide is heated in an oil bath at 90° C. for about 20 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and benzene. The organic layer is washed with water and brine and evaporated to dryness to yield crude 3',4'-dihydrospiro[cyclohexane-1,1(2'H)-naphthalen]-4-ylazide(u) as an oil.
Following the procedure of Example 19A but substituting other 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazides(t) as starting materials, such as
1. 5'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t),
2. 6'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methanesulfonate(t), and the like,
yields, respectively,
1. 5'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u),
2. 6'-acetylamido[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u), and the like.
EXAMPLE 20A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)]
A solution of the 3',4'-dihydrospiro[cyclohexan-1,1'-(2'H)-naphthalen]-4-ylazide(u) obtained in Example 19A in 75 ml. of tetrahydrofuran, is added to suspension of 0.65 g. of lithium aluminum hydride in 8 ml. of tetrahydrofuran, stirred at room temperature for about 5.5 hours and cooled in an ice bath. To this, 0.65 ml. of water, 0.65 ml. of 15% aqueous sodium hydroxide and 1.95 ml. of water are added successively. The resulting gel is collected on a filter, washed with ether and the filtrates evaporated to dryness. The residue is dissolved in a small amount of ether and an excess of 6.4 N hydrogen chloride in ether added. The precipitate is collected on a filter and recrystallized from methanol:ethyl acetate to yield 1.76 g. of 3',4'-dihydro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-amine hydrochloride[I(a)] melting at 271° to 273° C.
Following the procedure of Example 20A but substituting for hydrogen chloride another suitable (pharmacologically acceptable) acid, such as hydrobromic, sulfuric, phosphoric, nitric, benzoic, naphthoic, salicylic, tartaric, nicotinic, cyclohexanesulfamic, hexynoic, lactic, palmitic, glutaric, acetic, propionic, phenylbutyric acid, and the like, yields a corresponding acid addition salt of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine [I(a)].
Following the procedure of Example 20A but substituting another 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u) as starting material, such as
1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u),
2. 6'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylazide(u), and the like,
yields, respectively,
1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)],
2. 6'-methoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)], and the like.
EXAMPLE 21A
1-[3',4'-Dihydrospiro(cyclohexane-1,1'(2'H)-naphthlen)-4-yl]piperidine[I(a)
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride [I(a)] (obtained as in Example 20A), 1.9 g. of 1.5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux for about 18 hours. The mixture is allowed to cool, diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen4-yl]piperidine[I(a)].
Following the procedure of Example 21A but substituting the same and other (a) acid addition salts of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamines[I(a)] and (b) dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
1. 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and 1,4-dibromobutane,
2. 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and 1,6-diiodohexane,
3. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and 1,5-diiodopentane,
4. 6'-ethylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and 1,4-diiodobutane,
5. 7'-propoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and 1,6-diiodohexane, and the like,
yields, respectively,
1. 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]pyrrolidine[I(a)],
2. 1-[3',4'-dihydrospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]hexamethyleneimine[I(a)],
3. 1-[5'-bromospiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]piperidine[I(a)],
4. 1-[6'-ethylspiro(cyclohexane-1,1'(2'H)-naphthalen)-4-yl]pyrrolidine[I(a)],
5. 1-[7'-propoxyspiro(cyclohexane-1,1'-(2'H)-naphthalen)-4-yl]hexamethyleneimine[I(a)], and the like.
EXAMPLE 22A
4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride [I(a)]
A mixture of the free base prepared from 1 g. (0.00397 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride [I(a)] (obtained as in Example 20A), 0.81 g. of potassium iodide, 1.24 g. of potassium carbonate and 1.4 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 20 ml. of dimethylformamide is heated together in an oil bath at about 90° C. for about 20 hours. The solvent is removed under vacuum and the residue dissolved in water and benzene. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue, 8 ml. of 2.5 N hydrochloric acid and 16 ml. of methanol is stirred at room temperature for about 2 hours and most of the methanol removed under vacuum. The residual suspended solid is collected on a filter, washed with ether and recrystallized from methanol:ethyl acetate to give 0.65 g. (39.5% yield) of 4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-amino]butyrophenone hydrochloride[I(a)], having a melting point of 194° to 197° C.
Anal. Calcd. for C 25 H 31 ClFNO: C, 72.18; H, 7.51; N, 3.37,
Found: C, 72.42; H, 7.66; N, 3.14.
Following the procedure of Example 22A but substituting another 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride [I(a)] as starting material, such as
1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)],
2. 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)],
3. 7'-acetylamidospiro[cyclohexane-naphthalen]-4-ylamine hydrochloride[I(a)], and the like,
yields, respectively,
1. 4'-fluoro-4-[5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride[I(a)],
2. 4'-fluoro-4-[6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride[I(a)],
3. 4'-fluoro-4-[7'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride [I(a)], and the like.
Following the procedure of Example 22A but substituting another 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] as starting material and the 2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkanaryl ketone, such as
1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 4'-bromo-4-chlorobutyrophenone,
2. 6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-ethoxybutyrophenone,
3. 7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 3',4-dichlorobutyrophenone,
4. 6'-propionylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-chloro-4'-ethylvalerophenone, and the like, yields, respectively,
1. 4'-bromo-4-[5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride[I(a)],
2. 4'-ethoxy-4-[6'-methylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride[I(a)],
3. 3'-chloro-4-[7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]butyrophenone hydrochloride [I(a)],
4. 4'-ethyl-5-[6'-propionylamido[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamino]valerophenone[I(a)], and the like.
EXAMPLE 23A
Ethyl 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)]
To an ice cooled solution of the free base prepared from 1.53 g. (0.0061 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine hydrochloride[I(a)] (obtained as in Example 20A) in 12 ml. of pyridine, 0.95 ml. of ethyl chloroformate is added. The mixture is allowed to stand in the cold for about 5 hours and then poured in ice water. The solid that precipitates is collected on a filter and recrystallized from methylene chloride:benzene to give 1.36 g. (77.7% yield) of ethyl 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-carbamate[I(a)], melting at 163.5° to 165° C.
Anal. Calcd. for C 18 H 25 NO 2 : C, 75.22; H, 8.77; N, 4.87
Found: C, 74.91; H, 8.77; N, 4.83.
Following the procedure of Example 23A but substituting another 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] as starting material and another lower alkyl haloformate, such as
1. 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and methyl chloroformate,
2. 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ylamine[I(a)] and propyl bromoformate, and the like,
yields, respectively,
1. methyl 5'-bromospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)],
2. propyl 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)], and the like.
EXAMPLE 24A
3',4'-Dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine hydrochloride [I(a)]
To a suspension of 0.22 g. (0.0058 M) of lithium aluminum hydride in 10 ml. of tetrahydrofuran, a tetrahydrofuran solution of 1.3 g. (0.0045 M) of ethyl 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)] (prepared as in Example 23A) is added. The mixture is stirred to reflux for about 6 hours, at room temperature for about 18 hours, and then cooled in an ice bath. To this is added successively, 0.22 ml. of water, 0.22 ml. 15% aqueous sodium hydroxide solution and 0.66 ml. of water. The resulting inorganic gel is collected on a filter, rinsed with ether and the filtrates evaporated to dryness. The residue is dissolved in a small amount of ether and treated with an excess of 6.4 N hydrochloric acid in ether. The resulting precipitate is collected on a filter and recrystallized from methanol:ethyl acetate to give 0.81 g. (52.7% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]- 4-yl-N-methylamine hydrochloride[I(a)], having a melting point of 285° to 286° C.
Anal. Calcd. for C 16 H 24 ClN: C, 72.29; H, 9.10; N, 5.25;
Found: C, 72.60; H, 9.16; N, 5.35.
Following the procedure of Example 24A but substituting another lower alkyl 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)] as starting material, such as
1. ethyl 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)],
2. propyl 6'-propylspiro[cyclohexane-1,1'(2'H)-naphthalene]-4-carbamate[I(a)], and the like,
yields, respectively,
1. 5'-fluorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine hydrochloride[I(a)],
2. 6'-propylspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine hydrochloride[I(a)], and the like.
EXAMPLE 25A
4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]-butyrophenone hydrochloride[I(a)]
A mixture of the free base prepared from 0.81 g. (0.00306 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen-4-yl-N-methylamine hydrochloride[I(a)] (obtained as in Example 24A), 0.63 g. of potassium iodide, 0.96 g. of potassium carbonate and 0.87 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 15 ml. of dimethylformamide is heated together in an oil bath at about 90° C. for about 20 hours. The solvent is removed under vacuum and the residue dissolved in water and benzene. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue, 6 ml. of 2.5 N hydrochloric acid and 12 ml. of methanol is stirred at room temperature for about 1.5 hours and most of the methanol removed under vacuum. The residual suspended solid is collected on a filter, washed with ether and recrystallized from methanol:ethyl acetate to give 0.59 g. (44.8% yield) of 4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]butyrophenone hydrochloride[I(a)], having a melting point of 204° to 205.5° C.
Anal. Calcd. for C 26 H 33 ClFNO: C, 72.62; H, 7.74; N, 3.26,
Found: C, 72.69; H, 7.93; N, 3.03.
Following the procedure of Example 25A but substituting another 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-lower alkylamine[I(a)] as starting material and the 2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkyanaryl ketone, such as
1. 5'-chlorospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine[I(a)] and the 2,2-dimethyl-1,3-propane-diol of 4'-butoxy-4-chlorobutyrophenone,
2. 6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamine[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-2'-methylbutyrophenone,
3. 7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamine[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 3-bromo-3'-chloropropiophenone,
4. 8'-acetylamidospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamine[I(a)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-fluoro-4'-propylvalerophenone, and the like,
yields, respectively,
1. 4'-butoxy-4-[5'-chloropsiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]butyrophenone hydrochloride [I(a)],
2. 2'-methyl-4-[6'-ethoxyspiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-ethylamino]butyrophenone hydrochloride [I(a)],
3. 3'-chloro-3-[7'-nitrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-yl-N-methylamino]propiophenone hydrochloride [I(a)],
4. 4'-propyl-5-[8'-acetylamidospiro[cyclohexane-1,1'-(2'H)-naphthalen]-4-yl-N-ethylamino]valerophenone hydrochloride[I(a)], and the like.
EXAMPLE 1B
Methyl-4-hydroxycyclohexane carboxylate[2]
A solution of 200 g. of methyl-p-hydroxybenzoate[1] (prepared as in Ann. 141, 247) in 1700 ml. of absolute ethanol has 66 g. of 5% rhodium/aluminum catalyst added thereto and then hydrogenated until no further uptake of hydrogen is observed. The catalyst is collected on a filter and the filtrate evaporated to dryness to yield 216 g. of crude methyl-4-hydroxycyclohexane carboxylate(2), as an oil.
EXAMPLE 2B
4-Carbomethoxy-1-cyclohexanone[3]
The methyl-4-hydroxycyclohexane carboxylate prepared in Example 1B is dissolved in acetone with mechanical stirring and cooled in an ice bath to about 5° C. Jones reagent is added at a rate to keep the reaction temperature below about 20° C. for about 10 minutes. Most of the solvent is removed on a rotary evaporator and the residue taken up in 500 ml. of ether and 150 ml. of water. The organic layer is separated, washed successively with water, saturated aqueous sodium bicarbonate solution, and brine and evaporated to dryness to yield an oil, which on distillation under vacuum gives 47.4 g. of 4-carbomethoxy-1-cyclohexanone[3] having a boiling point of 82° to 85° C. at 0.55 to 0.75 mm. of Hg.
EXAMPLE 3B
4-Carbomethoxy-1-cyclohexanone ethylene ketal[4]
A mixture of 189.7 g. of 4-carbomethoxy-1-cyclohexanone[3] (obtained as in Example 2B) in 2000 ml. of benzene, 67.5 ml. of ethylene glycol and 2.7 g. of p-toluenesulfonic acid is heated at reflux under a Dean-Stark trap for about 5 hours. After cooling, the solution is washed with saturated aqueous sodium bicarbonate and brine. The oily residue remaining when the organic solvent is evaporated to dryness is distilled under vacuum to give 231.8 g. of 4-carbomethoxy-1-cyclohexanone ethylene ketal[4] having a boiling point of 95° to 100° C. at 0.30 mm. of Hg.
EXAMPLE 4B
4-Benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]
To a solution of 5 g. (0.05 M) of diisopropyl amine in 50 ml. of tetrahydrofuran cooled in ice:methanol, 32 ml. of 1.57 N butyl lithium in pentane is added over the course of about 5 minutes. There is then added, first, 10 g. (0.05 M) of 4-carbomethoxy-1-cyclohexanone ethylene ketal [4] (obtained as in Example 3B) in 50 ml. of tetrahydrufuran in the course of about 15 minutes, and then 8.5 g. (0.05 M) of α-bromotoluene (also named benzyl bromide) in 15 ml. of tetrahydrofuran in about 5 minutes. The clear solution is stirred at room temperature for about 1 hour, cooled in ice and treated with 50 ml. of saturated ammonium chloride solution. The organic layer is separated, diluted with benzene and washed successively with water, ice cold N hydrochloric acid solution, sodium bicarbonate solution and brine. The organic layer is evaporated to dryness and the oil that remains is distilled under vacuum to give 13.57 g. (93.5% of theoretical yield) of 4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] as a viscous oil having a boiling point of 155° to 156° C. at 0.25 mm. of Hg.
Anal. Calcd. for C 17 H 22 O 4 : C, 70.32; H, 7.64;
Found : C, 69.94; H, 7.60.
EXAMPLE 5B
4-(p-Methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]
To a solution of 11.7 g. (0.112 M) of diisopropylamine in 115 ml. of tetrahydrofuran cooled in ice:methanol, 75 ml. of 1.67 N butyl lithium in pentane is added over the course of about 12 minutes. There is then added, first, 23.1 g. (0.112 M) of 4-carbomethoxy-1-cyclohexanone ethylene ketal[5] (obtained as in Example 3B) in 115 ml. of tetrahydrofuran in the course of about 15 minutes, and then 14 g. (0.112 M) of α-chloro-p-xylene in 115 ml. of tetrahydrofuran. The mixture is stirred in the cold for about 1 hour and at room temperature for about 2 hours, and then 100 ml. of saturated aqueous ammonium chloride solution and benzene added. The organic layer is separated, washed successively with water, 2.5 N hydrochloric acid solution, water and brine, and then evaporated to dryness. The residue is distilled under vacuum to give 21.47 g. (64% yield) of 4-(p-methylbenzyl)-4 -carbomethoxy-1-cyclohexanone ethylene ketal[5] as a viscous oil having a boiling point of 166° to 168.5° C. at 0.3 mm. of Hg.
Anal. Calcd. for C 18 H 24 O 2 : C, 71.02; H, 7.95; M.W. 304
Found: C, 71.23; H, 8.03; m/e 304.
EXAMPLE 6B
4-(m-Methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]
To a solution of 10.1 g. (0.101 M) of diisopropylamine in 100 ml. of tetrahydrofuran cooled in ice:methanol, 62 ml. of 1.61 N butyl lithium in pentane is added. There is then added, first 20 g. (0.10 M) of 4-carbomethoxy-1-cyclohexanone ethylene ketal[4] (obtained as in Example 3B) in 100 ml. of tetrahydrofuran in the course of about 12 minutes, and then 18.5 g. of α-bromo-m-xylene in 100 ml. of tetrahydrofuran in about 12 minutes. The mixture is stirred in the cold for about 1 hour and at room temperature for about 1 hour, and then 100 ml. of saturated ammonium chloride solution and benzene added. The organic layer is separated, washed successively with water, 2.5 N hydrochloric acid solution, water, sodium bicarbonate solution and brine, and then evaporated to dryness. The residue is distilled under vacuum to give 21.32 g. (70% yield) of 4-(m-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] as a viscous oil having a boiling point of 160° to 163° C. at 0.4 mm. of Hg.
Anal. Calcd. for C 18 H 24 O 4 : C, 71.02; H, 7.95; M.W. 304;
Found: C, 71.05; H, 8.12; m/e 304;
EXAMPLE 7B
4-(m-Methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5]
To an ice cooled solution of 10.25 g. (0.102 M) of diisopropylamine in 100 ml. of tetrahydrofuran, 66 ml. of 1.67 N butyl lithium in pentane is added. There is then added, first, 19.6 g. (0.0995 M) of 4-carbomethoxy-1-cyclohexane ethylene ketal[4] (obtained as in Example 3B) in 100 ml. of tetrahydrofuran in the course of about 10 minutes, and then 15.3 g. of m-methoxylbenzyl chloride in 100 ml. of tetrahydrofuran in about 17 minutes. The mixture is stirred at room temperature for about 2 hours and treated with 100 ml. of saturated ammonium chloride solution and benzene. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water and brine, and then evaporated to dryness. The residue is distilled under vacuum to give 22.32 g. (70% yield) of 4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5] having a boiling point of 159° to 165° C. at 0.2 mm. of Hg.
Anal. Calcd. for C 18 H 24 O 2 : C, 67.48; H, 7.55
Found: C, 67.71; H, 7.81.
Following the procedures of Examples 4B through 7B but substituting other halides, such as
1. p-acetylamidobenzyl bromide,
2. m-chlorobenzyl bromide,
3. p-propylbenzyl bromide, and the like,
yields, respectively,
1. 4-(p-acetylamidobenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5] ,
2. 4-(m-chlorobenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5],
3. 4-(p-propylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5], and the like.
EXAMPLE 8B
1-Benzyl-4-cyclohexanone-1-carboxylic acid [7]
1. A mixture of 16.64 g. (0.057 M) of 4-benzyl-4-carbomethoxy-1-cyclohexane ethylene ketal[5] (prepared as in Example 4B) and 2.5 g. of postassium hydroxide in 100 ml. ethylene glycol is stirred at reflux for about 16 hours. The mixture is then allowed to cool and diluted with water. The solution is washed once with water and then made strongly acid with concentrated hydrochloric acid. The precipitated gum is extracted with ether and this solution washed first with water, then brine, and evaporated to dryness to give 4-benzyl-4-carboxy-1-cyclohexanone ethylene ketal [6].
2. A solution of the residue [6] and 13 ml. of 2.5 N hydrochloric acid in 130 ml. of acetone is stirred at room temperature for about 20 hours, most of the solvent removed under vacuum and the residue dissolved in ether. The organic layer is washed with water and brine and evaporated to dryness. The residual gum is chromatographed on a column of 800 ml. of acid washed silica gel with elution by 4% acetic acid in methylene chloride. The crystalline fractions are combined and recrystallized twice from methylene chloride:cyclohexane to give 5.62 g. (42% yield) of 1-benzyl-4-cyclohexanone-1-carboxylic acid[7] having a melting point of 120° to 123° C.
Anal. Calcd. for C 14 H 16 O 2 : C, 72.39; H, 6.94
Found: C, 72.24; H, 6.86
EXAMPLE 9B
1-(p-Methylbenzyl)-4-cyclohexanone-1-carboxylic acid [7]
1. A mixture of 21.47 g. (0.0706 M) of 4-(p-methyl-benzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal [5] (prepared in Example 5B) and 2.5 g. of potassium hydroxide in 100 ml. of ethylene glycol is stirred at reflux for about 16 hours. The mixture is then allowed to cool and diluted with water. The solution is washed once with water and then made strongly acidic with concentrated hydrochloric acid. The precipitated gum is extracted with ether and this solution washed with brine and evaporated to dryness to give 4-(p-methylbenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].
2. A solution of the residue[6] and 25 ml. of 2.5 N hydrochloric acid in 200 ml. of acetone is stirred at room temperature for about 24 hours, most of the solvent removed under vacuum and the residue dissolved in ether. The organic layer is washed with brine and evaporated to dryness. The residue is chromatographed on a column of 1,500 ml. of silica gel with elution by 3% acetic acid in methylene chloride. The crystalline fractions are combined to give 6.8 g. (39% yield) of 1-(p-methoxybenzyl)-4-cyclohexanone-1-carboxylic acid[7] as a waxy solid. A small sample is recrystallized from ether: petroleum ether to give crystals[7] having a melting point of 120° to 123° C.
Anal. Calcd. for C 15 H 18 O 3 : C, 73.14; H, 7.37
Found; C, 73.20; H, 7.60
EXAMPLE 10B
1-(m-Methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7]
1. A solution of 21.31 g. (0.0701 M) of 4-(m-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] (prepared in Example 6B) and 3.4 g. of potassium hydroxide in 140 ml. of ethylene glycol is heated at reflux for about 20 hours. The mixture is then allowed to cool, diluted with water and extracted with ether. The aqueous layer is then made strongly acidic and the precipitated gum extracted with ether. This extract is washed with water and brine and evaporated to dryness to yield 4-(m-methylbenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].
2. A solution of the residue[6] and 25 ml. of 2.5 N hydrochloric acid in 200 ml. of acetone is stirred at room temperature for about 16 hours, the solvent removed under vacuum and the residue extracted with ether. The extract is washed with water and brine and evaporated to dryness. The residue is chromatographed on 2000 ml. of acid washed silica gel with elution by 4% acetic acid in methylene chloride. The fractions found similar by thin layer chromatography are combined to give 14.8 g. (56% yield) of 1-(m-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7] as a waxy solid.
EXAMPLE 11B
1-(m-Methoxybenzyl)-4-cyclohexanone-1-carboxylic acid[7]
1. A mixture of 24.3 g. (0.076 M) of 4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5] (prepared as in Example 7B) and 4.35 g. of sodium hydroxide in 155 ml. of ethylene glycol is heated at reflux for about 42 hours. The mixture is then diluted with water and washed with ether. The organic layer is made acidic with hydrochloric acid the precipitated gum dissolved in ether. The ether solution is washed with brine and evaporated to dryness to give 4-(m-methoxybenzyl)-4-carboxy-1-cyclohexanone ethylene ketal[6].
2. A solution of the residue and 27 ml. of 2.5 N hydrochloric acid in 220 ml. of acetone is allowed to stand at room temperature for about 18 hours, then most of the solvent removed under vacuum and the residue dissolved in ether. The organic layer is washed with brine and evaporated to dryness. The residue is chromatographed on a column of acid washed silica gel with elution first by 0.5% acetic acid:methylene chloride then 2% acetic acid:methylene chloride. Those fractions found similar by thin layer chromatography are combined, the solvent evaporated and the resulting solid recrystallized twice from ether: Skellysolve B to give 7.18 g. (36% of theoretical yield) of 1-(m-methoxy-benzyl)-4-cyclohexanone-1-carboxylic acid[7] having a melting point of 109 to 112.5° C. An additional 3.82 g. (19% yield) of product [7] melting at 109° to 111° C. is obtained from the mother liquor.
Anal. Calcd. for C 15 H 18 O 4 : C, 68.68; H, 6.92
Found: C, 68.30; H, 6.92.
Following the procedures of Example 8B through 11B but substituting other 4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketals[5] as starting materials, such as
1. 4-(o-methylbenzyl)-4-carbomethoxy-1-cyclohexanone ethylene ketal[5],
yields,
1. 1-(o-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7].
EXAMPLE 12B
Spiro(cyclohexane-1,2'-indan)-1',4-dione[8]
To 100 ml. of freshly distilled hydrogen fluoride, (14.63 M) of 1-benzyl-4-cyclohexanone-1-carboxylic acid[7] (prepared as in Example 8B) is added. The solution is allowed to stand at room temperature for about 18 hours and then poured cautiously into saturated aqueous sodium bicarbonate solution. The precipitated gum is extracted with benzene. The organic layer is washed successively with water, aqueous sodium bicarbonate solution and brine, and then evaporated to dryness. The residue is chromatographed on a column of 1,500 ml. of silica gel with elution by 20% acetone in Skellysolve B. There is first obtained a small amount of by-product followed by 10.5 g. (78%) of spiro(cyclohexane-1,2'-indan)-1',4-dione[8], having a melting point of 70.5° to 72° C.
Anal. Calcd. for C 14 H 14 O 2 : C, 78.48; H, 6.59
Found: C, 78.43; H, 6.59.
The less polar by-product is recrystallized from petroleum ether to give 0.28 g. of a compound, which in view of its mass spectrum and elemental analysis is spiro(cyclohexane-1,2'-indan)-4,4-difluoro-1'-one.
EXAMPLE 13B
5'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8]
To 50 ml. of freshly distilled hydrogen fluoride, 6.8 g. (0.026 M) of 1-(p-methylbenzyl)-4-cyclohexanone-1-carboxylic acid [7] (prepared in Example 9B) is added. The solvent is allowed to evaporate over a period of about 3 days. The residue is dissolved in ether and this solution washed successively with water, aqueous sodium bicarbonate solution and brine. The solution is evaporated to dryness and the gum that remains is chromatographed on a column of 700 ml. of silica gel with elution by 20% acetone: Skellysolve B. The fractions found similar by thin layer chromatography are combined and rechromatographed on a column of 400 ml. of silica gel with elution by 20% acetone: Skellysolve B. The crystalline fractions are combined and recrystallized from acetone; Skellysolve B to give 2.06 g. (35% yield) of 5'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8] having a melting point of 110° to 113° C.
Anal. Calcd. for C 15 H 16 O 2 : C, 78.92; H, 7.06; M.W. 228.
Found: C, 78.92; H, 7.13; m/e 228.
EXAMPLE 14B
6'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8]
Onto 14.8 g. (0.060 M) of 1-(m-methylbenzyl)-4-cyclohexanone-1-carboxylic acid[7] (prepared in Example 10B), 100 ml. of hydrogen fluoride is distilled. Following about 2 days of standing at room temperature the solution is poured into saturated aqueous sodium bicarbonate solution. The precipitate is dissolved in ether and the organic washed successively with water, saturated aqueous sodium bicarbonate solution and brine and evaporated to dryness. The residue is chromatographed on a column of 1200 ml. of Florisil with elution by 10% acetone: Skellysolve B. The crystalline fractions are combined and recrystallized from acetone: Skellysolve B to give 7.3 g. (53% yield) of 6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione[8] having a melting point of 121° to 122.5° C.
Anal. Calcd. for C 15 H 16 O 2 : C, 78.92; H, 7.01.
Found: C, 78.79; H, 7.22.
EXAMPLE 15B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione[8]
A suspension of 15.63 g. (0.060 M) of 1-(m-methoxy-benzyl)-4-cyclohexanone-1-carboxylic acid [7] (prepared as in Example 11B) and 12.5 g. of phosphorus pentachloride in 190 ml. of monochlorobenzene is stirred mechanically under reflux for about 1.5 hours and at room temperature for about 1.5 hours. The mixture is then cooled in ice and treated with 6.85 ml. of stannic chloride. After about 0.5 hours of stirring in the cold and about 18 hours at room temperature, 96 ml. of 2.5 N hydrochloric acid is added in the course of about ten minutes. After about an additional hour of stirring, the organic layer is separated, washed successively with water, aqueous sodium bicarbonate solution and brine and evaporated to dryness. The residue is chromatographed on a column of 1200 ml. of silica gel with elution by 10% ethyl acetate in methylene chloride. The crystalline fractions are combined to give 7.51 g. (51% yield) of 5'-methoxyspiro[cyclohexane-1,2'-indan]-1',4-dione [8] having a melting point of 105° to 107° C., and an analytic sample melting at 110° to 112° C.
Anal. Calcd. for C 15 H 16 O 3 : C, 73.75; H, 6.60; M.W. 244.
Found: C, 73.75; H, 6.65; m/e 244.
Following the procedures of Examples 12B through 15B but substituting other 1-benzyl-4-cyclohexanone-1-carboxylic acids [7] as starting materials, such as
1-(p-ethylbenzyl)-4-cyclohexanone-1-carboxylic acid-[7], and the like, yields,
5'-ethylspiro(cyclohexane-1,2'-indan)-1',4-dione[8], and the like.
EXAMPLE 16B
Spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal[ 9]
A mixture of 1.77 g. (0.0083 M) of spiro(cyclohexane-1,2'-indan)-1',4-dione[8] (prepared as in Example 12B) 0.51 g. (0.46 ml; 0.0082 M) of ethylene glycol and 0.1 g. of p-toluenesulfonic acid in 50 ml. of benzene is heated at reflux under a Dean-Stark trap for about 4 hours. The mixture is allowed to cool, washed successively with aqueous sodium bicarbonate solution, water and brine and evaporated to dryness. The residual solid is recrystallized from cyclohexane to give 1.67 g. (75% yield) of spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal[ 9], having a melting point of 158° to 160.5° C; ν max . 1690 cm - 1.
Anal. Calcd. for C 16 H 18 O 3 : C, 74.39; H, 7.02; M.W. 258.
Found: C, 73.99; H, 6.98; m/e 258.
EXAMPLE 17B 5'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9]
A mixture of 2.06 g. (0.00905 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8 ] (prepared in Example 13B), 0.56 g. (0.50 ml.) of ethylene glycol and 0.1 g. of p-toluenesulfonic acid in 50 ml. of benzene is heated at reflux under a Dean-Stark trap for about 2 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution then water and evaporated to dryness. The residual solid is recrystallized from methylene chloride: cyclohexane to give 1.96 g. (86%) of 5'-methyl-spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal-[9], melting at 124° to 127° C.
Anal. Calcd. for C 17 H 20 O 3 : C, 74.97; H, 7.40.
Found: C, 74.97; H, 7.51.
Example 18B
6'-Methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9]
A mixture of 7.3 g. (0.032 M) of 6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared in Example 14B), 2.15 g. (1.95 ml.) of ethylene glycol and 0.5 g. of p-toluenesulfonic acid in 200 ml. of benzene is heated at reflux under a Dean-Stark trap for about 5 hours. The mixture is allowed to cool, washed successively with aqueous sodium bicarbonate solution, water and brine and evaporated to dryness. The residual solid is recrystallized from methylene chloride: Skellysolve B to give 7.94 g. (91% yield) of 6'-methylspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9] melting at 116° to 118° C.
Anal. Calcd. for c 17 H 20 O 3 : C, 74.97; H, 7.40.
Found: C, 75.33; H, 7.65.
EXAMPLE 19B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9]
A mixture of 4.89 g. (0.0196 M) of 6'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared as in Example 15B), 1.21 g. of ethylene glycol and 0.2 g. of p-toluenesulfonic acid in 100 ml. of benzene is heated at reflux under a Dean-Stark trap for about 5 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue is recrystallized twice from methylene chloride: Skellysolve B to give 4.13 g. (73% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9 ] having a melting point of 142° to 144° C.
Anal. Calcd. for C 17 H 20 O 4 : C, 70.81; H, 6.99.
Found: C, 71.06; H, 7.19.
Following the procedures of Examples 16B through 19B but substituting other spiro(cyclohexane-1,2'-indan)-1',4-diones [8] as starting materials, such as
1. 7'-acetylamidospiro(cyclohexane-1,2'-indan)-1',4-dione[8],
2. 5'-ethoxyspiro(cyclohexane-1,2'-indan)1', 4-dione [8], and the like,
yields, respectively,
1. 7'-acetylamidospiro(cyclohexane-1,2'-indan)- 1', 4-dione 4-ethylene ketal [9],
2. 5'-ethoxyspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9], and the like.
EXAMPLE 20B
Spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]
A mixture of 5g. (0.0194 M) of spiro(cyclohexane 1,2'-indan)-1',4-dione 4-ethylene ketal [9](prepared as in Example 16B), 2.6ml. of hydrazine hydrate and 3.76 g. of potassium hydroxide in 50 ml. of ethylene glycol is heated at reflux for about 1.5 hours. Material is then removed by distillation to bring the pot temperature to 200° C. After about 5 hours of additional heating at reflux, the mixture is allowed to cool and diluted with water. The precipitated solid is collected on a filter, dried and recrystallized from petroleum ether to give 4 g. (85% yield) of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], having a melting point of 70° to 74° C.
Anal. Calcd. for C 16 H 20 O 2 : C, 78.65; H, 8.25.
Found: C, 78.39; H, 8.19.
EXAMPLE 21B
5'-Methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]
A mixture of 7.3 g. (0.027 M) of 5'-methylspiro(cyclohexane -1,2'-indan)-1', 4-dione 4-ethylene ketal [9] (prepared as in Example 17B), 3.8 ml. of hydrazine hydrate and 5.52 g. of potassium hydroxide in 70 ml. of ethylene glycol is heated at reflux for about 1 hour. Material is then removed by distillation to bring the pot temperature to 200° C. Following about 18 hours of heating at reflux the mixture is allowed to cool and poured into water and extracted with ether. The organic extract is washed with water and brine and evaporated to dryness, to give 5'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10].
EXAMPLE 22B
6'-Methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10]
A mixture of 7.3 g. (0.027 M) of 6'-methylspiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9] (prepared as in Example 18B), 3.8 ml. of hydrazine hydrate and 5.52 g. of potassium hydroxide in 70 ml. of ethylene glycol is heated at reflux for about 1 hour. Material is then removed by distillation to bring the pot temperature to 200° C. Following about 18 hours of heating at reflux the mixture is allowed to cool and poured into water. The precipitated oil is extracted with ether. This organic extract is washed with water and brine and evaporated to dryness, to give 7.01 g. (about 99% yield) of 6'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10] having a melting point of 37+ to 41° C. This material, having a nuclear magnetic resonance (NMR) spectrum in agreement with the expected structure, is not satisfactorily recrystallized.
EXAMPLE 23B
5'-Methoxyspiro(cyclohexane-1',2-indan)-4-one ethylene ketal [10]
A mixture of 4.57 g. (0.0158 M) of 5'-methoxyspiro-(cyclohexane-1,2'-indan)-1',4 -dione 4-ethylene ketal [9] (prepared as in Example 19B), 2.45 g. of hydrazine hydrate and 3.15 g. of potassium hydroxide in 40 ml. of ethylene glycol is heated at reflux for about 1 hour. Solvent is removed by distillation to bring the reaction mixture to 200° C. Following about 1.5 hours at this temperature the mixture is poured into water and well extracted with ether. The ether extracts are combined and evaporated to dryness. The residue is chromatographed on a 250 ml. column of silica gel with elution by 10% acetone in Skellysolve B to give 2.07 g. (48% yield) of 5'-methoxyspiro(cyclohexane-1',2-indan)-4-one ethylene ketal [10] having a melting point of 59° to 61° C. The analytical sample from an earlier experiment melted at 65° to 66.5° C.
Anal. Calcd. for C 17 H 22 O 3 : C, 74.22; H, 8.08.
Found: C, 74.57; H, 8.24.
The aqueous portion (i.e., not extracted by ether), above, is "acidified" with solid carbon dioxide. The precipitated solid is collected on a filter and recrystallized from methanol to give 0.51 g. of by-product, 5"-hydroxydispiro [1,3-dioxolane-2,1'-cyclohexane-4',2"-indan]-1"-one hydrazone, having melting ranges of 243° to 246° C. and 285° to 290° C.
Anal. Calcd. for C 16 H 20 N 2 O 3 : C, 66.69; H, 6.99; N, 9.71; M.W. 288.
Found; C, 66.16; H, 7.14; N, 9.96; m/e 288.
Following the procedures of Example 20B through 23B but substituting other spiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketals [9]as starting materials, such as
5'-chlorospiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9], and the like, yields,
5'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10], and the like.
Example 24B
Spiro(cyclohexane -1,2'-indan)-4-one, oxime [12 ]
1. A mixture of 4g. (0.016 M) of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10] (prepared in Example 20B) and 8 ml. of 2.5 N hydrochoric acid in 80 ml. of acetone is heated at reflux for about 4 hours. Most of the solvent is removed under vacuum and ether added. The organic layer is separated, washed with water and brine and evaporated to dryness. The residue is chromatographed on a 350 ml. column of silica gel with elution by methylene chloride. Those fractions similar by thin layer chromatography are combined to give spiro(cyclohexane-1,2'-indan)-4-one [11] as an amorphous gum.
2. A mixture of the gum [11] obtained in (1), above, 3 g. of hydroxylamine hydrochloride and 10 ml. of water in 100 ml. of tetrahydrofuran is heated at reflux for about 15 hours. Most of the solvent is removed under vacuum and the residue diluted with water. The precipitated solid is recrystallized from cyclohexanone to give 3.1 g. (90% yield) of spiro(cyclohexane-1,2'-indan)-4-one oxime [12] having a melting point of 120° to 122° C.
Anal. Calcd. for C 14 H 17 NO: C, 78.10; H, 7.96; N, 6.51.
Found: C, 78.08; H, 7.85; N, 6.50.
Following the procedure of Example 24B but substituting other spiro(cyclohexane-1,2'-indan)-4-one ethylene ketals [10] as starting materials, such as
1. 7'-bromospiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10],
3. 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one, ethylene ketal [10], and the like, yields, respectively,
1. 7'-bromospiro(cyclohexane-1,2'-indan)-4-one [11] and its oxime [12],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one [11] and its oxime [12],
3. 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one-[11] and its oxime [12], and the like.
EXAMPLE 25B
Spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13 ]
A solution of 3.1 g. spiro(cyclohexane-1,2'-indan)-4-one oxime [12] (prepared in Example 24B) and 6 ml. of acetic anhydride in 25 ml. of pyridine is allowed to stand at room temperature for about 6 hours. The reaction mixture is then poured into ice: water and the solid collected on a filter. The solid is recrystallized from Skellysolve B to give 2.94 g. (88% yield) of spiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13] having a melting point of 91° to 94° C.
Anal. Calcd. for C 16 H 19 NO 2 : C, 74.68; H, 7.44; N, 5.44.
Found: C, 74.43; H, 7.35; N, 5.49.
Following the procedure of Example 25B but substituting other spiro(cyclohexane-1,2'-indan)-4-one oximes [12] as starting materials, such as
1. 6'-chlorospiro(cyclohexane-1,2'-indan)-4-one, oxime [12],
2. 7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime [12], and the like,
yields, respectively,
1. 6'-chlorospiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],
2. 7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13], and the like.
EXAMPLE 26B
Sprio(cyclohexane-1,2'-indan)-4-amine hydrochloride-[I (b) ]
To an ice-cooled solution of 2.94 g. (0.0114 M) of spiro(cyclohexane-1,2'-indan)-4-one oxime acetate [13 ](prepared in Example 25B) in 50ml. of tetrahydrofuran, 15 ml. of N diborane in tetrahydrofuran is added dropwise. Following about 6 hours of standing in the cold, 1 ml. of water is added. The solvent is then removed under vacuum and the residue stirred for about 1 hour at room temperature with 90 ml. of 2.5 N hydrochloric acid covered by ether. The aqueous layer is then made strongly basic, the organic layer washed with water and brine and evaporated to dryness. The residue is dissolved in ether and this solution treated with 5 N hydrochloric acid in ether. The resulting precipitate is recrystallized from methanol: ethyl acetate to give 1.12 g. (41% yield) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I (b) ], having a melting point of 270° to 273° C.
Anal. Calcd. for C 14 H 20 ClN: C, 70.71; H, 8.48; N, 5.89.
Found: C, 70.68; H, 8.55; N, 5.69.
Following the procedure of Example 26B but substituting other spiro(cyclohexane-1,2'-indan)-4-one acetate oximes [13] as starting materials, such as
1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13],
3. 7'-methoxyspiro(cyclohexane-1,2'-indan)-4-one, oxime acetate [13], and the like,
yields, respectively,
1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-amine [I (b) ],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine [I (b) ],
3. 7'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine [I (b) ], and the like.
EXAMPLE 27B
Spiro(cyclohexane-1,2'-indan)-4-ol [14]
To a solution of 8.33 g. (0.042 M) of crude spiro(cyclohexane-1,2'-indan)-4-one[11] [obtained as in (1) of Example 23B] in 85 ml. of ethanol, 1.6 g. of sodium borohydride is added. Following about 6 hours of stirring at room temperature, most of the solvent is removed under vacuum. The residue is suspended in ether and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on a column of 800 ml. of silica gel with elution by 10% acetone in methylene chloride. The crystalline fractions are combined and recrystallized from petroleum ether to give 5.52 g. (66% yield) of spiro(cyclohexane-1,2'-indan)-4-ol [14] having a melting point of 76° to 78° C.
Anal. Calcd. for C 14 H 18 O: C, 83.12; H, 8.97.
Found: C, 83.33; H, 8.92.
Following the procedure of Example 27B but substituting other spiro(cyclohexane-1,2'-indan)-4-ones [11] as starting materials, such as
1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-one [11],
2. 6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one [11], and the like,
yields, respectively,
1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-ol [14],
2. 6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-ol [14], and the like.
EXAMPLE 28B
5'-Methylspiro(cyclohexane-1,2'-indan)-4-ol [14]
1. A solution of 7.01 g. (0.027 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10] (obtained as in Example 21B) and 10 ml. of 2.5 N hydrochloric acid in 100 ml. of acetone is allowed to stand at room temperature for about 17 hours. The solvent is then removed under vacuum and the residue suspended in water and ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on a column of silica gel with elution by 10% acetone: Skellysolve B. The crystalline fractions are combined and recrystallized from petroleum ether to give 4.43 g. (76% yield) of 5'-methyl(cyclohexane-1,2'-indan)-4-one [11], melting at 68° to 70° C.
Anal. Calcd. for C 15 H 18 O: C, 84.07; H, 8.47.
Found: C, 83.92; H, 8.79.
2. To a solution of 4.43 g. of the 5'-methylspiro(cyclohexane-1,2'-indan)-4-one [11] obtained in (1), above, in 100 ml. of 95% isopropanol, 0.8 g. of sodium borohydride is added. Following about 5.5 hours of standing at room temperature most of the solvent is removed under vacuum. The residue is dissolved in water and ether. The organic layer is washed with water and brine and then evaporated to dryness, to give 4.55 g. (97%) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-ol[ 14] as a gum which showed a single spot on thin layer chromatography.
EXAMPLE 29B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-ol[ 14]
1. A solution of 2.87 g. (0.0105 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[ 10] (obtained as in Example 23B) and 6.5 ml. of 2.5 N hydrochloric acid in 60 ml. of acetone is allowed to stand at room temperature for about 18 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized from Skellysolve B to give 1.95 g. (81% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one[ 11] melting at 89° to 91° C.
Anal. Calcd. for C 15 H 18 O 2 : C, 78.23; H, 7.88.
Found: C, 77.96; H, 7.96.
2. A suspension of 1.95 g. of the 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one[ 11] obtained in (1), above, in 100 ml. of isopropanol is warmed to bring the solid into solution. There is then added 0.35 g. of sodium borohydride and the mixture stirred at room temperature for about 7 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The residue is washed with water and brine and evaporated to dryness. The product, 1.86 g. of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol[ 14], is an oil having a nuclear magnetic resonance (NMR) spectrum in agreement with the expected structure.
Following the procedures of Examples 28B and 29B but substituting other spiro(cyclohexane-1,2'-indan)-4-one ethylene ketals[ 10] as starting materials, such as
7'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[ 10], and the like, yields,
7'-fluorospiro(cyclohexane-1,2'-indan)-4-ol[ 14], and the like.
EXAMPLE 30B
Spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15]
A mixture of 5.52 g. (0.027 M) of spiro(cyclohexane-1,2'-indan)-[4-ol[14] (obtained in Example 27B) in 50 ml. of ice cold pyridine is treated with 5.5 ml. of methane sulfonyl chloride. After standing for about 7 hours in the cold the mixture is diluted with ice: water. The precipitated solid is recrystallized from acetone: Skellysolve B to give 7.15 g. (93% yield) of spiro(cyclohexane- 1,2'-indan)-4-ol methanesulfonate[ 15], melting at 100° to 102° C.
Anal. Calcd. for C 15 H 20 O 3 S: C, 64.25; H, 7.19.
Found; C, 63.87; H, 7.50.
EXAMPLE 31B
5'-Methylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15]
To an ice cold solution of 4.55 g. (0.021 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-ol[ 14] (obtained in Example 28B) in 40 ml. of pyridine, 4.5 ml. of methanesulfonyl chloride is added. After standing about 5 hours in the cold the mixture is poured into ice: water. The precipitated gum is extracted with ether and the extract washed successively with water, 2.5 N hydrochloric acid, water and brine. The extract is evaporated to dryness and the solid that remains is recrystallized from ether: petroleum ether to give 5.38 g. (83%) of 5'-methylspiro(cyclohexane)-1,2'-indan)-4-ol methanesulfonate[ 15], melting at 64° to 66° C.
Anal. Calcd. for C 16 H 22 O 3 S: C, 65.27; H, 7.53.
Found: C, 65.41; H, 7.69.
EXAMPLE 32B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15 ]
An ice cold solution of 1.86 g. (0.008 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol[14] (obtained in Example 29B) in 18 ml. of pyridine is treated with 2 ml. of methane sulfonyl chloride. After standing for about 5 hours in the cold the mixture is poured onto ice: water. The precipitated solid is recrystallized from methylene chloride: Skellysolve B to give 2.1 g. (85% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15], melting at 63° to 67° C.
Anal. Calcd. for C 16 H 22 O 4 S: C, 61.91; H, 7.14.
Found: C, 61.80; H, 7.14.
Following the procedures of Example 30B through 32B but substituting other spiro(cyclohexane-1,2'-indan)-4 -ols[ 14] as starting materials, such as
1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-ol[14],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-ol[14],
3. 7'-isopropoxyspiro(cyclohexane-1,2'-indan)-4-ol-[14], and the like,
yields, respectively,
1. 5'bromospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [15],
3. 7'-isopropoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15], and the like.
EXAMPLE 33B
Spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride I(b)]
1. A mixture of 7.15 g. (0.0256 M) of spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15] (obtained in Example 30B) and 7 g. of sodium azide in 70 ml. of dimethylformamide is stirred in an oil bath at about 90° C. for about 17 hours. The solvent is then removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine to give spiro(cyclohexane-1,2'-indan)-4-ylazide[ 16].
2. A solution of the crude spiro(cyclohexane-1,2'-indan)-4ylazide[ 16] obtained in (1), above, in 75 ml. of tetrahydrofuran is added to a well stirred suspension of 1 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. Following about 5 hours of stirring at room temperature the mixture is cooled in ice and treated successively with 1 ml. of water, 1 ml. of 15% aqueous sodium hydroxide solution and 3 ml. of water. The inorganic gel is removed by filtration and the filtrate evaporated to dryness. The residue is dissolved in ether and this solution treated with 5 N hydrogen chloride in ether. The precipitated solid is recrystallized from methanol: ethyl acetate to give 4.58 g. (76% yield) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] , melting at 280° to 282° C.
EXAMPLE 34B
5'-Methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)]
1. A mixture of 5.38 g. (0.0183 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15] (prepared in Example 31B) and 5.4 g. of sodium azide in 55 ml. of dimethylformamide is stirred in an oil bath at about 100° C. for about 18 hours. The solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness to give 5'-methylspiro(cyclohexane-1,2'-indan)-4-ylazide[16].
2. A solution of the 5'-methylspiro(cyclohexane-1,2'-indan)-4-ylazide[ 16] obtained in (1), above, in 60 ml. of tetrahydrofuran is added to a well stirred suspension of 0.75 g. of lithium aluminum hydride in 20 ml. of tetrahydrofuran in the course of about 30 minutes. After about 4 hours the mixture is cooled in ice and treated successively with 0.75 ml. water, 0.75 ml. of 15% aqueous sodium hydroxide solution and 2.25 ml. of water. The inorganic gel is removed by filtration, rinsed with methylene chloride and ether and the filtrate evaporated to dryness. The residue is dissolved in ether and the solution treated with 5 N hydrogen chloride in ether. The precipitated solid is recrystallized from methylene chloride: ethyl acetate to give 3.89 g. (85%) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] , melting at 248° to 252° C.
Anal. Calcd. for C 15 H 22 ClN: C, 71.54; H, 8.81; N, 5.56.
Found: C, 71.19; H, 8.85; N, 5.42.
EXAMPLE 35B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)]
1. A mixture of 2.1 g. (0.0068 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15] (obtained in Example 32B) and 2.1 g. of sodium azide in 20 ml. of dimethylformamide is stirred in an oil bath at about 90° C. for about 16 hours. The solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness to give 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ylazide[ 16].
2. A solution of the 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-ylazide[ 16] obtained in (1), above, in 50 ml. of tetrahydrofuran to 0.26 g. of lithium aluminum hydride in 8 ml. of tetrahydrofuran in the course of about 10 minutes. Following about 4.5 hours of stirring at room temperature the mixture is cooled in ice and there is added successively 0.26 ml. of water, 0.26 ml. of 15% aqueous sodium hydroxide solution and 0.78 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. A solution of the residue in ether is treated with 6 N hydrogen chloride in ether. The precipitated solid is recrystallized from methanol: methylene chloride: ethyl acetate to give 0.69 g. (38% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] , having a melting point of 274° to 277° C.
Anal. Calcd. for C 15 H 22 ClNO: C, 67.27; H, 8.28; N, 5.23.
Found: C, 67.25; H, 8.18; N, 4.98.
Concentration of the mother liquors gives 0.43 g. (23%) of an apparently polymorphic form of the product [I(b)] , having a melting point of 246° to 248° C.
Anal. Found: C, 66.98; H, 8.50; N, 4.87; m/e 231.
Following the procedures of Examples 33B through 35B but substituting other spiro(cyclohexane-1,2'-indan)-4-ol methanesulfonates[ 15] as starting materials, such as
1. 5'-fluorospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15],
2. 6'-isopropylspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[ 15], and the like,
yields, respectively,
1. 5'-fluorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] ,
2. 6'-isopropylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] , and the like.
Following the procedures of the immediately preceding paragraph and of Examples 33B through 35B but substituting other pharmacologically acceptable acids for hydrogen chloride, e.g., sulfuric, nitric, acetic, citric, benzoic, nicotinic, and the like, yields corresponding spiro(cyclohexane-1,2'-indan)-4-amine acid addition salts[ I(b)] .
EXAMPLE 36B
1-Spiro(cyclohexane-1,2'-indan)-4-yl piperidine hydrochloride[ I(b)]
To a suspension of 1.53 g. (0.0065 M) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] (prepared as in Example 33B) in 30 ml. of ethanol, there is added 1.58 ml. of 4.2 N sodium methoxide in methanol. Following about 1 hour of stirring, 1.62 g. of potassium carbonate and 0.97 ml. of 1,5-diiodopentane is added and the mixture heated to reflux. After about 18 hours the mixture is allowed to cool and most of the solvent removed under vacuum. The residue is partitioned between ether and water, the organic layer washed with water and brine and then evaporated to dryness. The residual solid is dissolved in ether and this solution treated with 5 N hydrogen chloride in ether. The resulting precipitate is recrystallized from methylene chloride: ethyl acetate to give 1.53 g. (77% of theoretical yield of 1-spiro(cyclohexane-1,2'-indan)-4-yl piperidine hydrochloride[ I(b)] , having a melting point of 282° to 286° C.
Anal. Calcd. for C 19 H 28 ClN: C, 74.60; H, 9.23; N, 4.58.
Found: C, 74.13; H, 9.27; N, 4.71.
Following the procedure of Example 36B but substituting the same and other (a) acid addition salts of spiro(cyclohexane-1,2'-indan)-4-amines[ I(b)] and (b) the same and other dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
1. spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [ I(b)] and 1,4-dibromobutane,
2. spiro(cyclohexane-1,2'-indan)-4-amine hydrobromide [ I(b)] and 1,6-diiodohexane,
3. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[ I(b)] and 1,5-diiodopentane,
4. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine nitrate[ I(b)] and 1,4-diiodobutane, and the like, yields, respectively,
1. 1-spiro(cyclohexane-1,2'-indan)-4-yl pyrrolidine hydrochloride[ I(b)] ,
2. 1-spiro(cyclohexane-1,2'-indan)-4-yl hexamethyl-eneimine hydrochloride[ I(b)] ,
3. 1-[5'-chlorospiro(cyclohexane-1,2'-indan)-4-yl] piperidine hydrochloride[ I(b)] ,
4. 1-[6'-ethylspiro(cyclohexane-1,2'-indan)-4-yl]-pyrrolidine hydrochloride[ I(b)] , and the like.
EXAMPLE 37B
4'-Fluoro-4-[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[ I(b)]
To a solution of 1.12 g. (0.0047 M) of spiro(cyclohexan-1,2'-indan)-4-amine hydrochloride[ I(b)] (prepared as in Example 33B) in 30 ml. of dimethylformamide, there is added 0.22, g. of sodium hydride. Following about 1 hour of stirring at room temperature, 0.81 g. of potassium iodide, 1.32 g. of potassium carbonate and 1.14 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added. The mixture is then stirred in an oil bath for about 18 hours at about 90° C. The solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is then stirred with 15 ml. of methanol and 7.5 ml. of 2.5 N hydrochloric acid for about 2 hours. Most of the methanol is removed under vacuum and the solid collected on a filter. Two recrystallizations from methylene chloride: ethyl acetate give 0.84 g. (46% yield) of 4'-fluoro-4-[[spiro[cyclohexane-1,2'-indan]-4-yl]aminobutyrophenone hydrochloride[ I(b)] , having a melting point of 195° to 198° C.
Anal. Calcd. for C 24 H 29 ClFNO: C, 71.71; H, 7.27.
Found: C, 71.68; H, 7.14.
EXAMPLE 38B
4'-Fluoro-4-[[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
A suspension of 1.5 g. (0.0049 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 34B) in 30 ml. of methylene chloride is shaken with 25 ml. of N sodium hydroxide solution until all the solid is dissolved. The organic layer is separated and evaporated to dryness. To a solution of the residue in 25 ml. of dimethylformamide, 1 g. of potassium iodide, 1.53 g. of potassium carbonate and 1.41 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added. Following about 18 hours of heating in an oil bath at about 90° C., the solvent is removed under vacuum. The residue is dissolved in benzene and water, the organic layer washed with water and brine and then evaporated to dryness. A mixture of the residue in 10 ml. of 2.5 N hydrochloric acid and 20 ml. of methanol is stirred for about 2 hours at room temperature. Most of the methanol is then removed under vacuum and the solid collected on a filter. This is recrystallized from methanol: ethyl acetate to give 0.61 g. (30% yield) of 4'-fluoro-4-[[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]-amino]butyrophenone hydrochlorde[I(b)], melting at 204° to 206° C.
Anal. Calcd. for C 25 H 31 ClFNO: C, 72.18; H, 7.51; N, 3.37.
Found: C, 72.28; H, 7.73; N, 3.29.
EXAMPLE 39B
4'-Fluoro-4-[[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
A suspension of 0.69 g. (0.0026 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared in Example 35B) in 15 ml. of methylene chloride is shaken with 10 ml. of N sodium hydroxide solution until all of the solid is dissolved. The organic layer is separated and evaporated to dryness. To a solution of the residue in 15 ml. of dimethylformamide, 0.52 g. of potassium iodide, 0.81 g. of potassium carbonate and 0.75 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added. After about 18 hours of heating at about 90° C., the solvent is removed under vacuum. The residue is dissolved in benzene and water, the organic layer washed with water and brine and evaporated to dryness. The residue is dissolved in 5 ml. of 2.5 N hydrochloric acid and 10 ml. of methanol. After standing for about 3 hours at room temperature most of the methanol is removed under vacuum. The solid that precipitates is recrystallized from methylene chloride: ethyl acetate to give 0.52 g. (46%) of 4'-fluoro-[[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)], melting at 190° to 193° C.
Anal. Calcd. for C 25 H 31 ClFNO 2 : C, 69.51; H, 7.23; N, 3.24.
Found: C, 69,62; H, 7.20; N, 3.11.
Following the procedures of Examples 37B through 39B but substituting the same and other (a) acid addition salts of spiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and (b) the 2,2-dimethyl-1,3-propanediol ketals of the same and other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts as starting materials, such as
1. spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3-bromo-4'-ethylpropiophenone,
2. 7'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrobromide[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3',4-dichlorobutyrophenone,
3. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-2'-ethoxybutyrophenone,
4. 4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-chloro-4'-ethylvalerophenone, and the like,
yields, respectively,
1. 4'-ethyl-3[[spiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenone hydrochloride[I(b)],
2. 3'-chloro-4-[[7'-chlorospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)],
3. 2'-ethoxy-4-[[6'-ethylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)],
4. 4'-ethyl-5-[[4'-acetylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenone hydrochloride[I(b)], and the like.
EXAMPLE 40B
Ethyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
A suspension of 3.03 g. (0.0128 M) of spiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 33B) in 65 ml. of methylene chloride is shaken with 50 ml. of N sodium hydroxide solution until the solid is completely dissolved. The organic layer is separated and evaporated to dryness. To an ice cooled solution of the residue in 25 ml. of pyridine, 2 ml. of ethyl chloroformate is added dropwise. After about 5 hours in the cold the mixture is poured onto ice: water. The precipitated solid is recrystallized from Skellysolve B to give 2.9 g. (83%) of ethyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], melting at 70° to 73° C.
EXAMPLE 41B
Ethyl 5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
A solution of the amine free base prepared from 1.97 g. (0.00785 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (obtained as in Example 34B), in 16 ml. of pyridine, is cooled in an ice bath. After the addition of 1.25 ml. of ethyl chloroformate the mixture is allowed to stand in the cold for about 5.5 hours and then poured into ice water. The gum that precipitates is extracted with ether. The combined extracts are washed successively with water, ice cold 2.5 N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and evaporated to dryness. The residue is chromatographed over a 250 ml. column of silica gel with elution by 5% ethyl acetate: methylene chloride. The fractions shown alike by TLC are combined to give 2.19 g. of ethyl 5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], having a melting point of 55° to 60.5° C.
EXAMPLE 42B
Ethyl 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
To an ice cooled solution of the amine free base prepared from 2.38 g. (0.00926 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (obtained as in Example 35B), in 0.82 ml. of triethylamine and 40 ml. of tetrahydrofuran, 0.87 ml. of ethyl chloroformate is added. The mixture is kept in the cold for about 6 hours and then evaporated to dryness under vacuum. The residue is dissolved in water and ether and the organic layer washed with water and brine and then evaporated to dryness. The residue is chromatographed on a 250 ml. column of silica gel with elution by 10% acetone: Skellysolve B. The fractions shown alike by TLC are combined to yield 2.22 g. (79%) of ethyl 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] as a waxy solid.
Following the procedures of Examples 40B through 42B but substituting another spiro(cyclohexane-1,2'-indan -4-amine[I(b)] and another lower alkyl haloformate, such as
1. 5'-chlorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and methyl chloroformate,
2. 4'-ethylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and propyl chloroformate, and the like,
yields, respectively,
1. methyl 5'-chlorospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],
2. propyl 4'-ethylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], and the like.
EXAMPLE 43B
Spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)]
A solution of 2.9 g. (0.0106 M) of ethyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared in Example 40B) in 50 ml. of tetrahydrofuran, is added to a well stirred suspension of 0.5 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. The mixture is heated at reflux for about 6 hours and then cooled in ice. There is added successively 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. An ether solution of the residue is treated with 6 N hydrochloric acid to give 1.8 g. (66%) of spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)], melting at 251° to 254° C.
Anal. Calcd. for C 15 H 22 ClN.1/3H 2 O: C, 69.88; H, 9.22; N, 5.43.
Found: C, 69.99; H. 8.55; N, 5.25.
EXAMPLE 44B
5'-Methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)]
To a well stirred suspension of 0.33 g. of lithium aluminum hydride in 8 ml. of tetrahydrofuran, a solution of 2.19 g. (0.00764 M) of ethyl 5'-methylspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared in Example 41B) in 50 ml. of tetrahydrofuran is added. The mixture is stirred at room temperature for about 6 hours. After cooling in an ice bath, there is added successively 0.33 ml. of water, 0.33 ml. of 15% sodium hydroxide solution and 0.99 ml. of water. The resulting inorganic gel is collected on a filter, rinsed well with ether and the filtrate evaporated to dryness. A solution of the residual gum in 35 ml. of tetrahydrofuran is added to a well stirred suspension of 0.33 g. of lithium aluminum hydride in 5 ml. of tetrahydrofuran. After about 6 hours of stirring at room temperature the reaction mixture is treated as above. The residual gum is dissolved in a small amount of ether and extracted 3 times with 20 ml. of 2.5 N hydrochloric acid. The combined extracts are washed with ether and made basic. The material that precipitates is extracted with ether and the extracts evaporated to dryness to give 5'-methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)] as gum.
EXAMPLE 45B
5'-Methoxyspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)]
To a well stirred suspendion of 0.32 g. of lithium aluminum hydride in 8 ml. of tetrahydrofuran, a solution of 2.22 g. (0.00732 M) of ethyl 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared in Example 42B) in 50 ml. of tetrahydrofuran is added. After about 18 hours of stirring at room temperature the mixture is cooled in an ice bath and there is added successively 0.32 ml. of water, 0.32 ml. of 15% aqueous sodium hydroxide solution and 96 ml. of water. The resulting precipitate is collected on a filter and the filtrate evaporated to dryness. A solution of the residue in a small amount of ether is extracted with 2.5 N hydrochloric acid. A precipitate suspended in the acid layer is extracted with methylene chloride and evaporated to dryness. The acid portion is made basic, extracted with ether and evaporated to dryness. A solution of the latter residue in ether is treated with an excess of ethereal hydrochloric acid. A precipitate is collected on a filter, combined with the residue from the methylene chloride extract, and recrystallized from methanol: ether to give 0.56 g. (35.1% yield) of 5'-methoxyspiro(cyclohexane-1,2-indan)-4-methylamine hydrochloride-[I(b)], melting at 225° to 229° C.
Anal. Calcd. for C 16 H 24 ClNO.1/2CH 3 OH: C, 66.53; H, 8.80; N, 4.70
Found: C, 66.74; H, 8.54; N, 4.82.
Following the procedures of Examples 34B through 45B but substituting another lower alkyl spiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] as starting material, such as
1. ethyl 5'-bromospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],
2. propyl 4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], and the like,
yields, respectively,
1. 5'-bromospiro(cyclohexane-1,2'-indan)-4-methyl-amine hydrochloride[I(b)],
2. 4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-methyl-amine hydrochloride[I(b)], and the like.
EXAMPLE 46B
4'-Fluoro-4-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
To a suspension of 1 g. (0.0040 M) of spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] (prepared as in Example 43B) in 20 ml. of dimethylformamide, 0.17 g. of sodium hydride is added. After about 1 hour, 0.8 g. of potassium iodide, 1.25 g. of potassium carbonate and 1.15 g. of the 2,2-dimethyl-1,3-propandiol ketal of 4-chloro-4'-fluorobutyrophenone is added to the mixture. The mixture is heated in an oil bath at about 110° C. for about 17 hours and allowed to cool. The solvent is then removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue and 7.5 ml. of 2.5 N hydrochloric acid in 15 ml. of methanol is stirred at room temperature for about 2 hours. Most of the methanol is removed under vacuum and the precipitated solid collected on a filter. This is recrystallized twice from methylene chloride: [ethyl acetate to give 0.77 g] (45%) of 4'-fluoro-4-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)], melting at 195° to 197° C., and also named 4'-fluoro-4-[spiro[cyclohexane-1,2'-indan)-4-yl-N-methylamino]butyrophenone hydrochloride.
Anal. Calcd. for C 25 H 31 ClFNO.1/2H 2 O: C, 70.65; H, 7.35; N, 3.29.
Found: C, 71.10; H, 7.44; N, 3.20.
EXAMPLE 47B
4'-Fluoro-4-[methyl[5'-methylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
A mixture of 0.72 g. (0.00314 M) of 5'-methylspiro(cyclohexane-1,2'-indan)-4-methylamine[I(b)] (prepared in Example 44B), 0.99 g. of potassium carbonate, 0.65 g. of potassium iodide and 0.9 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 16 ml. of dimethylformamide is heated in an oil bath at about 90° C. for about 18 hours. Most of the solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is stirred with 12 ml. of methanol and 6 ml. of 2.5 N hydrochloric acid for about 3 hours at room temperature. Most of the methanol is removed under vacuum and the residue extracted with methylene chloride. The extract is washed with N sodium hydroxide solution and evaporated to dryness. The residue is chromatographed on a 200 ml. column of silica gel with elution by 30% Skellysolve B: methylene chloride saturated with ammonium hydroxide. Those fractions found alike by TLC are dissolved in methylene chloride. The latter solution is washed with 2.5 N hydrochloric acid, evaporated to dryness and recrystallized from methanol: ether to yield 0.25 g. (18.5%) of 4'-fluoro-4-[methyl[5'-methylspiro[cyclohexane-1,2'-indan]butyrophenone hydrochloride[I(b)], melting at 212.5° to 214° C.
Anal. Calcd. for C 26 H 33 ClFNO: C, 72.62; H, 7.74; N, 3.26.
Found: C, 72.17; H, 7.79; N, 3.26.
EXAMPLE 48B
4'-Fluoro-4-[methyl[5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochoride[I(b)]
A mixture of the amine free base prepared from 0.84 g. (0.0030 M) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] (obtained as in Example 45B), 0.95 g. of potassium carbonate, 0.62 g. of potassium iodide and 0.86 g. of the 2,2-dimethyl-1,3-propane-diol ketal of 4-chloro-4'-fluorobutyrophenone in 15 ml. of dimethylformamide is heated in an oil bath at about 90° C. for about 18 hours. Most of the solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and then evaporated to dryness. A solution of the residue in 12 ml. of methanol and 6 ml. of 2.5 N hydrochloric acid is stirred at room temperature for about 3 hours. Most of the methanol is removed under vacuum and the residue extracted with methylene chloride. The residue is washed with N aqueous sodium hydroxide solution and evaporated to dryness. The residue is chromatographed on a 200 ml. of column of silica gel with elution by 30% Skellysolve B: methylene chloride saturated with ammonium hydroxide. Those fractions found alike by TLC are pooled and evaporated to dryness. The residue is streaked onto 3 preparative TLC plates and eluted with methylene chloride saturated with ammonium hydroxide. The band having the strongest ultraviolet absorbtion is eluted and evaporated to dryness to give 0.45 g. (33.6% yield) of p-fluoro-4-[methyl]5'-methoxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochlorede[I(b)] as an amorphous foam.
Following the procedures of Example 46B through 48B but substituting the same and other (a) acid addition salts of spiro(cyclohexane-1,2'-indan)-4-lower alkylamines [I(b)] and (b) the 2,2-dimethyl-1,3-propanediol ketal of ω-haloalkanaryl ketones in stoichiometrically appropriate amounts as starting materials, such as
1. spiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3'-bromo-3-chloropropiophenone,
2. 6'-ethylspiro(cyclohexane-1,2'-indan)-4-methyl-amine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-2'-ethoxybutyrophenone,
3. 5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-chloro-4'-propylvalerophenone and the like,
yields, respectively,
1. 3'-bromo-3-[methyl[spiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenonehydrochloride[I(b)],
2. 2'-ethoxy-4-[methyl[6'-ethylspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)],
3. 4'-propyl-5-[methyl[5'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenone hydrochloride[I(b)], and the like.
EXAMPLE 49B
1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17]
A solution of 2.6 g. (0.01 M) of spiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9] (prepared as in Example 16B) in 50 ml. of tetrahydrofuran is added to a well stirred suspension of 0.5 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran. The mixture is stirred at room temperature for about 5 hours, cooled in ice and treated successively with 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. The inorganic gel is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from cyclohexane to give 2.45 g. (95%) of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17 ], having a melting point of 125° to 128° C.
Anal. Calcd. for C 16 H 20 O 3 : C, 73.82; H, 7.74.
Found: C, 73.48; H, 7.78.
Following the procedure of Example 49B but substituting other spiro(cyclohexane-1,2'-indan)-1,4-dione alkylene ketals[9] as starting materials, such as
5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9] yields,
1'-hydroxy-5'-methoxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17].
EXAMPLE 50B
1'-Acetoxyspiro(cyclohexane-1,2'-indan)-4-one[19]
1. A solution of 2.45 g. (0.0094 M) of 1'-hydroxy-spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17] (prepared in Example 49B) and 5 ml. of 2.5 N hydrochloric acid in 50 ml. of acetone is allowed to stand for about 17 hours at room temperature. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness to give 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one[18], as a gum.
2. A solution of the 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one[18] obtained in (1), above, and 4 ml. of acetic anhydride in 16 ml. of pyridine is allowed to stand at room temperature for about 7 hours and then poured into ice:water. The precipitate is extracted with ether. This extract is washed successively with water, ice cold 2.5 N hydrochloric acid, water and saturated aqueous sodium bicarbonate solution and then evaporated to dryness. The residual solid is recrystallized from Skellysolve B to give 1.82 g. (75% yield) of 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-one[19], melting at 87° to 89° C.
Anal. Calcd. for C 16 H 18 O 3 : C, 74.39; H, 7.02.
Found: C, 73.93; H, 6.95.
Following the procedure of Example 50B but substituting other 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one alkylene ketals[17] and an anhydride of another hydrocarbon carboxylic acid for acetic anhydride, such as
1. 1'-hydroxy-4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17] and propionic anhydride,
2. 1'-hydroxy-5'-ethylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17] and isopropionic anhydride, and the like,
yields, respectively,
1. 1'-propionyloxy-4'-acetylamidospiro(cyclohexane-1,2'-indan)-4-one[19],
2. 1'-isopropionyloxy-5'-ethylspiro(cyclohexane-1,2'-indan)-4-one[19], and the like.
EXAMPLE 51B
1'-Acetoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[21]
1. To a solution of 1.82 g. (0.0071 M) of 1'-acetoxy(cyclohexane-1,2'-indan)-4-one[19] (prepared in Example 50B) in 25 of 95% isopropanol, 0.32 g. of sodium borohydride is added. Following about 1 hour of stirring at room tempeerature most of the solvent is removed under vacuum. The residue is dissolved in ether and water, the organic layer is washed with water and brine and evaporated to dryness to give 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol[20].
2. The residual gummy 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol[20] obtained in (1), above, is dissolved in pyridine. This solution is cooled in ice and treated with 1.7 ml. of methanesulfonyl chloride. After standing in the cold for about 17 hours the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water and brine and evaporated to dryness. The residue is recrystallized twice from a mixture of ether and petroleum ether to give 1.54 g. (65% yield) of 1'-acetoxyspiro(cyclohexane-1,2'-indan-4-ol methanesulfonate[21] having a melting point of 97° to 100° C.
Anal. Calcd. for C 17 H 20 O 5 S: C, 60.69; H, 5.99; M.W. 338.
Found: C, 60.60; H, 6.58; m/e 338.
Following the procedure of Example 51B but substituting other 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ones[19] and other lower alkylsulfonyl halides, such as
1. 1'-propionyloxy-5'-chlorospiro(cyclohexane-1,2'-indan)-4-one[19] and ethanesulfonyl bromide,
2. 1'-butyroyloxy-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-one[19] and butanesulfonyl chloride, and the like,
yields respectively.
1. 1'-propionyloxy-5'-chlorospiro(cyclohexane-1,2'-indan)-4-ol ethanesulfonate[21],
2. 1'-butyryloxy-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-ol butanesulfonate[21], and the like.
EXAMPLE 52B
1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)]; also named 4-aminospiro(cyclohexane-1,2'-indan)-1'-ol[I(b)]
A mixture of 5 g. (0.015 M) of 1'-acetoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[21] (obtained as in Example 51B) and 5 g. of sodium azide in 50 ml. of dimethylformamide is stirred for about 17 hours in an oil bath at about 90° C. The solvent is then removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and then evaporated to dryness to give 1'-acetoxyspiro(cyclohexane1,2'-indan)-4-ylazide[22].
A solution of the crude azide[22] in 80 ml. of tetrahydrofuran is added to 1.2 g. of lithium aluminum hydride in 20 ml. of tetrahydrofuran. After about 4.5 hours of stirring at room temperature the mixture is cooled in ice and treated successively with 1.2 ml. of water, 1.2 ml. of 15% aqueous sodium hydroxide solution and 3.6 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. The residue is recrystallized from a small amount of ethyl acetate to give 1.71 g. (53% of theoretical yield) of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)], melting at 156° to 160° C. the analytical sample melts at 158° to 161° C.
Anal. Calcd. for C 14 H 19 NO: C, 77.38; H, 8.81; N, 6.45.
Found: C, 76.98; H, 8.79; N, 6.41.
Extracting the thus obtained free base form of the compound with ether and treating the extract with the an ethereal solution of a suitable acid (e.g., hydrochloric), gives the corresponding acid addition salt form of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)].
Following the procedure of Example 52B but substituting other 1'-acyloxyspiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonates[21] as starting mateials, such as
1. 1'-acetoxy-4'-ethylspiro(cyclohexane-1,2'-indan)-4-ol propanesulfonate[21],
2. 1'-propionyloxy-5'-fluorospiro(cyclohexane-1,2'-indan)-4-ol ethanesulfonate[21], and the like,
yields, respectively,
1. 1'-hydroxy-4'-ethylspiro(cyclohexane-1,2'-indan)-4-amine[I(b)],
2. 1'-hydroxy-5'-fluorospiro(cyclohexane-1,2'-indan)-4-amine[I(b)], and the like.
EXAMPLE 53B
4'-Fluoro-4-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
A mixture of 1.71 g. (0.0079 M) of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] (prepared in Example 51B), 1.58 g. of potassium iodide, 4.25 g. of potassium carbonate and 2.28 g. of the 2,2-dimethyl-1,3-propanediol of 4-chloro-p-fluorobutyrophenone in 40 ml. of dimethylformamide is stirred for about 17 hours in an oil bath at about 90° C. The solvent is then removed under vacuum and the residue partitioned between water and benzene. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue and 7.5 ml. of 2.5 N hydrochloric acid in 15 ml. of methanol is stirred at room temperature for about 4 hours. Most of the methanol is removed under vacuum and the precipitated solid collected on a filter. This material is recrystallized to give 1.03 g. (33% yield) of 4'-fluoro-4-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)], having a melting point of 190° to 193° C.
Anal. Calcd. for C 24 H 29 ClFNO 2 : C, 68.97; H, 6.99 N, 3.35.
Found: C, 69.37; H, 7.77 N, 3.11.
Following the procedure of Example 53B but substituting the same and other (a) 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and (b) the 2,2-dimethyl-1,3-propanediol ketals of ω-haloalkanaryl ketones in stoichiometrically appropriate amounts as starting materials, such as
1. 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 2-bromo-4-ethylpropiophenone,
2. 1'-hydroxy-7'-fluorospiro(cyclohexane-1,2'-indan)-4-amine[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3',4-dichlorobutyrophenone,
3. 1'-hydroxy-6'-ethoxyspiro(cyclohexane-1,2'-indan)-4-amine[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-3-ethoxybutyrophenone, and the like,
yields, respectively,
1. 4'-ethyl-3-[[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenone hydrochloride[I(b)],
2. 3'-chloro-4-[[7'-fluoro-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride-[I(b)],
3. 3'-ethoxy-4-[[6'-ethoxy-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)], and the like.
EXAMPLE 54B
Ethyl 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
A suspension of 3.5 g. of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (obtained as in the paragraph immediately following Example 52B) in 65 ml. of methylene chloride is shaken with 50 ml. of N sodium hydroxide solution until the solid is completely dissolved. The organic layer is separated and evaporated to dryness. To an ice cooled solution of the residue in 25 ml. of pyridine, 2 ml. of ethyl chloroformate is added dropwise. After about 5 hours in the cold the mixture is poured into ice and water. The precipitated solid is recrystallized from Skellysolve B to give ethyl 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate(I(b)].
EXAMPLE 55B
1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)]
A solution of 3 g. of ethyl 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared as in Example 54B) in 50 ml. of tetrahydrofuran, is added to a well stirred suspension of 0.5 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. The mixture is heated at reflux for about 6 hours and then cooled in ice. There is added successively 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. The inorganic gel is separated by filtration and the filtrate evaporated to dryness. An ether solution of the residue is treated with 6 N hydrochloric acid to give 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)].
EXAMPLE 56B
1-[1'-Hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)]
Following the procedure of Example 36B but substituting a stoichiometrically appropriate amount of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in the first paragraph following Example 52B) as starting material, yields 1-[1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)].
Following the procedure of Example 56B but substituting other 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine acid addition salts[I(b)] and other dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
1. 5'-chloro-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and 1,6-diiodohexane,
2. 1'-hydroxy-4'-propoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and 1,4-dibromobutane, and the like,
yields, respectively,
1. 1-[5'-chloro-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-yl]hexamethyleneimine hydrochloride[I(b)],
2. 1-[1'-hydroxy-4'-propoxyspiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidine hydrochloride[I(b)], and the like.
EXAMPLE 57B
4'-fluoro-4-[methyl[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
Following the procedure of Examples 46B through 48B but substituting a stoichiometrically appropriate amount of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] (prepared as in Example 55B) as starting material, yields4'-fluoro-4-[methyl[1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)].
Following the procedure of Example 57B but substituting other 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-lower alkylamines[I(b)] and the 2,2-dimethyl-1,3-propanediol ketals of ω-haloalkanaryl ketones in stoichiometrically appropriate amounts as starting materials, such as
4'-ethoxy-1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-propylamine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-3'-ethylbutyrophenone, yields,
3'-ethyl-4-[propyl[4'-ethoxy-1'-hydroxyspiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)].
EXAMPLE 58B
1'-Chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23]
A solution of 6.5 g. (0.025 M) of 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[17] (prepared as in Example 49B) in 86 ml. of tetrahydrofuran is cooled in ice: methanol. To this there is added dropwise 15.6 ml. of 1.64 N butyl lithium in pentane, and after about 5 minutes, 2.04 ml. (3.03 g.) of methane sulfonyl chloride in 43 ml. of tetrahydrofuran. After standing for about 4 hours in the cold, the solvent is removed under vacuum. The residue is treated with ether and the inorganic solid collected on a filter. The filtrate is evaporated to dryness and the residue recrystallized from petroleum ether to give 6.06 g. (87%) of 1'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23], having a melting point of 103.5 to 108° C.
Anal. Calcd. for C 16 H 19 ClO 2 : Calcd. M.W. 278.
Found: m/e 278.
Following the procedure of Example 58B but substituting other 1'-hydroxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketals and other lower alkyl sulfonyl halides, such as
1. 1'-hydroxy-4'-chlorospiro(cyclohexane-1,2'indan)-4-one ethylene ketal[17] and ethane sulfonyl bromide,
2. 1'-hydroxy-6'-propoxyspiro(cyclohexane-1,2'indan)-4-one ethylene ketal[17] and ethane sulfonyl chloride, and the like,
yields, respectively,
1. 1'-bromo-4'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23],
2. 1'-chloro-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23], and the like.
EXAMPLE 59B
1'-Aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24]
A mixture of 3.5 g. (0.013 M) of 1'-chlorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23] (prepared as in Example 58B) and 3.5 g. of sodium azide in dimethylformamide is stirred in an oil bath at about 90° C. for about 17 hours. The solvent is removed under vacuum and the solid dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. A solution of the residue in 60 ml. of tetrahydrofuran is added to 0.5 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran. After standing for about 4.5 hours the mixture is cooled in ice and treated successively with 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide solution and 1.5 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. The residual gum is dissolved in ether and treated with 5 N hydrochloric acid in ether, to give 2.42 g. (81% yield) of 1'-aminospiro(cyclohexane1,2'-indan)-4-one ethylene ketal[24], having a melting point of 224° to 227° C.
Anal. Calcd. for C 16 H 22 ClNO 2 : M.W. 259
Found: m/e 259.
Following the procedure of Example 59B but substituting other 1'-halospiro(cyclohexane-1,2'-indan)-4-one ethylene ketals[23] as starting materials, such as
1. 1'-bromo-5'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23],
2. 1'-chloro-6'-nitrospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[23], and the like,
yields, respectively,
1. 1'-amino-5'-fluorospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24],
2. 1'-amino-6'-nitrospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24], and the like.
EXAMPLE 60B
1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26]
1. A solution of 7 g. of 1'-aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24] (prepared as in Example 59B) and 30 ml. of acetic anhydride in 60 ml. of pyridine is allowed to stand at room temperature for about 5 hours. The mixture is poured into ice: water and the precipitated gum extracted with ether. The organic layer is washed successively with watere, 2.5 N hydrochloric acid and brine and evaporated to dryness to give 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[25].
2. The residual 1'-acetamidospiro(cyclohexane-1,2'indan)-4-one ethylene ketal[25], obtained in (1), above, and 10 ml. of 2.5 N hydrochloric acid are dissolved in 100 ml. acetone. After about 20 hours at room temperature most of the solvent is removed under vacuum. The residue is dissolved in methylene chloride and water. The organic layer is washed with water and brine and evaporated to dryness. The residual gum is chromatographed on a 600 ml. column of silica gel with elution by 25% acetone in methylene chloride. The crystalline fractions are eluted with ethyl acetate: cyclohexane to give 3.81 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26], having a melting point of 113° to 116° C.
Following the procedure of Example 60B but substituting another 1'-aminospiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24] and another anhydride of a hydrocarbon carboxylic acid, such as
1. 1'-amino-4'-ethylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24] and propionic anhydride,
2. 1'-amino-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[24] and isopropionic anhydride, and the like,
yields, respectively,
1. 4'-ethyl-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-one [26],
2. 1'-isopropionylamido-6'-propoxyspiro(cyclohexane-1,2'-indan)-4-one[26], and the like.
EXAMPLE 61B
1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ols[27]
To 3.81 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[26] (prepared in Example 60B) in 100 ml. of isopropanol, 0.6 g. of sodium borohydride is added. After about 5 hours most of the solvent is removed under vacuum and the residue suspended in water. The resulting solid is collected on a filter and recrystallized from aqueous methanol. There is obtained first 0.9 g. (24% yield) of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol(isomer A)-[27], having a melting point of 247° to 250° C.
Anal. Calcd. for C 16 H 21 NO 2 : C, 74.10; H, 8.16; N, 5.40.
Found: C, 73.70; H, 8.19; N, 5.01.
On standing, there is obtained from the mother liquors 1.21 g. (32%) of 1'-acetamidospiro(cyclohexane1,2'-indan)-4-ol (isomer B)[27], having a melting point of 184° to 186° C.
Anal. Found: C, 73.91; H, 8.23; N, 5.30.
Following the procedure of Example 61B but substituting other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ones[26], such as
1. 1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-one[26],
2. 1'-isopropionylamido-5'-propylspiro(cyclohexane-1,2'-indan)-4-one[26], and the like,
yields, respectively,
1. 1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-ols[27],
2. 1'-isopropionylamido-5'-propylspiro(cyclohexane-1,2'-indan)-4-ols[27], and the like.
EXAMPLE 62B
1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomer A)[28]
A mixture of 0.9 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol (isomer A) [27] (prepared in Example 61B) in 20 ml. of pyridine is warmed until all the solid has dissolved. There is then added 1 ml. of methane sulfonyl chloride. Follwoing about 4 hours of standing at room temperature, most of the solvent is removed under vacuum. The residue is then dissolved in water and methylene chloride, and the organic layer washed successively with water, 2.5 N hydrochloric acid, water and brine. The solution is evaporated to dryness and the residue recrystallized from acetone: Skellysolve B to give 0.72 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomer A)[28], having a melting point of 137° to 139° C.
Anal. Calcd. for C 17 H 23 NO 4 S: C, 60.51; H, 6,87; N, 4.15.
Found: C, 60.10; H, 6.85; N, 4.00.
EXAMPLE 63B
1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomer B) [28]
To an ice cold solution of 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B) [27 ] (prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methane sulfonyl chloride is added. After about 5 hours in the cold the mixture is poured into ice: water. The solid that precipitates is recrystallized from acetone: Skellysolve B to give 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomer B) [28], melting at 161° to 163° C.
Anal. Calcd. for C 17 H 23 NO 4 S: C, 60.61; H, 6.87; N, 4.15; M.W. 337.
Found: C, 60.40; H, 6.97; N, 4.21; m/e 337.
Following the procedures of Examples 62B and 63but substituting other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ols[27], such as
1'-propionylamido-5'-propoxyspiro(cyclohexane-1,2'-indan)-4-ol (isomer A) [27],
yields,
1'-propionylamido-5'-propoxyspiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate (isomer A)[28].
EXAMPLE 64B
1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]
Following the procedure of Example 33B but substituting 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[28] (prepared as in Examples 62B or 63B) as starting material, yields 1'-acetomidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)].
Following the procedure of Example 64B but substituting other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol lower alkylsulfonates[28] as starting materials, such as
1. 1'-acetamido-4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-ol ethanesulfonate[28],
2. 1'-isopropionylamido-5'-fluorospiro(cyclohexane-1,2'-indan)-4-ol propanesulfonate[28], and the like,
yields, respectively,
1. 1'-acetamido-4'-ethoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)],
2. 1'-isopropionylamido-5'-fluorospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)], and the like.
EXAMPLE 65B
1'-Acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)]
Following the procedure of Example 36B but substituting 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 64B) as starting material, yields 1'-acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)].
Following the procedure of Example 65B but substituting other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amine acid addition salts [I(b)] and other dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
1. 1'-acetamido-7'-ethylspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]and 1,4-dibromobutane,
2. 5'-amino-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and 1,5-diiodopentane, and the like,
yields, respectively,
1. 1'-acetamido-1-[7'-ethylspiro(cyclohexane-1, 2'-indan)-4-yl]pyrrolidine hydrochloride[I(b)], 2. 1-[5'-amino-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride [I(b)], and the like.
EXAMPLE 66B
4'-fluoro-4-[[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl ]amino]butyrophenone hydrochloride[I(b)]
Following the procedure of Example 37B but substituting 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 64B) as starting material, yields 4'-fluoro-4[[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I-(b)].
Following the procedure of Example 66B but substituting acid addition salts of other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts, such as
1. 4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3-chloro-4'-methyl propiophenone,
2. 5'-ethyl-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-3'-ethoxybutyrophenone, and the like,
yields, respectively,
1. 4'-methyl-3-[[4'chloro-1'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenone hydrochloride[I(b)],
2. 3'-ethoxy14-[[5'-ethyl-1'-isopropionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)], and the like.
EXAMPLE 67B
Ethyl 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
Following the procedures of Example 40B through 42B but substituting 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 64B) as starting material, yields ethyl 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)].
Following the procedure of Example 67B but substituting acid addition salts of other 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines and other lower alkyl haloformates as starting materials, such as
1. 5'-bromo-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and propyl chloroformate,
2. 4'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'indan)-4-amine hydrochloride[I(b)] and butyl chloroformate, and the like,
yields, respectively,
1. propyl 5'-bromo-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)],
2. butyl 4'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], and the like.
EXAMPLE 68B
1'-Acetamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)]
Following the procedure of Example 43B but substituting ethyl 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)] (prepared as in Example 67B) as starting material, yields 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)].
Following the procedure of Example 68B but substituting other lower alkyl 1'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates[I(b)] as starting materials, such as
1. propyl 4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
2. butyl 5'-ethylamino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], and the like,
yields, respectively,
1. 4'-chloro-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)],
2. 5'-ethylamino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)], and the like.
EXAMPLE 69B
4'-fluoro-4[methyl[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
Following the procedure of Example 46B but substituting 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] (prepared as in Example 68B) as starting material, yields 4'-fluoro-4[methyl[1'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)].
Following the procedure of Example 69B but substituting acid addition salts of other 1'-acylamidospiro[cyclohexane-1,2'-indan)-4-lower alkylamines[I(b)] and the 2,2-dimethyl-1,3-propanediol ketals of other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts as starting materials, such as
1. 6'-ethoxy-1'-propionylamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3'-bromo-3-chloropropiophenone,
2. 5'-amino-1'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-chloro-2'-propoxyvalerophenone, and the like,
yields, respectively,
1. 3'-bromo-3-[methyl[6'-ethoxy-1'-propionylamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]propiophenone hydrochloride[I(b)],
2. 2'-propoxy-5-[methyl[5'-amino-1'-isopropionyl-amidospiro[cyclohexane-1,2'-indan]-4-yl]amino]valerophenone hydrochloride[I(b)], and the like.
EXAMPLE 70B
5'-Nitrospiro(cyclohexane-1,2'-indan)-4-one[29]
To an ice cooled solution of 9.04 g. (0.045 M) of spiro(cyclohexane-1,2'-indan)-4-one[11] [prepared as in (a) of Example 24B] in 45 ml. of trifluoroacetic acid, 9 ml. of nitric acid is added. After reaction in the cold for about 2 hours, the solution is poured onto ice: water. The precipitated solid is chromatographed on 1 l. of silica gel and eluted with 25% acetone: Skellysolve B. The crystalline fractions obtained are combined and recrystallized from acetone: Skellysolve B to give 7.23 g. (65% yield) of 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29] having a melting point of 124° to 128° C. The analytical sample melted at 126° to 127.5° C.
Anal. Calcd. for C 14 H 15 NO 3 : C, 68.55; H, 6.16; N, 5.71.
Found: C, 68.38; H, 6.24; N, 5.95.
EXAMPLE 71B
5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-one[31]
1. A suspension of 0.5 g. of palladium on carbon catalyst in a solution of 7.89 g. (0.32 M) of 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29] (obtained as in Example 70B) in 150 ml. of ethyl acetate is shaken under hydrogen. After about 3 hours of shaking an additional 0.5 g. of the same catalyst is added and shaking continued. When the theoretical uptake of hydrogen is observed, the catalyst is removed by filtration and a solution of 6.1 g. of p-toluenesulfonic acid in a small volume of methanol is added. The solvent is removed under vacuum and recrystallization from methanol: acetone attempted, but the ocurrence, on standing in the cold for about 65 hours, of extensive decomposition, is apparent. The material is converted to the free base, 5'-aminospiro(cyclohexane-1,2'indan)-4-one[30] .
2. A solution of the product [30], obtained in (1), above, in 40 ml. of pyridine is treated with 10 ml. of acetic anhydride. After about 5 hours the mixture is poured onto ice: water and the resulting precipitate extracted with methylene chloride. This solution is washed successively with water, 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is chromatographed on a column of 700 ml. of silica and eluted with 25% acetone: methylene chloride. The crystalline fractions are combined and recrystallized from methanol to give 3.15 g. (38%) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[31], melting at 169° to 171° C.
Anal. Calcd. for C 16 H 19 NO 2 : C, 74.68; H, 7.44; N, 5.44; M.W. 257 .
Found: C, 74.36; H, 7.54; N, 5.48; m/e 257.
Following the procedure of Example 71B but substituting other 5'-nitrospiro(cyclohexane-1,2'-indan)-4-one-[29] and other anhydrides of hydrocarbon carboxylic acids as starting materials, such as
6'-ethoxy-5'-nitrospiro(cyclohexane-1,2'-indan)-4-one[29]and propionic anhydride, yields,
6'-ethoxy-5'-propionamidospiro(cyclohexane-1,2'indan)-4-one[31] .
EXAMPLE 72B
5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33]
1. To 3.15 g. (0.012 M) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-one[31] (obtained in Example 71B) dissolved in 50 ml. of 95% isopropanol with warming on a steam bath, 0.5 g. of sodium borohydride is added. After about 4 hours of standing at room temperature, the solvent is removed under vacuum. The residue is dissolved in methylene chloride and water. The organic layer is washed with water and brine and then evaporated to dryness to give 3.03 g. of 5'-acetamidospiro(cyclohexane-1,2'-indan4-ol[32], having a melting point of 148° to 152° C.
2. A solution of the product [32], obtained in (1), above, in 30 ml. of pyridine is cooled in ice and 3 ml. methanesulfonyl chloride added. After about 5 hours in the cold, the mixture is poured onto ice: water and extracted with methylene chloride. The solution is washed successively with water, 2.5 N hydrochloric acid, water and brine and evaporated to dryness. The residue is chromatographed on a column of 300 ml. of Florisil and eluted with 25% acetone: Skellysolve B. The crystalline fractions are combined and recrystallized from ethyl acetate: cyclohexane. There is obtained 1 g. (25%) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33] having a melting point of 145° to 147° C., and a second crop of 0.2 g. (5%) melting at 143° to 145° C.
Anal. Calcd. for C 17 H 23 NO 4 S: C, 60.51; H, 6.87; N, 4.15.
Found: C, 60.52; H, 7.00; N, 4.10.
Following the procedure of Example 72B but substituting other 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ones[31], such as
4'-fluoro-5'-propionamidospiro(cyclohexane-1,2'indan)-4-one[31],
yields,
4'-fluoro-5'-propionamidospiro(cyclohexane-1,2'indan-4-ol methanesulfonate[33].
EXAMPLE 73B
5'-Acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]
1. A mixture of 1.2 g. (0.0036 M) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate[33] (obtained in Example 72B) and 1.2 g. of sodium azide in 10 ml. of dimethylformamide is stirred for about 20 hours in an oil bath at about 90° C. The solvent is then removed under vacuum and the residue partitioned between water and benzene. The organic layer is washed with water and brine and then evaporated to dryness to give 5'-acetamidospiro(cyclohexane-1,2'-indan)-41ylazide[34].
2. A solution of the residue[34], obtained in (1), above, in 150 ml. of ethyl acetate is shaken under hydrogen in the presence of 0.15 g. of 10% palladium on carbon catalyst. the catalyst is collected on a filter and the filtrate evaporated to dryness. The residue is dissolved in methanol and treated with 6 N hydrochloric acid in ether. This solution is evaporated to dryness and recrystallized from methanol: ethyl acetate, to give 0.67 g. (63% yield) of 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)], also named N-[4-aminospiro[cyclohexane1,2'-indan]-5'-yl]acetamide hydrochloride, melting at 270° to 275° C. (with decomposition).
Anal. Calcd. for C 16 H 23 ClN 2 O.1/2H 2 O: C, 63.24; H, 7.96; N, 9.22; M.W. (free base) 258.
Found: C, 62.80; H, 8.04; N, 8.72; m/e 258.
Following the procedure of Example 73B but substituting other 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-ol methanesulfonates[33] as starting materials, such as
1. 6'-ethyl-5'-propionamidospiro(cyclohexane-1,2'indan)-4-ol methanesulfonate[33],
2. 7'-bromo-5'-isopropionamidospiro(cyclohexane1,2'-indan)-4-ol methanesulfonate[33], and the like,
yields, respectively,
1. 6'-ethyl-5'-propionamidospiro(cyclohexane-1,2'indan)-4-amine hydrochloride[I(b)],
2. 7'-bromo-5'-isopropionamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)], and the like.
EXAMPLE 74B
5'-Acetamido-1-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)]
Following the procedure of Example 36B but substituting 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 73B) as starting material, yields 5'-acetamido-1-[spiro(cyclohexane-1,2'-indan)-4-yl]piperidine hydrochloride[I(b)].
Following the procedure of Example 74B but substituting other 5'-acylamido(cyclohexane-1,2'-indan)-4-amine acid addition salts[I(b)] and other dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
5'-acetamido-7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and 1,4-diiodobutane, and the like,
yields,
5'-acetamido-1-[7'-ethoxyspiro(cyclohexane-1,2'-indan)-4-yl]pyrrolidine hydrochloride[I(b)], and the like.
EXAMPLE 75B
4'-Fluoro-4-[[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b) ]
Following the procedure of Example 37B but substituting 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] (prepared as in Example 73B) as starting material, yields 4'-fluoro-4-[[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride [I(b)].
Following the procedure of Example 75B but substituting acid addition salts of other 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-amines[I(b)] and other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts, such as
6'-ethyl-5'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-3'-ethoxybutyrophenone,
yields,
3'-ethoxy-4-[[6'-ethyl-5'-isopropionylamidospiro[cyclohexane-1,2'-indan]4-yl]amino]butyrophenone hydrochloride[I(b)].
EXAMPLE 76B
Ethyl 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)]
Following the procedure of Example 40B but substituting 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[1(b)] (prepared as in Example 73B) as starting material, yields ethyl 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate[1(b)].
Following the procedure of Example 76B but substituting acid addition salts of other 5'-acylamidospiro(cyclohdexane-1,2'-indan)-4-amines and other lower alkyl haloformates as starting materials, such as
4'-propyl-5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)]and propyl chloroformate,
yields,
propyl 4'-propyl-5'-propionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)].
EXAMPLE 77B
5'-Acetamidospiro(cyclohexane-1,2'indan)-4-methylamine hydrochloride[I(b)]
Following the procedure of Example 43B but substituting ethyl 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-carbamate [I(b) ] (prepared as in Example 76B) as starting material, gives 5'-acetamidospiro(cyclohexane-1,2'-indan)4-methylamine hydrochloride[I(b) ].
Following the procedure of Example 77B but substituting other lower alkyl 5'-acylamidospiro(cyclohexane-1,2'-indan)-4-carbamates[I(b)] as starting materials, such as
butyl 7'-ethoxy-5'-isopropionylamidospiro(cyclohexane-1,2'-indan)-4-carbamate[I(b)], and the like,
yields,
7'-ethoxy-5'-isopropionylamidospiro(cyclohexane1,2'-indan)-4-propylamine hydrochloride[I(b)], and the like.
EXAMPLE 78B
4'-Fluoro-4-[methyl[5'-acetamidospiro[cyclohexane-1,2'-indan]-4-yl]amino]butyrophenone hydrochloride[I(b)]
Following the procedure of Example 46B but substituting 5'-acetamidospiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride[I(b)] (prepared as in Example 77B) as starting material, yields 4'-fluoro-4-[methyl[5'-acetamidospiro[cyclohexane-1,2'-indan]4-yl]amino]butyrophenone hydrochloride [I(b)].
EXAMPLE 79B
4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetic acid[36]
1. A chip of iodine is added to a well stirred mixture of 5.87 g. (0.029 M) of spiro(cyclohexane-1,2'-indan)-4-one [11] ]prepared as in (1) of Example 24B], 6 g. of the known compound methyl α-bromopropionate and 4 g. of zinc wool, and the reaction started by heating the mixture of reflux. After about 6 hours the mixture is allowed to cool, the excess metal separated on a filter, and the filtrate washed successively with 2.5 N hydrochloric acid, water and brine and then evaporated to dryness. The residue is chromatographed on a column of 800 ml. of silica gel and eluted with 5% acetone: Skellysolve B. The fractions similar by thin layer chromatography are combined to give 4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetate[35] as an oil.
2. A mixture of the oily ester [35], obtained in (1), above, 10 ml. of 50% aqueous sodium hydroxide solution and 10 ml. of water in 100 ml. of methanol, is stirred with heating at reflux for about 17 hours. The solvent is then removed under vacuum. A suspension of the residue in water and ether is made strongly acidic, the organic layer washed with brine and water and then evaporated to dryness. The residual solid is recrystallized from ether: Skellysolve B to give 3.98 g. (50%) of 4-hydroxy-α-methylspiro(cyclohexane-1,2'-indan)-4-acetic acid-[36], melting at 111° to 114° C.
Anal. Calcd. for C 17 H 22 O 3 : C, 74.48; H, 8.30.
Found: C, 74.42; H, 8.08. EXAMPLE 80B Sprio(cyclohexane-1,240 -indan)-Δ 4 ,.sup.α -acetic acid[38]
1. To 4.02 g. of triethylphosphono acetate in 50 ml. of tetrahydrofuran, 0.84 g. of 56% sodium hydride (in mineral oil) is added. After about 10 minutes, 3.59 g. (0.018 M) of spiro(cyclohexane-1,2-'-indan)-4-one[11] [prepared as in (1) of Example 24B] in 50 ml. of tetrahydrofuran, is added. The mixture is heated at reflux for about 3 hours and allowed to cool. After standing at room temperature for about 17 hours, 100 ml. of 2.5 N hydrochloric acid is added. The organic layer is separated, washed with water and brine and evaporated to dryness to give spiro(cyclohexane-1,2'-indan)-Δ 4 ,.sup.α -acetate [37].
2. A mixture of the residual gum [36], obtained in (1), above, 6 ml. of 50% aqueous sodium hydroxide solution and 10 ml. of water in 100 ml. of methanol is heated at reflux for about 5 hours. The methanol is then removed under vacuum, the resulting residue diluted with water and acidified, and the precipitate that forms extracted with ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized twice from acetone: Skellysolve B to give 2.67 g. (61% yield) of spiro(cyclohexane-1,2'-indan)-Δ 4 ,.sup.α -acetic acid[38], melting at 119° to 121° C.
Anal. Calcd. for C 16 H 18 O 2 : C, 79.31; H, 7.49.
Found: C, 79.38; H, 7.70.
EXAMPLE 81B
spiro(cyclohexane-1,2'-indan)acetic acid[39] A mixture of 1.67 g. (0.0069 M) of spiro(cyclohexane-1,2'-indan)-Δ 4 ,.sup.α -acetic acid [38] (prepared as in Example 80B) and 0.15 g. of Adams catalyst is shaken under hydrogen until the theoretical uptake is observed (about 25 hours). The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ether: Skellysolve B to give 1.48 g. (88%) of spiro(cyclohexane11,2'-indan)acetic acid[39] having a melting point of 134° to 137°C.
Anal. Calcd. for C 16 H 20 O 2 : C, 78.65; H, 8.25.
Found: C, 78.50; H, 8.17.
EXAMPLE 82B
1'-Hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [40]
A solution of 5 g. (0.019 M) of spiro(cyclohexane-1,2'-indan)-1', 4-dione 4-ethylene ketal [9](prepared as in Example 16B) in 60 ml. of tetrahydrofuran is added to 67 ml. of 3M methyl magnesium bromide in ether. After standing for about 17 hours at room temperature, the mixture is cooled in ice and treated cautiously with 50 ml. of saturated ammonium chloride. The organic layer is separated, diluted with benzene and washed with water and brine. The solution is evaporated to dryness and recrystallized from methylene chloride: cyclohexane to give 3.7 g. (71%) of 1'-hydroxy-1' -methylspiro(cyclohexane- 1,2'-indan)-4-one ethylene ketal [40], melting at 140° to 143°C.
Anal. Calcd for C 17 H 22 O 3 : C, 74.47; H, 8.08.
Found: C, 74.21; H, 8.09.
Following the procedure of Example 82B but substituting other spiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketals[9] as starting materials, such as
4'-ethoxyspiro(cyclohexane-1,2'-indan)-1',4-dione ethylene ketal[9], yields,
4'-ethoxy-1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[40].
EXAMPLE 83B
1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-one [41]
A solution of 9.82 g. (0.036 M) of 1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [40](prepared as in Example 82B) and 25 ml. of 2.5 N hydrochloric acid in 250 ml. of acetone is stirred at room temperature for about 17 hours. The solvent is then removed under vacuum and the residue dissolved in ether and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized from petroleum ether to give 5.12 g. (67%) of 1'-exomethylenespiro(cyclohexane-1,2'-indan)-4-one[41], having a melting point of 60° to 62°C. The NMR spectrum of this compound is in agreement with its expected structure.
Following the procedure of Example 83B but substituting other 1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketals[40] as starting materials, such as
6'-chloro-1'-hydroxy-1'-methylspiro(cyclohexane-1,2'-indan)-4-one ethylene ketal[40], yields,
6'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'indan)-4-one[41].
EXAMPLE 84B
1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42]
A mixture of 2.17 g. (0.010 M) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41] (prepared as in Example 83B) and 0.75 g. of sodium borohydride in 40 ml. of isopropanol is stirred at room temperature for about 6 hours. The solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on a column of 250 ml. of silica gel and eluted with 20% acetone: Skellysolve B. There is obtained 0.08 g. of solid, having a melting point of 65° to 69° C. and an NMR spectrum in agreement with the structure of a compound having its hydroxy substitutent in the axial position, namely, 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-trans-ol[42]. This is followed by a gum that crystallizes only in the presence of water, giving 1.71 g. (78% yield) of product melting at 57° to 61° C. and an NMR spectrum in agreement with the structure of a compound having its hydroxy substituent in the equatorial position, namely, 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-cis-ol[42].
Following the procedure of Example 84B but substituting other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ones [41] as starting materials, such as
1. 4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41],
2. 5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-one[41], and the like,
yields, respectively,
1. trans and cis 4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42],
2. trans and cis 5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42], and the like.
EXAMPLE 85B
1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43]
To an ice cold solution of 4.26 g. (0.020 M) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42] (prepared as in Example 84β) in 40 ml. of pyridine, 4.3 ml. of methanesulfonyl chloride is added. After about 7 hours the mixture is poured into ice: water. The gum that precipitates is extracted with ether and the organic layer washed successively with water, 2.5 N hydrochloric acid, water and brine, then evaporated to dryness. The residue is recrystallized from a small amount of methanol to give 4.82 g. (83%) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43], have a melting point of 72° to 74° C.
Anal. Calcd. for C 16 H 20 O 3 S: C, 65.72; H, 6.89; M.W. 292.
Found: C, 65.12; H, 7.12; m/e 292.
Following the procedure of Example 85B but substituting other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)4-ols[42] as starting materials, such as
7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol[42],
yields,
7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43].
EXAMPLE 86B
1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)]
A mixture of 5.65 g. (0.019 M) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [43] (prepared as in Example 85B) and 5.65 g. of sodium azide is heated for about 17 hours in an oil bath at about 90° C. The solvent is removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine evaporated to dryness to give 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ylazide[44]. The residue [44] in 80 ml. of tetrahydrofuran is added to 0.75 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran. After about 5 hours at room temperature the mixture is cooled in ice and treated successively with 0.75 ml. of water, 0.75 ml. of water, 0.75 ml. of 15% aqueous sodium hydroxide solution and 2.25 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. An ether solution of the residue is treated with 6 N hydrogen chloride in ether. The precipitated salt is recrystallized from methylene chloride to give 3.08 g. (61%) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)], having a melting point of 250° to 253° C.
Anal. Calcd. for C 15 H 20 ClN.H 2 O: C, 67.29; H, 8.29; N, 5.23.
Found: C, 67.50; H, 7.92; N, 5.21.
Following the procedure of Example 86B but substituting other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)4-ol methanesulfonates [43] as starting materials, such as
5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-ol methanesulfonate [I(b)],
yields,
5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)].
EXAMPLE 87B
1-[1'-Methylenespiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)]
The amine prepared from 1.41 g. (0.0056 M) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)], 1,81 g. of 1,5-diiodopentane and 1.55 g. of potassium carbonate in 15 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture is allowed to cool, diluted with water and the solid collected on a filter. The solid is recrystallized from methanol to give 1.05 g. (67% yield) of 1-[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]piperidine [I(b)], also named 1'exo-methylenespiro(cyclohexane-1,2'-indan)piperidine, having a melting point of 93° to 95° C.
Anal. Calcd. for C 20 H 27 N: C, 85,35; H, 9.67; N, 4.90.
Found: C, 85.58; H, 9.99; N, 5.24.
Following the procedure of Example 87B but substituting other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine acid addition salts [I(b)]and other dihaloalkanes in stoichiometrically appropriate amounts as starting materials, such as
5'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride[I(b)] and 1,6-dibromohexane,
yields,
1-[5'-chloro-1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl] hexamethyleneimine hydrochloride [I(b)].
EXAMPLE 88B
4'-Fluoro-4-[[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenone hydrochloride [I(b)]
A mixture of the free base obtained from 2 g. (0.0080 M) of 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] (prepared as in Example 86B), 1.6 g. of potassium iodide, 2.49 g. of potassium carbonate and 2.32 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 40 ml. of dimethylformamide is stirred in an oil bath at about 90° C. for about 18 hours. The solvent is then removed under vacuum and the residue dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is stirred with 15 ml. of 2.5 N hydrochloric acid and 30 ml. of methanol for about 3 hours. The methanol is then removed and the solid collected on a filter. This material is recrystallized from methanol: ethyl acetate to give 0.95 g. (29%) of 4'-fluoro-4-[[1'-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenone hydrochloride [I(b)], having a melting point of 208° to 211° C.
Anal. Calcd. for C 25 H 29 ClFNO: C, 72.53; H, 7.06; N, 3.38.
Found: C, 72.20; H, 7.19; N, 3.68.
Following the procedure of Example 88B but substituting acid addition salts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amines [I(b)] and other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts, such as
4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 3-chloro-4'-methylpropiophenone,
yields.
4'-methyl-3-[[4'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]propionphenone hydrochloride [I(b)].
EXAMPLE 89B
Ethyl 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)]
Following the procedure of Example 40B but substituting 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] (prepared as in Example 86B) as starting material, yields, ethyl-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)].
Following the procedure of Example 89B but substituting acid addition salts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amines [I(b)] and other lower alkyl haloformates, such as
6'-chloro-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-amine hydrochloride [I(b)] and butyl chloroformate,
yields,
butyl 6'-chloro-1'-exo-methylenespiro(cyclohexane1,2'-indan)-4-carbamate [I(b)].
EXAMPLE 90B
1'-Exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride [I(b)]
Following the procedure of Example 43B but substituting ethyl 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamate [I(b)] (prepared as in Example 89B) as starting material, yields 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride [I(b)].
Following the procedure of Example 90B but substituting other lower alkyl 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-carbamates [I(b)] as starting materials, such as
butyl 5'-ethoxy-1'-exo-methylenespiro(cyclohexane1,2'-indan)-4-carbamate [I(b)],
yields,
5'-ethoxy-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride [I(b)], and the like.
EXAMPLE 91B
4'-Fluoro-4-[methyl[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenone hydrochloride [I(b)]
Following the procedure of Example 46B but substituting 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methyl-amine hydrochloride [I(b)] (prepared as in Example 90B) as starting material, yields 4'-fluoro-4-[methyl[1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]butyrophenone hydrochloride [I(b)].
Following the procedure of Example 91B but substituting acid addition salts of other 1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-lower alkylamines [I(b)] and the 2,2-dimethyl-1,3-propanediol ketals of other ω-haloalkanaryl ketones in stoichiometrically appropriate amounts, such as
7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-methylamine hydrochloride [I(b)] and the 2,2-dimethyl-1,3-propanediol ketal of 5-chloro-4'-propylvalerophenone,
yields,
4'-propyl-5-[methyl[7'-bromo-1'-exo-methylenespiro(cyclohexane-1,2'-indan)-4-yl]amino]valerophenone hydrochloride [I(b)].
EXAMPLE 1C
4-Benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal(1)
A solution of 22.3 g. (0.77 M) of 4-benzyl-4-carbomethoxy-1-cyclohexaneone ethylene ketal [5] (prepared as in Example 4B) in 220 ml. of tetrahydrofuran is added to 3 g. of lithium aluminum hydride in 30 ml. of tetrahydrofuran. The mixture is stirred at reflux temperature for about 5.5 hours and then cooled in ice. There is added successively 3 ml. of water, 3 ml. of aqueous 15% sodium hydroxide solution and 9 ml. of water. The inorganic gel is collected on a filter and the filtrate evaporated to dryness. The residue is recrystallized from methylene chloride: Skellysolve B to give 18.8 g. (93% yield) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal (1), having a melting point of 76° to 78° C.
Anal. Calcd. for C 16 H 22 O 3 : C, 73.25; H, 8.45.
Found: C, 73.08; H, 8.65.
Following the procedure of Example 1C but substituting other 4-benzyl-4-carbomethoxy-1-cyclohexanone ethylene ketals [5] as starting materials, such as
1. 4-(p-methylbenzyl)-4-carbomethoxy-1-cyclohexane ethylene ketal [5],
2. 4-(m-methoxybenzyl)-4-carbomethoxy-1-cyclohexane ethylene ketal [5], and the like,
yields respectively,
1. 4-(p-methylbenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal (1),
2. 4-(m-methoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal (1), and the like.
EXAMPLE 2C
4-Benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2)
To an ice cold solution of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal (1) (prepared in Example 1C) in 100 ml. of pyridine, 19 ml. of methanesulfonyl chloride is added. After standing in the cold for about 5.5 hours, the mixture is poured into ice: water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, ice cold 2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, and then evaporated to dryness. The residual solid is recrystallized from methylene chloride: Skellysolve B to give 21.1 g. (86%) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2).
Following the procedure of Example 2C but substituting other 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketals (1) as starting materials, such as
1. 4-(p-ethoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal (1),
2. 4-(m-propionylamidobenzyl)-4-hydroxymethylcyclohexan-1-ethylene ketal (1), and the like,
yields, respectively,
1. 4-(p-ethoxybenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2),
2. 4-(m-propionylamidobenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2), and the like.
EXAMPLE 3C
4-Benzylcyclohexan-4-acetic acid-1-one ethylene ketal (4)
1. A mixture of 18.6 g. (0.055 M) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2) (prepared as in Example 2C) and 18 g. of potassium cyanide in 180 ml. of hexamethylphosphoramide is heated for about 17 hours in an oil bath at about 145° C. The resulting gel is allowed to cool, diluted to 800 ml. with water and extracted with benzene. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on 1 l. of silica gel and eluted with 25% ethyl acetate in Skellysolve B and the fractions found similar to TLC pooled to give 4-benzyl-4-cyanocyclohexan-1-one ethylene ketal (3).
2. The product (3), obtained in part (1), above, is heated with 14.5 g. of potassium hydroxide in 105 ml. of ethylene glycol for about 17 hours. The mixture is then allowed to cool, diluted with water and washed once with ether. The aqueous layer is then covered with ether and cautiously acidified. The organic layer separated, washed with brine and evaporated to dryness. The residue is recrystallized from cyclohexane to give 12.3 g. (77%) of 4-benzylcyclohexan-4-acetic acid-1-one ethylene ketal (4), melting at 116° to 118° C. The analytical sample has a melting point of 118° to 120° C.
Anal. Calcd. for C 17 H 22 O 4 : C, 70.32; H, 7.64.
Found: C, 70.50; H, 7.83.
Following the procedure of Example 3C but substituting other 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketals (2) as starting materials, such as
1. 4-(o-aminobenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2),
2. 4-(m-fluorobenzyl)-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2), and the like,
yields, respectively,
1. 4-(o-aminobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),
2. 4-(m-fluorobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4), and the like.
EXAMPLE 4C
4-Benzylcyclohexan-4-acetic acid-1-one (5)
A solution of 12.3 g. of 4-benzylcyclohexan-4-acetic acid-1-one ethylene ketal (4) (prepared in Example 3C) and 18 ml. of 2.5 N hydrochloric acid in 180 ml. of acetone is stirred at room temperature for about 62 hours. Most of the solvent is removed under vacuum and the residue dissolved in ether and water. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized from ether: Skellysolve B to give 7.94 g. (76%) of 4-benzylcyclohexan-4-acetic acid-1-one (5), having a melting point of 85° to 87° C. The analytical sample has a melting point of 91° to 92° C.
Anal. Calcd. for C 15 H 18 O 3 : C, 73.15; H, 7.37.
Found: C, 73.01; H, 7.58.
Following the procedure of Example 4C but substituting other 4-benzylcyclohexan-4-acetic acid-1-one ethylene ketals (4) as starting materials, such as
1. 4-(p-ethoxybenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4),
2. 4-(m-nitrobenzyl)cyclohexan-4-acetic acid-1-one ethylene ketal (4), and the like,
yields, respectively,
1. 4-(p-ethoxybenzyl)cyclohexan-4-acetic acid-1-one (5),
2. 4-(m-nitrobenzyl)cyclohexan-4-acetic acid-1-one (5),
and the like.
EXAMPLE 5C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6)
A solution of 6.43 g. (0.026 M) of 4-benzylcyclohexan-4-acetic acid-1-one (5) (prepared as in Example 4C) in 40 ml. of freshly distilled hydrogen fluoride is allowed to evaporate at room temperature for about 62 hours. The residue is dissolved in methylene chloride and this solution is washed successively with aqueous sodium bicarbonate solution, water and brine. The solution is evaporated to dryness and chromatographed on a colulmn of 650 ml. of silica gel and eluted with 20% acetone: Skellysolve B. The crystalline fractions are combined and recrystallized from 20% acetone: Skellysolve B to give 1.95 g. (33%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene-4',4-dione (6), having a melting point of 158° to 160° C.
Anal. Calcd. for C 15 H 16 O: C, 78.92; H, 7.06; M.W. 228.
Found: C, 78.69; H, 7.31; m/e 228.
Following the procedure of Example 5C but substituting other 4-benzylcyclohexan-4-acetic acid-1-ones (5) as starting materials, such as
1. 4-(6'-methylaminobenzyl)cyclohexan-4-acetic acid-1-one (5),
2. 4-(7'-chlorobenzyl)cyclohexan-4-acetic acid-1-one (5), and the like,
yields, respectively,
1. 3',4'-dihydro[6'-methylaminospiro[cyclohexane-1,2'(1'H)-naphthalene]-1',4-dione (6),
2. 3',4'-dihydro[7'-chlorospiro[cyclohexane-1,2'-(1'H)-naphthalene]-1',4-dione (6), and the like.
EXAMPLE 6C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione, 4-(ethylene ketal) (7)
A mixture of 2.65 g. (0.012 M) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione (6) (prepared as in Example 5C), 0.72 g. (0.65 ml.) of ethylene glycol and 0.20 g. of p-toluenesulfonic acid in 100 ml. of benzene is heated at reflux under a Dean-Stark trap for about 14 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution and brine and evaporated to dryness. The residue is chromatographed on a 300 ml. column of silica gel and eluted with 25% ethyl acetate: Skellysolve B to give 2.2 g. (70%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]4',4-dione, ethylene ketal (7), melting at 90° to 91.5° C.
Anal. Calcd. for C 17 H 20 O 3 : C, 74.97; H, 7.40.
Found: C, 75.00; H, 7.66.
Following the procedure of Example 6C but substituting other 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-diones (6) as starting materials, such as
1. 3',4'-dihydro[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-1',4-dione (6),
2. 3',4'-dihydro[6'-ethylspiro[cyclohexane-1,2'-(1'H)-naphthalene]-4',4-dione (6), and the like,
yields, respective
1. 3',4'-dihydro[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione, 4-(ethylene ketal) (7),
2. 3',4'-dihydro[6'-ethylspiro[cyclohexane-1,2'-(1'H)-naphthalene]-4',4-dione, 4-(ethylene ketal) (7), and the like.
EXAMPLE 7C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal (8)
A mixture of 2.2 g. (0.0081 M) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione, 4-(ethylene ketal) (7) (prepared in Example 7C), 1.2 ml. of hydrazine hydrate and 1.6 g. of potassium hydroxide, is heated at reflux for about 1 hour. Solvent is removed by distillation to bring the temperature of the reaction mixture to about 200° C., and the refluxing is continued for about 17 hours, The mixture is then poured into water and extracted with ether. The organic layer is washed with water and brine and evaporated to dryness. The residue is recrystallized from petroleum ether to give 1.86 g. (88%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen] 4-one, ethylene ketal (8), having having a melting point of 79° to 81° C.
Anal. Calcd. for C 17 H 22 O 2 : C, 79.03; H, 8.59.
Found: C, 79.14; H, 8.72.
Following the procedure of Example 7C but substituting other 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione, 4-(ethylene ketals) (7) as starting materials, such as
3',4'-dihydro[7'-nitrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4',4-dione, 4-(2,2-dimethyltrimethylene ketal) (7)
yields,
3',4'-dihydro[7'-nitrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-one, ethylene ketal (8).
EXAMPLE 8C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10)
1. A mixture of 1.86 g. (0.0072 mole) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal (8) (prepared in Example 7C) and 2 ml. of 2.5 N hydrochloric acid in 40 ml. of acetone is heated at reflux for about 17 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and then evaporated to dryness to give 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (9).
2. The residue (9), obtained in part (1), above, is dissolved in 50 ml. of 95% isopropanol and treated with 1 g. of sodium borohydride. After about 5 hours the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine, evaporated to dryness, the crude produce chromatographed on a 170 ml. column of silica gel and eluted with methylene chloride. There is first obtained 0.24 g. of starting material (8). The product fractions are combined and recrystallized from Skellysolve B to give 0.65 g. (42%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10), melting at 78° to 82° C.
Anal. Calcd. for C 15 H 20 O: C, 82.28; H, 9.32. M.W. 216.
Found: C, 83.37; H, 9.43, m/e 216.
Following the procedure of Example 8C but substituting other 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketals (8) as starting materials, such as
3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, 2,2-dimethyltriethylene ketal (8), yields,
3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10).
EXAMPLE 9C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol methanesulfonate (11)
To an ice cold solution of 2.16 g. (0.01 M) of 3', ,4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10) (prepared as in Example 8C) in 10 ml. of pyridine, 2 ml. of methanesulfonyl chloride is added. After about 4 hours in the cold, the mixture is poured onto ice: water. The resulting solid precipitate is collected on a filter and recrystallized from ether: petroleum ether to give 2.52 g. (86%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol methansulfonate (11), melting at 66° to 69° C.
Anal. Calcd. for C 16 H 22 O 3 S: C, 65.27; H, 7.53
Found: C, 65.38; H, 7.54.
Following the procedure of Example 9C but substituting other 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ols (10) and other lower alkyl sulfonyl halides as starting materials, such as
3',4'-dihydro[5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol (10) and propane sulfonyl bromide, yields,
3',4'-dihydro[5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol propanesulfonate (11).
EXAMPLE 10C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)]
A mixture of 2.52 g. (0.0085 M) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol methanesulfonate (11) (prepared in Example 9C) and 2.5 g. of sodium azide in 25 ml. of dimethylformamide is heated for about 17 hours in an oil bath at about 90° C. The solvent is then removed under vacuum and the residue, 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-napthalen]-4-ylazide, dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. A solution of the residue in 60 ml. of tetrahydrofuran is added to 0.35 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran. After stirring for about 4 hours at room temperature, the mixture is cooled in ice and treated successively with 0.35 ml. of water, 0.35 ml. of aqueous 15% sodium hydroxide solution and 1.05 ml. of water. The resulting inorganic gel is collected on a filter and the filtrate evaporated to dryness. A solution of the residue in ether is treated with 6 N hydrogen chloride in ether. The resulting solid is recrystallized from methylene chloride: ethyl acetate to give 1.65 g. (77%) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)], melting at 208° to 211° C.
Following the procedure of Example 10C but substituting other 3',4'-dihydrospiro[cyclohexane-1,2'(1'-H)-naphthalen]-4-ol lower alkylsulfonates (11) as starting materials, such as
3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ol propanesulfonate (11), yields,
3',4'-dihydro[6'-fluorospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)].
EXAMPLE 11C
1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)]
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of 1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture after cooling is diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)].
Following the procedure of Example 11C but substituting acid addition salts of the same and other 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamines [I(c)] and other dihaloalkanes, such as
1. 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] and 1,4-diiodobutane,
2. 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] and 1,6-diiodohexane,
3. 5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] and 1,5-diiodopentane and the like,
yields respectively,
1. 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl pyrrolidine [I(c)],
2. 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl hexamethyleneimine [I(c)],
3. 1-[5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl piperidine [I(c)], and the like.
EXAMPLE 12C
4'-Fluoro-4-[[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenone hydrochloride [I(c)]
The free base from 1.65 g. (0.0066 M) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared in Example 10C), 1.34 g. of potassium iodide, 2.06 g. of potassium carbonate and 1.9 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 35 ml. of dimethylformamide are heated in an oil bath at about 90° C. for about 18 hours. The solvent is removed under vacuum and the residue that remains in dissolved in benzene and water. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue and 10 ml. of 2.5 N hydrochloric acid in 20 ml. of methanol is stirred at room temperature for about 4 hours. The methanol is then removed under vacuum and the solid collected on a filter. This material is recrystallized twice from methylene chloride: ethyl acetate to give 1.07 g. (39% yield) of 4'-fluoro-4-[[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenone hydrochloride [I(c), having a melting point of 182° to 184° C.
Anal. Calcd for C 25 H 31 ClFNO: C, 72.18; H, 7.51; N, 3.37; M.W. 379.
Found: C, 72.20; H, 7.53; N, 3.47; m/e 379.
Following the procedure of Example 12C but substituting another 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] as starting material and the 2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkanaryl ketone, such as
5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of 4'-bromo-4-chlorobutyrophenone,
yields,
4'-bromo-4-[[5'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]amino]butyrophenone hydrochloride [I(c)].
EXAMPLE 13C
Ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)]
To an ice cooled solution of the free base prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C) in 12 ml. of pyridine, 1 ml. of ethyl chloroformate is added. The mixture is allowed to stand in the cold for about 5 hours and then poured into ice water. The solid that precipitates is collected on a filter and recrystallized from methylene chloride: benzene to give ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)].
Following the procedure of Example 13C but substituting another 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] as starting material and another lower alkyl haloformate, such as
5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine [I(c)] and propyl bromoformate, and the like,
yields,
propyl 5'-ethoxyspiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)].
EXAMPLE 14C
3',4'-Dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine hydrochloride [I(c)]
To a suspension of 0.22 g. of lithium aluminum hydride in 10 ml. of tetrahydrofuran, a tetrahydrofuran solution of 1.3 g. of ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)] (prepared as in Example 13C) is added. The mixture is stirred at reflux temperature for about 6 hours, at room temperature for about 18 hours, and cooled in an ice bath. To this is added successively, 0.22 ml. of water, 0.22 ml. of 15% aqueous sodium hydroxide solution and 0.66 ml. of water. The resulting inorganic gel is collected on a filter, rinsed with ether and the filtrates evaporated to dryness. The residue is dissolved in a small amount of ether and treated with an excess of 6.4 N hydrogen chloride in ether. The resulting precipitate is collected on a filter and recrystallized from methanol: ethyl acetate to give 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]- 4-yl-N-methyl-amine hydrochloride [I(c)].
Following the procedure of Example 14C but substituting another lower alkyl 3',4'-dihydrospiro[cyclohexane-1,2'-(1'H)-naphthalene]-4-carbamate [I(c)] as starting material, such as
ethyl 5'-isopropylspiro[cyclohexane-1,2'(1'H)-naphthalen3]-4-carbamate [I(c)], yields,
5'-isopropylspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine hydrochloride [I(c)].
EXAMPLE 15C
4'-Fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]-butyrophenone hydrochloride [I(c)]
A mixture of the free base prepared from 0.81 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine hydrochloride [I(c)] (obtained as in Example 14C), 0.63 g. of potassium iodide, 0.96 g. of potassium carbonate and 0.87 g. of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone in 15 ml. of dimethylformamide is heated together in an oil bath at about 90° C. for about 20 hours. The solvent is removed under vacuum and the residue dissolved in water and benzene. The organic layer is washed with water and brine and evaporated to dryness. A mixture of the residue, 6 ml. of 2.5 N hydrochloric acid and 12 ml. of methanol is stirred at room temperature for about 1.5 hours and most of the methanol removed under vacuum. The residual suspended solid is collected on a filter, washed with ether and recrystallized from methanol: ethyl acetate to give 4'-fluoro-4-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]butyrophenone hydrochloride [I(c)].
Following the procedure of Example 15C but substituting another 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-lower alkylamine [I(c)] as starting material and the 2,2-dimethyl-1,3-propanediol ketal of another ω-haloalkanaryl ketone, such as
1. 6'-bromospiro(cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamine [I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-methoxybutyrophenone,
2. 5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-ethylamine [I(c)] and the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-2'-ethylbutyrophenone, and the like.
yields, respectively,
1. 4'-methoxy-4-[6'-bromospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-methylamino]butyrophenone hydrochloride [I(c)],
2. 2'-ethyl-4-[5'-propoxyspiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl-N-ethylamino]butyrophenone hydrochloride [I(c)], and the like.
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This invention relates to novel benzospiran derivatives embraced by the formula ##SPC1##
Wherein the sum of A and B is at least the integer 2; A is selected from the group consisting of --(CH 2 ) n -- wherein n is 1 through 5 and --(C n H 2n -- 2 XY)-- wherein X is selected from the group consisting of hydroxy, acetoxy, amino and acetamido and Y is hydrogen, and X when taken together with Y is selected from the group consisting of =O and =CR 3 R 4 wherein R 3 and R 4 are selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; B is absent or --(CH 2 ) n -- wherein n is 1 through 3; R 1 is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R 2 is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, ##EQU1## WHEREIN N IS 2 THROUGH 5 AND Ar is phenyl having zero through three substituents selected from the group consisting of lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms, bromine, chlorine and fluorine; R 1 and R 2 taken together with --N< is a saturated heterocyclic amino radical selected from the group consisting of unsubstituted and substituted pyrrolidino, piperidino, and hexamethylenimino; Z is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, lower alkoxy of 1 through 3 carbon atoms, nitro, amino, monoalkylamino of 1 through 3 carbon atoms, acylamido of 1 through 4 carbon atoms, bromine, chlorine and fluorine; and a pharmacologically acceptable acid addition salt thereof. It also relates to intermediates and processes for the preparation of the aforesaid novel compounds (1) and novel derivatives thereof. The administration to humans and animals of the novel compounds (1) depresses their central nervous systems and lowers their blood pressures.
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FIELD OF THE INVENTION
[0001] This invention relates in general to portable fluid storage tanks and, in particular, to a large capacity portable fluid storage tank used to store well fracturing fluids.
BACKGROUND OF THE INVENTION
[0002] Portable fluid storage tanks used to store well fracturing fluids are well known in the art. Such tanks are available in two general types: trailer tanks and skidded tanks. Trailer tanks are horizontal tanks shaped much like a semi-truck trailer and have at least one rear axle with wheels. Trailer tanks generally have a capacity of about 350-500 barrels. They are towed by a trailer tractor to a well site and parked in side-by-side and back-to-back double rows. A frac manifold must be installed between each pair of double rows to pump fluid from the tanks. Skidded tanks are cylindrical tanks with skids welded to a side surface. The skidded tanks generally have a capacity of about 200-500 barrels. The skidded tanks are transported to a well site on specially designed trucks or trailers, where they are offloaded and normally tipped to an upright position using cables or chains pulled by winches or a suitable vehicle.
[0003] Each type of tank has its advantages and disadvantages. Trailer tanks have a low profile but occupy a large area per barrel of fluid capacity. Skidded tanks, once tipped upright, occupy less area per barrel of fluid capacity, but they require much more handling, space for the tipping operation, and they cannot be as closely packed because of the tipping operation.
[0004] Fracturing a gas well in a shale formation, for example, often requires a very large volume of fracturing fluid. Since it is only economical to fracture the well in a single uninterrupted procedure due to equipment rental and labor costs, all of the required fracturing fluid must be stored at the well site before the fracturing operation begins. If a large frac is to be performed, an appropriately sized area around the well must be prepared for the frac tanks and other equipment required to perform the fracturing operation. The required area must be acquired or leased, graded and, if necessary, covered with an appropriate surface aggregate. All of this is time-consuming, expensive and environmentally undesirable. It is therefore desirable to keep the well site as small as possible. In order to facilitate this, space-efficient fluid storage is advantageous.
[0005] There therefore exists a need for a portable fluid storage tank that provides space-efficient fluid storage.
SUMMARY OF THE INVENTION
[0006] It is therefore an object of the invention to provide a portable fluid storage tank that has a small footprint to provide space-efficient fluid storage.
[0007] The invention therefore provides a portable fluid storage tank, comprising: a base that supports the portable fluid storage tank in an upright position; a bottom wall connected to the base; at least one sidewall connected to the bottom wall; a top wall connected to the at least one sidewall; at least one through pipe having opposed ends, the at least one through pipe extending through the at least one sidewall at two separate places so that the respective opposed ends of the at least one through pipe are exposed on an exterior of the portable fluid storage tank and the at least one through pipe provides a fluid path through the portable fluid storage tank without fluid communication between the at least one through pipe and an interior of the portable fluid storage tank; and, at least one drain valve through which fluid may be removed from the portable fluid storage tank.
[0008] The invention further provides a portable fluid storage tank, comprising: a base that supports the portable fluid storage tank in an upright position; a bottom wall connected to the base; four sidewalls connected to the bottom wall; a top wall connected to the four sidewalls; a plurality of through pipes respectively having opposed ends, the plurality of through pipes respectively extending through two opposed ones of the four sidewalls, so that the respective opposed ends of the respective plurality of through pipes are exposed on an exterior of the portable fluid storage tank and the plurality of through pipes respectively provide a fluid path through the portable fluid storage tank without fluid communication between any one of the plurality of through pipes and an interior of the portable fluid storage tank; and, at least one drain valve through which fluid may be removed from the portable fluid storage tank.
[0009] The invention yet further provides a method of storing fracturing fluid at a well site, comprising: arranging at the well site a plurality of portable fluid storage tanks in rows and columns, the portable fluid storage tanks respectively comprising a plurality of through pipes that provide a fluid path through the respective portable fluid storage tanks without fluid communication between any one of the through pipes and an interior of the respective portable fluid storage tanks and at least one drain valve through which fluid may be removed from the portable fluid storage tank, the rows and columns being arranged so that a first row faces a frac manifold, and the number of rows in each column does not exceed the number of through pipes in each of the plurality of portable fluid storage tanks, plus one; connecting the drain valves of the portable fluid storage tanks in the first row directly to the frac manifold; and interconnecting the drain valves of the respective portable fluid storage tanks in the remaining rows to a through pipe in a next row closer to the frac manifold to commence a segregated fluid path to the frac manifold, daisy chaining each through pipe in a segregated fluid path to a through pipe in the first row, and connecting to the frac manifold each through pipe in the first row that forms part of one of the segregated fluid paths to create a complete segregated fluid path from each drain valve to the frac manifold.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Having thus generally described the nature of the invention, reference will now be made to the accompanying drawings, in which:
[0011] FIG. 1 is a schematic side elevational view of an embodiment of a portable fluid storage tank in accordance with the invention, showing a truck with a tilting bed used to transport the portable fluid storage tank to a well site;
[0012] FIG. 2 is a schematic bottom plan view of the portable fluid storage tank shown in FIG. 1 ;
[0013] FIG. 3 is a schematic top plan view of the portable fluid storage tank shown in FIG. 1 ;
[0014] FIG. 4 is a schematic cross-sectional view of a top end of the portable fluid storage tank shown in FIG. 1 , taken along lines 4 - 4 of FIG. 3 ;
[0015] FIG. 5 is a partial cross-sectional view of a handrail shown in FIG. 4 ;
[0016] FIG. 6 is a schematic cross-sectional view of a bottom end of the portable fluid storage tank shown in FIG. 1 , taken along lines 6 - 6 of FIG. 3 ;
[0017] FIG. 7 is a schematic side elevational view of the top end of the portable fluid storage tank shown in FIG. 1 , illustrating latch windows engaged by hydraulic latches of the tilting truck bed shown in FIG. 1 to secure the portable fluid storage tank to the tilting truck bed;
[0018] FIG. 8 is a schematic diagram of a portion of a cradle of the tilting truck bed used to transport the portable fluid storage tank shown in FIG. 1 ;
[0019] FIG. 9 is a schematic front elevational view of a hydraulic latch of the tilting truck bed shown in FIG. 1 ;
[0020] FIG. 10 is a schematic side elevational view of the hydraulic latch shown in FIG. 9 ;
[0021] FIG. 11 is a schematic side elevational view of one column of four portable fluid storage tanks in accordance with the invention connected to a frac fluid manifold at a well site and;
[0022] FIG. 12 is a rear elevational view of a row of four columns of the portable fluid storage tanks shown in FIG. 11 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] The invention provides a portable fluid storage tank especially adapted to store fracturing fluid used for well stimulation procedures. The portable fluid storage tank has a small footprint, a large fluid capacity, and through pipes that permit efficient use of well site space by enabling the connection of a plurality of rows of portable fluid storage tanks to a single frac manifold. Thus well site space and frac manifold rental expenses are reduced. The portable fluid storage tank also has a top end walkway with handrails to permit well site personnel to walk more safely across a top of rows of the portable fluid storage tanks, when required.
[0024] FIG. 1 is a schematic side elevational view of one embodiment of a portable fluid storage tank 20 in accordance with the invention. In this embodiment, the portable fluid storage tank 20 is substantially square with rounded corners 22 . In one embodiment, the portable fluid storage tank 20 is about 11′×11′ (3.35×3.35 m) and the rounded corners 22 each have a radius of about 2′ (0.61 m). A tank of this dimension with a height of about 30′ (9.15 m) has a capacity of about 750 barrels (119,242 L). In one embodiment the portable fluid storage tank 20 is constructed of ¼″ (6.3 mm) mild steel and has a weight of about 15,000 lb (6,818 kg). For corrosive fluid applications, the portable fluid storage tank 20 may be constructed of galvanized or stainless steel.
[0025] The portable fluid storage tank 20 is supported on a cross-shaped base 24 constructed from a plurality of 6′×6′ (15×15 cm) square steel tubes 26 welded to a bottom wall 21 of the portable fluid storage tank 20 , as will be explained below in more detail with reference to FIG. 2 . The square steel tubes 27 have a wall thickness of about ⅜″ (9.53 mm). A top wall 23 of the portable fluid storage tank 20 is constructed with a covered manhole 28 . A collapsible handrail 30 and a walkway 32 (see FIG. 3 ) are also connected to the top wall 23 , as will be explained in more detail below with reference to FIG. 3 .
[0026] In this embodiment, the portable fluid storage tank 20 includes at least two drain valves 34 , typically butterfly valves located adjacent a bottom wall 21 of the portable fluid storage tank 20 . The drain valves have an internal diameter of about 4″ (10 cm). The portable fluid storage tank also includes a plurality of through pipes 36 , which respectively extend completely through and are welded to opposite sidewalls of the portable fluid storage tank 20 . The through pipes 36 provide fluid passages through the portable fluid storage tank 20 to permit fluid to be pumped from other portable fluid storage tanks 20 , as will be explained below in more detail with reference to FIGS. 6 and 11 . Each of the through pipes 36 also has a diameter of about 4″ (10 cm).
[0027] The portable fluid storage tank 20 is transported by truck 40 having a tilting bed 42 . The tilting bed 42 is raised and lowered by a scissor frame 44 similar to one described, for example, in U.S. Pat. No. 4,148,528, which issued on Apr. 10, 1979 to Channell, the specification of which is incorporated herein by reference. The tilting bed 42 pivots around pivot pins 44 journaled through bearings installed in a rear end of the truck frame 46 . A tank cradle having tank cradle arms 48 supports the portable fluid storage tank 20 on the tilting bed 42 . The tank cradle arms 48 are curved to match the rounded corners of the portable fluid storage tank 20 as will be described below in more detail with reference to FIG. 8 . Hydraulic latches 50 , described below in more detail with reference to FIGS. 9 and 10 , in cooperation with a tilting bed end plate 52 secure the portable fluid storage tank 20 to the tilting bed 42 . As will be explained below in more detail with reference to FIG. 7 , the hydraulic latches 50 engage latch windows in a sidewall 60 of the portable fluid storage tank 20 and lift the portable fluid storage tank 20 upwardly until the top end wall 23 of the portable fluid storage tank 20 abuts the tilting bed end plate 52 to lock the portable fluid storage tank 20 to the tilting bed 42 .
[0028] FIG. 2 is a schematic bottom plan view of the portable fluid storage tank 20 shown in FIG. 1 . As explained above, the portable fluid storage tank 20 is supported on a base 24 constructed from a plurality of 6′×6′ (15.24×15.24 cm) square steel tube side members 26 a - 26 d having a wall thickness of about ⅜″ (9.5 mm). The steel tube side member 26 a is welded to the bottom wall 21 of the portable fluid storage tank 20 along a bottom edge of the front wall 54 . The steel tube side member 26 b is welded to the bottom wall 21 of the portable fluid storage tank 20 along a bottom edge of a left sidewall 56 . The steel tube side member 26 c is welded to the bottom wall 21 along a bottom edge of a rear sidewall 58 , and the steel tube side member 26 d is welded to the bottom wall 21 along a bottom edge of a right sidewall 60 . A steel tube cross-member 25 a of the same dimension is welded between the steel tube side members 26 b and 26 d. A steel tube cross-member 25 b is welded between the cross-member 25 a and the steel tube side member 26 a, and a steel tube cross-member 25 c is welded between the cross-member 25 a and the steel tube side member 26 c. The steel tube base 24 not only securely supports the portable fluid storage tank 20 , but also provides open channels into which steam, or the like, can be directed to release the portable fluid storage tank 20 if it freezes to the ground, which can occur under certain winter conditions.
[0029] As also explained above, two drain valves 34 a, 34 b are secured to a bottom of the front wall 54 . Fluid is pumped from the portable fluid storage tank 20 through one or both of the drain valves 34 a, 34 b. In this embodiment, four through pipes 36 a - 36 d are provided. Each through pipe 36 a - 36 d extends completely through the portable fluid storage tank 20 and is welded to the respective front wall 54 and a rear wall 58 . As will be explained below in more detail with reference to FIG. 6 , the through pipes 36 a - 36 d provide a fluid flow path through the portable fluid storage tank 20 , but there is no fluid communication between the through pipes 36 a - 36 d and the inside of the portable fluid storage tank 20 .
[0030] FIG. 3 is a schematic top plan view of the portable fluid storage tank 20 shown in FIG. 1 . As explained above, the top of the portable fluid storage tank 20 is provided with handrails 30 a, 30 b. The handrails 30 a, 30 b flank opposite sides of a walkway 32 which extends between the sidewalls 56 , 60 . The handrails 30 a, 30 b are supported by posts 68 that slide inside tubes welded inside a top of the portable fluid storage tank 20 , as will be explained below in more detail with reference to FIG. 4 . The walkway 32 is preferably constructed of steel plate with a textured surface, or some other non-slip surface treatment. In this embodiment, the manhole 28 is about 2′ (61 cm) in diameter and includes a manhole cover 62 that is hinged to the top wall 23 of the portable fluid storage tank 20 by a hinge 66 to permit the manhole cover 62 to be easily displaced so that fluid levels can be checked, etc. In this embodiment, the manhole 28 is round and the cover 62 is secured by a locking mechanism (not shown) operated by a hand wheel 64 , well known in the art. It should be understood that any shape of manhole and any type of manhole cover can be used, as can any type of locking mechanism for the cover.
[0031] FIG. 4 is a schematic cross-sectional view of a top end of the portable fluid storage tank 20 shown in FIG. 1 , taken along lines 4 - 4 of FIG. 3 . As explained above, the handrails 30 a and 30 b are supported by posts 68 , which are tubular or solid members that are received in hollow tubes 70 . The posts 68 and the tubes 70 may have any cross-sectional shape that permits the handrails 30 a and 30 b to be easily raised from a lowered position for transport to a raised position for field use, and vice versa. The tubes 70 extend through holes in the top wall 23 and are welded to the top wall 23 . Transverse bores near a top end of the tubes 70 and complementary bores through a bottom of the posts 68 receive pins 72 to lock the posts 68 in the raised position. A stabilizer 78 , which may be of plate or tubular stock, extends between the sidewalls 56 and 60 and is welded or otherwise secured to the respective sidewalls. The stabilizer 78 is welded to a bottom of each tube 70 to stabilize the respective tubes 70 and prevent fluid from migrating from the portable fluid tank into the bottom end of the tubes 70 . A rectangular beam 80 is welded to the sidewall 60 and to a bottom of the stabilizers 78 . The rectangular beam 80 reinforces the sidewall 60 at the latch windows, as will be explained below with reference to FIG. 7 .
[0032] FIG. 5 is a partial cross-sectional view of the handrail 30 b shown in FIG. 4 . As explained above, the posts 68 are supported in the raised position by pins 72 that are locked in place by lock pins 74 , which may be self-locking pins well known in the art, or any other suitable type of fastener. A transverse bore 76 through a top of the posts 68 near the handrail 30 b is used to lock the handrails in the lowered, transport position shown in FIG. 1 . The pins 72 and the lock pins 74 are used to lock the posts 68 in the lowered position.
[0033] FIG. 6 is a schematic cross-sectional view of a bottom end of the portable fluid storage tank 20 shown in FIG. 1 , taken along lines 6 - 6 of FIG. 3 . In this cross-section, only the through pipe 36 a can be seen. Each of the through pipes 36 a - 36 d extends completely through the portable fluid storage tank 20 , and opposed ends of each through pipe 36 a - 36 d extend about 6″ (15 cm) beyond the respective front sidewall 54 and the rear sidewall 58 . As can be seen, there is no fluid communication between the through pipes 36 a - 36 d and the inside of the portable fluid storage tank 20 . The through pipes 36 a - 36 d in this embodiment are conveniently located at about 3′6″ (1.09 m) above a top of the base 24 . However, the through pipes 36 a - 36 d may be located any convenient distance above the base 24 . The through pipes 36 a - 36 d are inserted through holes cut in the front sidewall 54 and the rear sidewall 58 . A circumferential weld 82 secures the through pipe 36 a to the rear sidewall 58 of the portable fluid storage tank 20 . A circumferential weld 84 secures of the through pipe 36 a to the front sidewall 54 . The other through pipes 36 b - 36 d are welded to the front sidewall 54 and a rear sidewall 58 in the same way.
[0034] As can be seen, the drain valves 34 a, 34 b are located as close to the bottom wall 21 as practical. A gusset 86 may be welded, on one or both sides of the valve opening (not shown), to the bottom wall 21 and the bottom of the front sidewall 54 to reinforce the front sidewall 54 against strain induced by the connection of the hoses, etc. to the drain valves 34 a, 34 b.
[0035] FIG. 7 is a schematic side elevational view of a top end of the portable fluid storage tank 20 shown in FIG. 1 , illustrating latch windows 88 a, 88 b that are engaged by the hydraulic latches 50 of the tilting truck bed 42 ( FIG. 1 ) to secure the portable fluid storage tank 40 to the tilting truck bed 42 . In this embodiment, a 6″×8″ rectangular tubular beam 80 having a wall thickness of about ⅜″ (9.5 mm). The tubular beam 80 has opposite ends 87 a, 87 b that are respectively contoured to closely mate with the rounded corners 22 of the sidewall 60 . The top, bottom and end edges of the tubular beam are welded to the sidewall 60 and the rounded corners 22 so that there is no fluid communication between the inside of the portable fluid storage tank 20 and the tubular beam 80 , and so that the tubular beam 80 is securely bonded to the sidewall 60 and the rounded corners 22 . The latch windows 88 a, 88 b are cut through the sidewall 60 and the front side of the tubular beam 80 . Angle iron or channel iron (not shown) may be welded around the perimeter of each of the windows 88 a, 88 b to further reinforce them. In this embodiment, the latch windows 88 a, 88 b are respectively about 12 inches (30 cm) long and 6 inches (15 cm) high.
[0036] FIG. 8 is a schematic diagram of one cradle arm 48 of the tilting truck bed 42 used to transport the portable fluid storage tank shown in FIG. 1 . In order to facilitate pickup or drop-off of the portable fluid storage tank 20 from/to a surface that may not be perfectly level, the cradle arms 48 on at least one side of the tilting truck bed 42 are preferably movable from a retracted transport position to an extended pickup and drop-off position. The cradle arm 48 shown in FIG. 8 is in the extended pickup/drop-off position. The cradle arm 48 reciprocates through a housing 92 , which may be constructed of tubular material. The housing 92 is welded or otherwise secured to a frame member 90 of the tilting truck bed 42 by gussets 94 , or any other suitable fastener. At least the inner end of the cradle arm 48 is hollow and slides over bar stock 96 secured to a cradle bed 98 also supported (not shown) by the tilting truck bed 42 . A hydraulic cylinder 100 is used to reciprocate the cradle arm 48 from the retracted transport position to the extended pickup position. A piston rod 102 of the hydraulic cylinder 100 is connected by a fastener 104 and a bushing 106 to the cradle arm 48 . The other cradle arms 48 on the same side of the tilting truck bed 42 are constructed in the same way. Alternatively, all of the cradle arms on the same side of the tilting truck bed 42 may be connected to a single hydraulic cylinder through a linkage (not shown) to move them from the travel position to the pickup/drop-off position.
[0037] FIG. 9 is a schematic front elevational view of one of two hydraulic latches 50 of the tilting truck bed 42 shown in FIG. 1 . Each of the hydraulic latches 50 has an outwardly extending tongue 120 , in this embodiment about 6 inches (15 cm) long and about 6 inches (15 cm) wide that is welded to a tubular or bar stock 122 having a free top end 124 and a journaled bottom end 126 . The free top end 124 is received in a tubular guide member 128 and reciprocates therein. The journaled bottom end 126 is secured by a fastener 130 to a ram 132 of a hydraulic cylinder 134 . The hydraulic cylinder 134 and the tubular guide member 128 are respectively secured to the tilting truck bed 42 .
[0038] FIG. 10 is a schematic side elevational view of the hydraulic latch 50 shown in FIG. 9 . The tilting truck bed 42 is not shown in this figure. As shown in FIG. 1 , the two hydraulic latches are positioned on the tilting truck bed 42 so that the outwardly extending tongues 120 enter the respective latch windows 88 a and 88 b when the truck is backed up in proper alignment against the portable fluid storage tank 20 . When the rams 132 of the hydraulic cylinders 134 are extended, the downward and inward curvatures 138 of the outwardly extending tongues 120 of the hydraulic latches 50 urge the portable fluid storage tank 20 against the tilting truck bed 42 . A cradle arm control is then operated to move the cradle arms to the travel position, as discussed above with reference to FIG. 8 . Further extension of the rams 132 raises the portable fluid storage tank 20 until the top end abuts the tilting truck bed end plate 52 ( FIG. 1 ), which locks the portable fluid storage tank 20 to the tilting truck bed 42 . After the portable fluid storage tank 20 is locked to the tilting truck bed 42 , the tilting truck bed 42 can be lowered into the transport position and the portable fluid storage tank 20 hauled to another location without additional strapping. To offload the portable fluid storage tank 20 , the loading operation is reversed, which permits the truck driver to offload the tank without assistance or auxiliary equipment and without any requirement to handle the tank or other equipment.
[0039] FIG. 11 is a schematic side elevational view of one column of four portable fluid storage tanks 20 a - 20 d connected to a frac fluid manifold 176 at a well site. The embodiment of the portable fluid storage tank 20 shown in FIGS. 1-8 permits up to 5 rows of frac tanks 20 to be connected to a single frac manifold 176 . The number of columns of tanks connected to the frac manifold is limited only by the length of the frac manifold 176 and/or the size of the well site. It should also be understood that the number of rows of portable fluid storage tanks 20 in a column is limited only by the number of through pipes 36 with which each portable fluid storage tank 20 is provisioned. Four through pipes 36 is exemplary only and any number of through pipes 36 may be provided in the portable fluid storage tank 20 in accordance with the invention.
[0040] In the example shown in FIG. 11 , the drain valve 34 a of the portable fluid storage tank 20 a is connected by a flexible hose 150 and a suitable connector 152 to the through pipe 36 a of the portable storage tank 20 b. The drain valve 34 a of the portable fluid storage tank 20 b is connected via hose 154 and connector 156 to the through pipe 36 a of the portable fluid storage tank 20 c. The through pipe 36 a of the portable fluid storage tank 20 b is connected to the through pipe 36 b (not visible) of the portable fluid storage tank 20 c by the connector 158 and the flexible hose 160 . The drain valve 34 a of the portable fluid storage tank 20 c is connected via hose 162 and connector 164 to the through pipe 34 a of the portable fluid storage tank 20 d. The through pipe 36 a of the portable fluid storage tank 20 c is connected via hose connector 166 and hose 168 to the through pipe 36 b (not visible) of portable fluid storage tank 20 d. The through pipe 36 c (not visible) of the portable fluid storage tank 20 c is connected via connectors (not visible) and hose 170 to the through pipe 36 c (not visible) of the portable fluid storage tank 20 d.
[0041] The drain valve 34 a of the portable fluid storage tank 20 d is connected via hose 172 and connector 174 to the frac manifold 176 , which is supported by frac manifold base 178 . The through pipe 36 a of the portable fluid storage tank 20 d is connected via connectors 180 and 184 and hose 182 to the frac manifold 176 . The through pipe 36 b (not visible) is connected to the frac manifold 176 by hose 186 and appropriate connectors (not visible), and the through pipe 36 c (not visible) of the portable fluid storage tank 20 d is connected to the frac manifold 176 by hose 188 and appropriate connectors (not visible).
[0042] Thus, each of the portable fluid storage tanks 20 a - 20 d is connected by a segregated fluid path to the frac manifold 176 . Fluid flow from any one of the portable fluid storage tanks 20 a - 20 d can be controlled using the respective drain valves and/or by frac manifold control functions available through a frac manifold control panel (not shown). Hose use and hose clutter is kept to a minimum and storage tank clustering density is substantially increased, so the well site space required for fracturing fluid storage is significantly reduced. It should be noted that the hose connections shown in FIG. 11 may be rigid pipe connections, the fluid paths between the respective portable fluid storage tanks 20 a - 20 d can be daisy-chained to the through pipes 36 in any order without affecting the integrity of the segregated fluid path, and the distance between the rows of portable fluid storage tanks can be reduced to any comfortable working space, i.e. as little as 2′-3′ (0.6-1 m).
[0043] FIG. 12 is a rear elevational view of a row of four adjacent columns of the portable fluid storage tanks 20 shown in FIG. 11 . Because of space constraints, only the row farthest from the frac manifold 176 , and only four columns of that row are shown. The portable fluid storage tanks 20 a (see FIG. 11 ), 20 d, 20 e and 20 f are positioned as closely together as is practical. Site conditions will have an effect, but 2″-10″ (15-37.5 cm) between the portable fluid storage tanks 20 in adjacent columns is normally achievable. After all of the portable fluid storage tanks 20 for a given row have been delivered and positioned, a portable stairway 200 , or the like, is set up on one end of the row. The portable stairway 200 is available in many different styles, and well known in the art. It has wheels 202 that permit it to be towed to a well site using a tow bar (not shown). A height adjustment mechanism schematically shown at 204 is used to adjust the stairway to the required height (30′). The stairs 206 and the handrails 208 are self-leveling.
[0044] The portable stairway 200 provides access to a top of the row of portable fluid storage tanks 20 . Once access is gained, the handrails 30 are raised and locked in place, as explained above with reference to FIGS. 4 and 5 . The handrails 30 a, 30 b help ensure that a row of the portable fluid storage tanks 20 can be more safely traversed by the frac crew, if required.
[0045] The portable fluid storage tanks 20 described above are square with rounded corners. However, it should be understood that they may be rectangular or cylindrical without departing from the spirit or scope of the invention. Furthermore, although the portable fluid storage tanks 20 described above are constructed from steel plate, fiberglass or plastic could be used for the same purpose.
[0046] The embodiments of the invention described above are therefore intended to be exemplary only. The scope of the invention is intended to be limited solely by the scope of the appended claims.
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A portable fluid storage tank has through pipes with opposed ends that extend through the tank at two separate places so that the opposed ends are exposed on an exterior of the portable fluid storage tank and the each through pipe provides a separate fluid path through the portable fluid storage tank without fluid communication between the through pipes or an interior of the portable fluid storage tank. Several rows of the portable fluid storage tanks can be connected to a single frac manifold to reduce well site space usage.
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BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to reels for fishing rods. In particular, it relates to fishing rod reels with gravity controlled brake assemblies that are automatically activated when a fishing line becomes slack.
2. Background Art
An annoying problem which confronts many fishermen is the unraveling of the fishing line spool when a fishing line which is rapidly being unwound under force suddenly loses that force when the line goes slack. For example, when a fishermen is casting a line, or when a fish strikes the line, the line is subjected to force which causes the fishing reel to unwind rapidly. When this happens, the spool holding the supply of fishing line spins rapidly to release extra line. Reels are designed to allow the spool to rapidly release fishing line so as not to reduce the distance for casting or to interfere with hooking the fish.
When the fishing line strikes the water after being cast, or when a fish changes direction, the fishing line may suddenly go slack. Even though the force pulling on the line is removed, the spool will continue to spin. This unnecessary spinning of the reel causes the fishing line to unravel and create a “bird's nest” within the reel assembly. When this happens, the fisherman is inconvenienced by having to rewind the spool to eliminate the bird's nest.
In some prior art fishing reels, a manual brake assembly is provided. The disadvantage associated with manual brake assemblies is that they require a high-level of skill on the part of the fisherman. The fisherman's timing must be precise to avoid prematurely braking the line too early and interfering with the casting or hooking the fish, or alternatively, to avoid braking the line too late which results in the creation of a bird's nest.
Attempts to correct this problem have resulted in the development of tension and centrifugal brakes. Tension brakes reduce the ability of the spool holding the fishing line to unravel which results in a reduced bird's nest problem. However, maintaining tension on the fishing line reduces performance by limiting casting distance. It would be advantageous to have a fishing line brake that does not maintain tension on the fishing line at all times.
Centrifugal brakes attempt to overcome this problem by only engaging the brake when the centrifugal clutch is engaged. While centrifugal brakes help to eliminate this problem, they also have significant drawbacks due to their complexity and cost. In addition, they add increased weight due to the number of components needed to effectuate this type of brake assembly.
While addressing the basic desirability of braking fishing lines with proper timing, the prior art has failed to provide a fishing line brake which is inexpensive to manufacture, which has a minimum number of components, which has a low weight, and which minimizes cost.
SUMMARY OF THE INVENTION
The present invention solves the foregoing problems by providing a low-cost, simple gravity brake which is automatically activated when the fishing line goes slack. The fishing line is fed through an opening in an arm of the brake assembly. When the line is taught, such as when it is being cast or when a fish strikes, the tension on the line is used to elevate the arm and disengage the brake. When the fishing line tension is relieved, such as when the line hits the water or when a fish changes direction, gravity automatically lowers the arm and engages the brake on the fishing reel line spool. The brake pads prevent the fishing line spool from rotating and thus prevent the unraveling of fishing line.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of a prior art fishing rod showing the fishing line under tension and extending from the fishing reel.
FIG. 2 is a top view of a prior art fishing rod, as shown in FIG. 1, in which the fishing line extends from the fishing reel under tension.
FIG. 3 is a side view of a prior art fishing rod, as shown in FIG. 1, in which the fishing line extends from the fishing reel and is not under tension.
FIG. 4 is a top view of a prior art fishing rod, as shown in FIG. 1, in which fishing line extends from the fishing reel and is not under tension. This figure also illustrates the formation of a bird's nest due to unraveling of the fishing line on the fishing reel spool.
FIG. 5 is a side view of a preferred embodiment of the invention in which the fishing line extends from the fishing reel spool through a gravity controlled fishing line brake under tension.
FIG. 6 is a top view of the preferred embodiment of FIG. 5 in which the fishing line extends from the fishing reel spool through a gravity controlled fishing line brake under tension.
FIG. 7 is a side view of the preferred embodiment of FIG. 5 in which the fishing line extends from the fishing reel spool through a gravity controlled fishing line brake. The line in this figure is slack.
FIG. 8 is a top view of the preferred embodiment of FIG. 5 in which the fishing line extends from the fishing reel spool through a gravity controlled fishing line brake. The line in this figure is slack, but no bird's nest is formed.
FIG. 9 is a side cutaway view of a preferred embodiment of the invention. This figure illustrates the fishing line which is under tension and extending from the fishing reel spool through the fishing line brake. The fishing line brake is disengaged by the fishing line tension in the brake pad is rotated away from the fishing reel spool.
FIG. 10 is a side cutaway view of the preferred embodiment of FIG. 9 which illustrates the engagement of the brake against the fishing reel spool when the tension on the fishing line is removed.
FIG. 11 is a top view of the preferred embodiment of FIG. 9 which illustrates the fishing line when it is under tension. The fishing line extends from the fishing reel spool through the fishing line brake. This figure also illustrates the brake pads used by the fishing line brake.
FIG. 12 is a side cutaway view of an alternative preferred embodiment in which the brake pad is directly attached to the brake arm. In this figure, the fishing line is shown under tension and the brake arm is disengaged.
FIG. 13 is a side cutaway view of the alternative preferred embodiment of FIG. 12 in which the brake pad is fully engaged with the fishing reel spool. In this figure, the fishing line is slack.
FIG. 14A is a perspective view of an alternative preferred embodiment of the brake arm in which the brake pad is directly attached to the brake arm.
FIG. 14B is a perspective view of another alternative preferred embodiment of the brake arm. In this embodiment, an adjustable counter balance weight is attached to the brake arm to control the amount of force applied by the brake arm to the fishing reel spool.
FIG. 15 is a perspective view of another alternative preferred embodiment. In this embodiment, the brake pad contacts the interior side of the fishing reel spool.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring 2 FIG. 1, this figure illustrates a typical prior art fishing rod 1 . The fishing rod 1 is comprised of the handle 2 , and a flexible rod section 4 attached to the handle to. A fishing line guide 10 is connected to the flexible rod section 4 via fishing line guide bracket 11 . Also shown is a fishing reel assembly that is mounted on the fishing rod 1 . The fishing reel assembly includes a fishing reel bracket 3 , opposing fishing reel side walls 5 (only one is shown in this figure), a fishing line winding assembly 6 and a fishing line winding crank 8 . The opposing fishing reel side walls 5 are secured by screws 7 .
This figure also shows a fishing line 9 extending from the fishing reel through the fishing line guide 10 . In this figure, the fishing line 9 is shown as a straight line 2 indicate that it is under tension.
In FIG. 2, a top view of the prior art fishing rod 1 of FIG. 2 is illustrated. This figure illustrates the opposing fishing reel side walls 5 being separated from one another by spacing rods 12 . Also shown in this figure is the fishing reel spool 13 which holds a supply of fishing line 9 . As was the case in the previous figure, the fishing line 9 is illustrated as a straight line to indicate that it is under tension.
The fishing line 9 will remain under tension while the fishing line is being cast, or while a fish is pulling on the line. Due to the tension, the fishing line 9 is not unraveled from the fishing reel spool 13 .
FIG. 3 illustrates a side view of the prior art fishing rod 1 after tension is removed from the fishing line 9 . When this happens, the fishing line goes slack and stops moving forward through the fishing line guides 10 . Unfortunately, the fishing reel spool 13 continues to spin and begins to unravel the fishing line 9 from the fishing reel spool 13 .
Tension is lost when the fishing line 9 hits the water and slows down as its sinks more slowly through the water than it flew through the air. Likewise, if a fish is hooked and swims away, the fishing line 9 will remain under tension. However, if the fish changes direction, tension may be lost and the fishing line 9 will go slack.
FIG. 4 illustrates the problems caused by lack of tension on fishing line 9 . When the fishing line 9 goes slack, it ceases to move in a forward direction away from the fishing reel. However, if the spool 13 was spinning as a result of being cast, or as a result of a fish pulling the fishing line 9 , the spool 13 will continue to spin thereby unraveling in the fishing line 9 . As the fishing line 9 unravels, it will remain in the fishing reel and form what is commonly termed a “bird's nest” 14 .
The formation of a bird's nest is annoying to fishermen because it interrupts the fishing. When the bird's nest is formed, the fisherman must stop fishing to unravel the bird's nest and rewind the fishing line 9 .
FIG. 5 shows a preferred embodiment of the invention in which a gravity controlled fishing line brake is installed in the fishing reel. The fishing line brake automatically locks the fishing reel spool 13 when the fishing line 9 goes slack. As a result, this invention provides a substantial improvement in convenience for fishermen because it eliminates the formation of bird's nests and eliminates the work associated with unraveling them which the fisherman would normally be burdened with.
This figure illustrates the fishing line 9 line under tension such as that which would be caused by casting the fishing line 9 . When the fishing line 9 is under tension, it pushes against the brake arm 15 and raises it up and away from the flexible rod 4 .
FIG. 6 is a top view of the embodiment of FIG. 5 . This can be seen in this figure the brake arm 15 is attached to a gear 17 . When the brake arm 15 is raised under tension from fishing line 9 , the gear 17 rotates. Gear 17 is intermeshed with gear 16 which is in turn attached to brake pads 18 . As gear 16 rotates under control of gear 17 , the brake pads 18 are rotated up and away from fishing reel spool 13 . As a result, when the fishing line 9 is under tension, it forces the brake arm 15 up which in turn forces the brake pads 18 up and away from the fishing reel spool 13 . This allows the fishing reel spool 13 to spin freely.
FIG. 7 is a side view of the embodiment to FIG. 5, except that in this view the fishing line 9 is not under tension and is slack. When the fishing line 9 becomes slack, it no longer provides tension to overcome the force of gravity and the brake arm 15 will move downward automatically under the force of gravity toward flexible rod 4 . Those skilled in the art will recognize that it is intended that when casting, the fishing reel should be substantially above the flexible rod 4 when the fishing rod 1 is in a horizontal position.
FIG. 8 shows a top view of the embodiment of FIG. 7 . In this figure, the fishing line 9 is shown as being slack after it has left the fishing reel. However, because the brake arm 15 has been pulled under the force of gravity toward flexible rod 4 , the rotation of gears 16 , 17 has forced brake pads 18 into contact with fishing reel spool 13 . Once fishing reel spool 13 is braked by brake pads 18 , the fishing reel spool 13 is prevented from spinning and the formation of a bird's nest 14 is prevented.
FIG. 9 shows a cutaway side view of the embodiment of FIG. 6 . In this view of the fishing line 9 is shown as being under tension. When under tension, the fishing line 9 raises the brake arm 15 in direction 19 . This rotates gears 17 and 16 such that brake pad 18 is elevated above the surface of fishing reel spool 13 . This allows fishing reel spool 13 to rotate freely.
FIG. 10 is a cutaway side view of the embodiment of FIG. 6, except that tension has been removed from fishing line 9 . When tension is removed, gravity forces brake arm 15 in direction 20 which is toward flexible rod 4 . As brake arm 15 moves toward flexible rod 4 , gears 16 and 17 are rotated such that brake pad 18 is forced into contact with fishing reel spool 13 . As noted above, this prevents any further spinning of fishing reel spool 13 and prevents the creation of a bird's nest.
FIG. 11 is a top view of an alternative preferred embodiment in which gears 16 and 17 are eliminated and brake pad 18 is directly attached to brake arm 15 . This provides a simplified construction. When tension is applied to fishing line 9 , the brake pads 18 are raised above fishing reel spool 13 in the same manner as discussed above. Likewise, when tension is removed, brake arm 15 falls toward flexible rod 4 and causes brake pads 18 to come in contact with, and stop the rotation of, fishing reel spool 13 .
FIG. 12 is a cutaway side view of the embodiment of FIG. 11 . In this figure, tension on fishing line 9 causes brake arm 15 to move upward in direction 19 . When this happens, brake arm 15 rotates brake pad 18 away from fishing reel spool 13 such that the fishing reel spool 13 can freely rotate.
FIG. 13 is a cutaway side view of the embodiment of FIG. 11 which illustrates the fishing line 9 in the slack configuration. If fishing line 9 goes slack, brake arm 15 is automatically forced by gravity in direction 20 . As brake arm 15 rotates toward flexible rod 4 , brake pad 18 is brought into contact with fishing reel spool 13 which causes fishing reel spool 13 to stop spinning.
FIG. 14A is another alternative preferred embodiment of brake arm 15 which illustrates the single brake pad 18 attached to the pivoting arm of brake arm 15 . This can be seen from this figure, it is advantageous for the brake pad to be asymmetrically mounted on the pivoting arm of brake arm 15 . In this configuration, the rotation of brake arm 15 can be used to alter the distance between brake pad 18 and fishing reel spool 13 .
FIG. 14B is another alternative preferred embodiment in which an adjustable weight 21 is attached to brake arm 15 to allow a fisherman to adjust how much tension is required to engage or release brake pads 18 from fishing reel spool 13 . In this figure, adjustable weight 21 is shown threaded onto support rod 22 via threads 23 . Those skilled in the art will recognize that any suitable weight adjustment means can be used, such as a sliding pressure fit weight, etc.
FIG. 15 is another alternative preferred embodiment in which the brake arm 15 has extensions that extend past the outside edges of the fishing reel spool 13 and allow the brake pads 18 to make contact with the fishing reel spool 13 on the opposite side of fishing reel spool 13 . This configuration allows the brake pads 18 to eliminate any contact between fishing line 9 and brake pads 18 . In addition, it also allows brake pad 18 to be concealed for cosmetic purposes which results in a more aesthetically pleasing brake arm 15 .
Brake arm 15 can be fabricated from any suitable material. Likewise, brake pads 18 would be preferably fabricated from a material which would provide sufficient friction to stop fishing reel spool 13 from spinning. In addition, the materials selected should be suitable for use in environments where water is present. The weight distribution of brake arm 15 must be such that the brake arm 15 will fall downward toward flexible rod 4 when the fishing reel is above flexible rod 4 under the force of gravity.
Those skilled in the art will also recognize that brake arm 15 does not have to be in any particular shape. For example, it does not need to have an aperture through which the fishing line passes and may in fact be structured with an opening to allow the fishing line 9 to be inserted from the side etc. In addition, it may even be formed as an arc, curve, etc. with the bottom of the brake arm not restricting movement of the fishing line 9 .
The fishing reel has been illustrated as a conventional fishing reel with enclosing side walls 5 . However, the features and advantages of the invention can be implemented in any fishing reel with a rotatable fishing reel spool 13 which carries a supply of fishing line 9 . For example, while the enclosing side walls 5 act as a fishing reel spool support assembly, they can be eliminated and replaced with a simple bracket capable of acting as a fishing reel spool support assembly to provide support for the fishing reel spool 13 and the brake arm 15 .
While the invention has been described with respect to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in detail may be made therein without departing from the spirit, scope, and teaching of the invention. For example, the material used to construct the layers may be anything suitable for use in fishing environments, the size and shape of the brake arm can vary. The material used to fabricate the brake pad or the size of the brake pad can vary, etc. Accordingly, the invention herein disclosed is to be limited only as specified in the following claims.
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An automatic gravity controlled fishing line brake which is automatically activated when the fishing line goes slack. The fishing line is fed through an opening in an arm of the brake assembly. When the line is taught, such as when it is being cast or when a fish strikes, the tension on the line is used to elevate the arm and disengage the brake. When the fishing line tension is relieved, such as when the line hits the water or when a fish changes direction, gravity automatically lowers the arm and engages the brake on the fishing reel line spool. The brake pads prevent the fishing line spool from rotating and thus prevent the unraveling of fishing line.
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This is a divisional of copending applicaton Ser. No. 08/118,139 filed on Sep. 8, 1993.
BACKGROUND OF THE INVENTION
1. Fields of the Invention
The present invention relates generally to a mobile cyclonic power wash system that uses sprayed water for cleaning flat surfaces such as concrete, asphalt, and other various hard surfaces, and more particularly, to a power wash system having a system which reclaims and filters the sprayed water and recycles the filtered water to the system for further use in cleaning. The present invention also relates to a mobile cyclone sprayer that has an improved rotary union, which passes high pressure, high temperature water to a spray bar which rotates at high speeds, and more particularly, to an improved leakproof rotary union seal formed between a non-rotatable silicon carbide seal surface and a rotatable silicon carbide seal surface which prevents the water from leaking through or around the seal. The power wash system with these new and improved features provides more effective and convenient cleaning of flat surfaces.
2. Discussion of Background and Prior Art
Apparatus and methods for selectively cleaning flat surfaces using a mobile cyclonic power wash system have been well known in the art. The mobile cyclonic power wash system generally sprays water at high rotating speeds to clean the surfaces. A typical mobile cyclonic power wash system includes a water storage means for holding the water to be used for cleaning, a water pumping system used for pumping and pressurizing the water from the storage means, and a water cyclone sprayer for spraying the water onto the surfaces. This power wash system can further include a water heating system for heating the water so that high temperature as well as high pressure water is provided for cleaning surfaces.
Halls et al. U.S. Pat. No. 4,191,589 ("Halls") and Sundheim U.S. Pat. No. 4,191,590 ("Sundheim") each disclosed a power wash system that uses a vacuum system, and these systems were designed to be used for cleaning carpets and hard surfaces such as streets and floors. Goerss U.S. Pat. No. 4,337,784 ("Goerss") disclosed a high pressure water system that is designed to be used for cleaning floor surfaces and floor gratings.
One of the problems with the prior art power wash systems is that none of them provided any means for recovering, filtering, and recycling the water sprayed by the power wash system. The prior art systems were not designed to be independent, self-contained systems in which the water is continuously reclaimed, filtered, and recycled for further use by the power wash system. Therefore, the operation of the prior art systems is limited by the amount of water that can be stored or transported by the system (i.e. by the capacity of the water storage means), and the operator of the system was inconvenienced in having to replenish additional water from an outside source when the stored water was depleted. In effect, these prior art systems required the use of large amounts of water, and these systems wasted the stored water since they did not have the capability of reclaiming and re-using it. Moreover, environmental objections are increasingly being raised to harmful wastes being dumped into local drainage systems. Thus, there is a need to reclaim the sprayed water used in outdoor cleaning systems.
Rotary unions used in water cyclone sprayers of mobile cyclonic power wash systems have been well known in the art.
As shown in FIG. 6, one typical prior art rotary union 200 comprised simply a circular housing 210 and a hollow rotary spindle 220. The spindle 220 has a flat radial seal ring flange 240 to support it in the housing 210. A spray bar 54 is attached to the bottom of spindle 220. A packing gland 250 is placed on the inlet side of flange 240, and a packing unit and nut 260 is placed on the outlet side of flange 240. Packing unit 260 is screwed to the housing 210 by screw threads in order to support the flange 240 and to seal the bottom end of the rotary union 200. As the glands 250 wore out, the nut on the packing unit 260 had to be continuously tightened to prevent leaking in the rotary union 200. Under high pressure and high temperature, the glands wore out rapidly.
The use of o-rings or similar sealing means to seal a rotating shaft are well known in the prior art. However, due to the high pressure and high temperature and high rpm environment in a cyclone power wash sprayer of the present invention, the prior art o-rings themselves cannot function as the primary sealing means between the stationary and rotating members of the sprayer. Moreover, when positioned directly in the high pressure, high temperature water flow path as a bypass seal, the prior art fails to disclose the additional means required to prevent the o-ring itself from being carried away with the water flowing past it.
Beck U.S. Pat. No. 4,391,450 disclosed a shaft seal that uses two seal surfaces, one rotatable and the other stationary to provide the seal for the rotary union. The problem with this system is that it uses a hard material, such as silicon carbide, for the rotating seal surface, while using a softer material, such as boron nitride, for the stationary seal surface. Thus, the softer seal surface rapidly wears out against the harder seal surface. Therefore, a more effective means for sealing the rotary union is desired to overcome these problems.
High water pressure and high speed rotation of the spray bar is required in mobile power washers in order to remove ground in dirt, grease, oil, grime, and the like from the surfaces. The main purpose of the rotary union in such devices is to act as a coupling for passing the high temperature, high pressure water to the high speed rotating spray bar without leaking through or around the rotary union. The problem with the prior art rotary unions described above is that the parts of the rotary union wore out very fast because the device was operated under high pressure, high temperature and at high rpm. The rapid wearing out of these parts caused the seal of the rotary union to leak with the result that the water cyclone sprayer could not function properly or effectively.
In overcoming the problems and limitations of the prior art, it is an object of the present invention to clean flat surfaces using a mobile cyclonic power wash system with a water reclamation and filter recycling system, which reclaims and filters the water sprayed by the power wash system and has the capacity to return up to 100% of the water used by the power wash system as filtered water to be further used for cleaning by the power wash system.
It is a further object of the present invention to clean flat surfaces using a mobile cyclonic power wash system with an improved rotary union seal formed between a non-rotatable sealing surface engaging a high speed rotatable sealing surface with the high pressure, high temperature water flowing through a central bore through the union.
It is another object of the present invention to clean flat surfaces using a mobile cyclonic power wash system with an improved rotary union having an o-ring preventing bypass of the high pressure, high temperature water around the high speed rotary union.
SUMMARY OF THE INVENTION
Set forth below is a brief summary of the invention in order to solve the foregoing problems and achieve the foregoing and other objects, benefits, and advantages in accordance with the purposes of the present invention as embodied and broadly described herein.
One aspect of the invention is in a cyclonic power wash system which uses high pressure water for selectively cleaning flat surfaces. The system includes a water storage means for holding water to be used for cleaning, a water pumping system for pumping and pressurizing the water from the storage means and a water cyclone sprayer for spraying the water onto the surfaces. The improvement in the system includes a water reclamation and filter recycling system for reclaiming and filtering water that is sprayed by the system and recycling the filtered water into the storage means so that it can be further used for cleaning by the system. The system also preferably includes a water heater for heating the water.
A further feature of this aspect of the invention is a hollow reclamation ring attached to the bottom of the cyclone sprayer having a plurality of holes on the bottom side of the ring through which the sprayed water is reclaimed, a water filtration tank coupled to the reclamation ring, a vacuum source coupled to the filtration tank providing a low pressure at the reclamation ring for vacuuming the sprayed water and transporting it to the filtration tank, and means to transport the filtered water back to the storage means for re-use.
A still further feature of this aspect of the invention is the construction of the filtration tank which includes an inlet at the top, a removable slanting trough below the inlet with a screened outlet at the bottom of the trough for filtering large matter from the water, a plurality of cascading chambers for allowing the water to successively fill a chamber and flow over into an adjacent, chamber leaving behind smaller matter still present in the water continuously passing cleaner water to the next chamber, and a plurality of baffles for preventing latter and water from being directly vacuumed into the inlet of the vacuum pump system.
A still further feature of this aspect of the invention is a mobile platform on which the system components are mounted for transport to a job site.
A further aspect of the invention is in the water cyclone sprayer of the power wash system, which sprays high pressure, high temperature water at a high rotating speed. The improvement in this sprayer is in the rotary union seal, which is formed between two silicon carbide surfaces, one stationary and the other rotatable at high rpm with the water passing through a central bore through the sealing members which prevents leakage through the rotary union seal, and an o-ring which prevents leakage around the rotary union seal.
A further feature of this aspect of the invention is the method of effecting the seals in the rotary union which includes non-rotatably, slidingly mounting within the central bore of the housing a cylindrical support member which has affixed to one end thereof a first silicon carbide seal face. The support member has a central bore therethrough and the sliding mounting forms an interface between the central bore of the housing and the outer surface of the cylindrical support member. The method further includes slidingly sealing the interface by sandwiching an o-ring between the other end of the cylindrical support member and a downwardly biased washer with the o-ring slidingly engaging the housing central bore, retainingly, rotatably supporting within another central bore of the housing a spindle having a second silicon carbide seal face affixed to that end of the spindle adjacent the cylindrical support member and having a central bore therethrough to its discharge end; thereby, forming a rotary union by sealingly engaging the first and second silicon seal faces. In this method fluid, i.e. water, entering the inlet end of the housing passes through the central bores of the members, o-ring, spindle and rotary union and out the discharge end of the spindle without leaking around or through the seal at the rotary union.
A further feature of this aspect of the invention includes supporting the inner bore of the o-ring by a downwardly axially extended inner bore portion of the biased washer and an upwardly axially extended inner bore portion of the other end of the cylindrical support member. This construction prevents the o-ring from being blown into the central bore of the cylindrical support member by the high pressure water present at the interface.
A still further feature of this aspect of the invention includes applying an upward force to the spindle to further sealingly engage the seal faces in reaction to the downward force of the fluid exiting from the nozzles affixed to the hollow spray bar, and applying a horizontal rotational force to rotate the spindle and spray bar at high rpm in reaction to the horizontal force of the water peripherally exiting from the nozzles affixed to each extremity of the spray bar.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1--Front perspective view of a mobile cyclonic power wash system having a water reclamation and filter recycling system and an improved rotary union of the present invention.
FIG. 2--Rear elevation view of a mobile cyclonic power wash system having a water reclamation and filter recycling system and an improved rotary union taken along the line 2--2 of FIG. 1.
FIG. 3--Bottom perspective view of a water cyclone sprayer of the present invention with a water reclamation ring attached.
FIG. 3A--Cross-sectional view of the water reclamation ring taken along the line 3A--3A of FIG. 3.
FIG. 4--Front elevation view of the vacuum source for the water reclamation and filter recycling system of the present invention.
FIG. 5--Front sectional elevation view of the water filtration tank for the water reclamation and filter recycling system of the present invention.
FIG. 5A--Side sectional elevation view of the water filtration tank for the water reclamation and filter recycling system taken along the line 5A--5A of FIG. 5.
FIG. 6--Sectional elevation view of a prior art rotary union comprising packing glands and packing units for the seal of a rotary union.
FIG. 7--Sectional elevation view of a first subassembly of components for the proved rotary union of the present invention.
FIG. 7A--Enlarged elevation view in partial section of the first floating silicon carbide seal member that is a part of the improved rotary union shown in FIG. 7.
FIG. 7B--Bottom elevational view taken along the line 7B--7B of FIG. 7 showing the non-rational engagement of the upper floating seal support member.
FIG. 7C--Perspective view of the upside down T-shaped cylindrical support member.
FIG. 8--Sectional elevation view of the second subassembly of components for the improved rotary union.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIGS. 1 and 2 respectively show front and rear views of a mobile cyclonic power wash system 10 which includes the novel water reclamation and filter recycling system 60 (shown generally in FIG. 3 but also including elements shown in FIGS. 3A, 4 and 5) for reclaiming and filtering water that is sprayed by the system and recycling the filtered water into a storage means 20 so that the water is re-used for cleaning. FIGS. 7, 7A and 8 respectively show elevation views of a first subassembly of components 110 and second subassembly of components 150 for an improved rotary union 100 (shown generally in FIGS. 7 and 8) used in the cyclonic power sprayer 50 in the power wash system 10. These features of the power wash system 10 are now described in more detail.
The Power Wash System
As seen in FIGS. 1 and 2, the mobile cyclonic power wash system 10 includes a water storage means 20 for holding the water to be used for cleaning by the system 10, a water pumping system 30 for pumping and pressurizing the water from the storage means 20, a water cyclone sprayer 50 for spraying the water to the surfaces to be cleaned, and a mobile platform 70 on which various system 10 components are mounted so that the power wash system 10 is transportable from job site to job site. A water heater 40 may also be included as part of the power wash system 10 for heating the water.
As a further option, the power wash system 10 can include a chemical treatment system 90. The treatment system 90 would be used prior to operating the power wash system 10 to apply chemicals to the surfaces to be cleaned in order to loosen hard to remove dirt, grease, oil, grime, and the like from these surfaces. The treatment system 90 comprises an independently power operated pump 91 which pumps the chemicals through a hose 92 and to a spray gun 93. The chemicals are then sprayed to the surfaces through spray gun 93.
The power wash system 10 operates by having the water in the storage means 20 pumped and pressurized by the pumping system 30. The pumping system 30 is typically a water pump that is driven by a gas-powered engine 31 which also powers a generator 35. The water may then be either pumped to a water heater 40 so that the water may be heated or directly pumped to a water cyclone sprayer 50 if no heat is desired. If the water is directed to a water heater 40, then the heater 40, which is powered by the generator 35, burns diesel fuel stored in fuel tank 41 to heat the water to an operating temperature of 250° F. A thermostatic electrical switch (not shown) turns the oil burner "on" when the water temperature falls to 230° F. and "off" when the water temperature rises to 255° F.
The water is then directed through a water transporting hose 51 and lever type on/off valve 58 to a water cyclone sprayer 50. The water under high pressure and/or high temperature is sprayed through the sprayer 50 onto the surfaces to be cleaned. As shown in FIG. 1, the sprayer 50 comprises a mobile base 52 and a handle 53 mounted to base 52 so that the operator can move the sprayer 50 over various surfaces. FIG. 3 shows that the sprayer 50 (turned upside down in FIG. 3) has a spray bar 54 mounted underneath the sprayer 50 within the base 52. The spray bar 54 has nozzles 55 at its ends at a downward vertical angle of 6°-20° relative to the horizontal through which the water is downwardly sprayed onto the surfaces to be cleaned. A rotary union, such as the rotary union 200 shown in FIG. 6 or the rotary union 100 shown in FIGS. 7, 7A and 8 is mounted atop the center portion of base 52 underneath cover 57, and the spray bar 54 is attached to the spindle of the rotary union (i.e. spindle of rotary union 100 or 200). The horizontal reaction forces to high pressure and/or high temperature water passing through the rotary union and exiting through jets 55 causes the spray bar 54 to rotate at a very high speed, and the water is, in effect, sprayed at a downward angle onto the surfaces through nozzles 55 rotating at a high speed. This power wash system 10 is able to clean dirt, grease, oil, grime, and the like from flat surfaces such as asphalt lots and concrete floors. The power wash system 10 can also be adapted to be used at night by having lights 80, powered by generator 35, mounted to the mobile platform 70.
The Water Reclamation and Filter Recycling System
The improvement that has been made to this power wash system 10 is that a water reclamation and filter recycling system 60 has been included as part of the system 10 to reclaim and filter the water sprayed by the power wash system 10 and to further return the filtered water back to storage means 20 for further use in cleaning by power wash system 10. The reclamation and recycling system 60 comprises a detachable water reclamation ring 62 as shown in FIG. 3, a vacuum source 300 as shown in FIG. 4, and a filtration tank 400 as shown in FIG. 5.
As shown in FIG. 3, the ring 62 is mounted to the bottom side perimeter of the base 52 of sprayer 50 encircling spray bar 54. After the sprayer 50 sprays the water onto the surfaces, the water can then be reclaimed from the surfaces through this ring 62. As shown in FIGS. 3 and 3A, the ring 62 is hollow and contains a plurality of holes 63, which are on the bottom side of the ring 62 and these holes 63 face the surfaces to be cleaned. A transporting hose 61 is attached to an end of ring 62 so that the water can be transported to a filtration tank 400.
The water (along with stones, debris and other matter small enough to fit through holes 63) is vacuumed or sucked through the holes 63 and through the hose 61 to a filtration tank 400 by the use of vacuum source 300 in FIG. 4. Vacuum source 300 comprises a vacuum pump 310 and a gas driven motor 320 which drives and operates the pump 310. The vacuum source 300 may further comprise a silencer 330 attached to the pump 310 and an exhaust muffler 340 attached to the motor 320 so that the vacuum source 300 may be operated with less noise (i.e. for quieter operations in or near residential areas).
The water is then passed through the filtration tank 400 so that the water is filtered and cleaned for re-use by the power wash system 10. As shown in FIGS. 4 and 5, one way of passing the water through the filtration tank 400 is by attaching the inlet 360 of the vacuum source 300 to the clean end of tank 400 (i.e. the right side of tank 400 in FIG. 5) using an attaching means 350. The vacuum source creates a low pressure in tank 400, transport hose 61 and reclamation ring 62 which sucks the water through holes 63 of ring 62, through hose 61, and then through the entire tank 400.
As shown in FIGS. 5 and 5A, the filtration tank 400 comprises an inlet 410 located at the top, a removable slanting trough 420 located in the upper portion of the tank, a screened trough outlet 425 located at the bottom of trough 420, a plurality of cascading chambers 430 located in the lower portion of the tank, a drain 432 for each chamber 430, and baffles 433 also located in the central portion of the tank between the trough outlet 425 and the vacuum source inlet 360.
The reclaimed water is passed to the tank 400 through inlet 410, and the water flows downwardly along the trough 420 to the screened outlet 425. Large debris and particles are removed from the water when the water passes through screened outlet 425, and the debris and particles are left in the trough 420 in the upper portion of the tank 400. The trough 420 is removable from tank 400 so that the large debris and particles can be easily cleaned from it.
The water is then successively passed to a plurality of cascading chambers 430. The chambers 430 are each separated by a series of dividing walls 431 that are descending in height. The water successively fills each chamber and then flows over to the next adjacent chamber so that debris and particles still present in the water are left in the chambers 430, and cleaner water is continuously passed to the next chamber. The water is then sufficiently cleaned for re-use when it reaches the last chamber 436.
The filtered water exits the tank 400 through outlet 435 located in the last chamber 436 after passing through a one-way, spring loaded, water check valve (not shown) and is transported by gravity feed or by pump (not shown) through a transport means 440 to storage means 20 so that the filtered water is returned to be further used for cleaning by the power wash system 10. If a pump is used, the pump may be automatically operated by a float switch (not shown) which regulates the water level between predetermined high (pump ON) and low (pump OFF) water levels. A drain 432 is provided for each chamber 430 so that the debris and particles that remain in these chambers can be removed.
A plurality of baffles 433 are located below the trough 420 and generally above the chambers 430 to prevent debris, particles, and water from being directly vacuumed into inlet 360 of vacuum source 300. These baffles 433 ensure that the vacuum source 300 and the reclamation and recycling system 60 operate properly.
Detailed Description of the Improved Rotary Union
As stated earlier, a rotary union is typically mounted in the central portion atop the base 52 of the sprayer 50, and it acts as a seal and coupling for passing high pressure and high temperature water to the spray bar 54. The rotary union is used to maintain the water pressure sufficiently high so that the spray bar 54 rotatingly sprays the water downwardly at high speeds.
The problem with prior art rotary unions (i.e. rotary union 200 of FIG. 6) was that the parts of the rotary unions generally wore out at a fairly fast rate because the device was operated under high pressure and high temperature. The wearing out of these parts would cause the seal of these rotary unions to leak, and the result would be that the water cyclone sprayer 50 would not function properly or effectively.
FIGS. 7, 7A, 7B and 8 show subassemblies of components for an improved rotary union 100 according to the present invention. This rotary union 100 is a more effective coupling for passing high temperature and high pressure water to a spray bar 54 without causing any leaks in the sprayer 50 and for sufficiently maintaining the water pressure high enough to provide very high speed rotation of the spray bar 54. This improved rotary union 100 is also designed to be more durable since its components do not wear out as fast as the components of the prior art rotary unions. At high temperatures small amounts of water can "weep" through the engaging surfaces of the silicon carbide components.
The improved rotary union 100 includes a first subassembly of components 110 fixedly and non-rotatably mounted to the frame attached to the base 52 of the sprayer 50 and a second subassembly of components 150 rotatably mounted within the first subassembly 110. The first subassembly 110 provides a first silicon carbide seal surface 125 which is fixed, and the second subassembly 150 provides a second silicon carbide seal surface 165 which rotates at high speed and presses against the first silicon carbide seal surface 125 to create the more effective seal for water passing through the central bore of rotary union 100.
As shown in FIG. 7, the first subassembly of components 110 comprises a fixed housing 130, which is mounted to the base 52 of the sprayer 50, and a first floating silicon carbide seal member 120, which is non-rotatably, slidably mounted in cylindrical recess 115 in the housing 130 below the inlet 140 and above the recess 145. The housing 130 has an inlet 140 located at its upper portion for receiving the water that is to be sprayed by sprayer 50 and has a recess 145 located at its lower portion for receiving the second subassembly of components 150.
FIG. 7A shows an enlarged side view of the first floating silicon carbide seal member 120. The seal member 120 comprises an upside down T-shaped cylindrical support member 121, a silicon carbide component 124 affixed at the discharge end of member 121, an o-ring 128, an inlet end member which may be a flat washer 126, and a steel spring 127. Spring 127 biases washer 126, o-ring 128 and support member 121 downwardly so that surface 125 presses against surface 165 when installed as a unit. The T-shaped cylindrical member 121, o-ring 128 and washer 126 have a central inside bore 122. As best seen in FIGS. 7B and FIG. 7C, member 121 has at its lower end a pair of recesses 132 which engage a pair of lugs 133 in the housing 130 to permit slidable (floating) but non-rotational movement of member 121 in recess 115. (Alternatively, member 121 may be formed with a pair of lugs which fit into recesses in housing 130). T-shaped member 121 at its other end also has a raised lip 123 at its upper portion extending into the central bore 121 of o-ring 128 and supporting its inner surface. The silicon carbide component 124 is affixed to the bottom of the T-shaped cylindrical member 121 and provides the first silicon carbide seal surface 125, which faces downwardly. The o-ring 128 is placed on top of the raised lip 123 of the cylindrical member 121, and the inner bore of the o-ring 128 abuts the raised lip 123.
The flat washer 126 is placed on top of the o-ring 128. The flat washer 126 comprises a countersunk inner bore 129, which extends partially into the inner bore of the o-ring 128 and abuts and supports its inner surface. The o-ring 128, in effect, is sandwiched between the end of raised lip 123 of the cylindrical member 121, on its one hand, and the end of countersunk bore 129 of the flat washer 126, on the other hand. The vertical edges 131 of washer 126 slidingly engage in the inner walls of recess 115 as shown in FIG. 7. This sandwiching feature prevents the o-ring 128 from being blown into the inner bore 122 of the cylindrical member 121 by the high pressure, high temperature water which is present at the interface between o-ring edges 131 and the outside diameter of member 121, on the one hand, and the walls of recess 115, on the other hand. This feature overcomes the problem with prior art rotary unions which have o-rings that are more easily blown into the inner bore by the high pressure or high temperature water. This sandwiching feature provides a novel way of retaining the o-ring 128 at its set location for proper operation of the rotary union. In this manner, o-ring 128 effectively seals the aforesaid interface and prevents high pressure water from by-passing the rotary union seal at surfaces 125, 165 by attempting to go around member 121 through the interface (slide fit) with recess 115 and cylindrical member 121.
FIG. 8 shows the second subassembly of components 150. The second subassembly 150 comprises a rotating spindle 170, a silicon carbide component 160, a roller bearing unit 180, a shaft collar 185, a spring clip retaining washer 190, and a sealing ring 195. The rotating spindle 170 has a central bore 161 to allow the water to flow through the rotary union 100. The silicon carbide component 160 is mounted at the top of the rotating spindle 170 to provide the second silicon carbide seal surface 165. In operation the second silicon carbide seal surface 165 is pressed and rotated against the first silicon carbide seal surface 125 to form an effective seal which prevents high pressure water passing through the rotary union 100 from leaking through the seal.
The sealing surfaces have been described in the preferred embodiment as being silicon carbide. The sealing surfaces may also be made of tungsten carbide or any other hard, durable material used as a sealing surface which is soft enough to effectively make a seal at the sealing surfaces yet is hard enough to give a long life to the sealing surfaces such as is provided by silicon carbide under the conditions in which the present invention is operated. Using silicon carbide sealing surfaces the lifetime of the sealing surfaces is in excess of 16,000 hours operating at 3000 psi, 250° F. and 1500 rpm.
The roller bearing unit 180 is attached to the central portion of the rotating spindle 170, and this unit 180 provides rotating support to the rotating spindle 170. The shaft collar 185 is also attached to the upper portion of the rotating spindle 170 for holding and supporting the roller bearing unit 180 to the rotating spindle 170. The roller bearing unit 180 comprises a pair of roller bearing rings 182, bearing supports 181 attached to the shaft collar 185, and a bearing spacer 183 attached between the two bearing rings 182. One roller bearing ring is mounted on top of the other at the central portion of the spindle 170. The roller bearing rings 182 provide the rolling function for rotating the spindle 170, and the bearing supports 181 hold the roller bearing rings 182 in position on the rotating spindle 170. The bearing spacer 183 separates the two rings 182 so that these rings can rotate independently.
The spring clip retaining washer 190 is attached below the roller bearing unit 180, and this washer 190 retains the second subassembly of components 150 within the first subassembly of components 110. The washer 190 is retained within a recess 146 at the lower portion of the first subassembly 110 to hold the second subassembly 150 in the first subassembly 110.
The rotating spindle 170 has a threaded portion 198 at its lower end for attaching and engaging a rotating spray bar 54. At each peripheral end of spray bar 54 is a nozzle 55 affixed with the open end of each nozzle pointing in opposite directions in a plane substantially perpendicular to the spray bar and at a downward vertical angle of about 6° to 20°.
The upward reaction force to the downward force component of high pressure water exiting through nozzles 55 of spray bar 54 causes the second subassembly of components 150 to move upwardly towards the first subassembly of components 110 pressing face 165 upwardly against the downward bias of spring 127 and into sealing contact with face 125. The horizontal reaction forces to the horizontal force component of high pressure water exiting through nozzles 55 of spray bar 54 causes the spray bar to rotate at very high rpm, i.e. 1500 rpm operating speed and 2000 rpm rated maximum speed. During operation the second silicon carbide surface 165 rotates against the first silicon carbide surface 125, and a sealing relationship is established between the two surfaces for water passing through the rotary union 100 at high pressure and temperature without leaking through or around the rotary union seal. Operational pressure of 3000 psi at 250° F. and 1500 rpm are readily achievable with the present invention.
A working model of the invention can be made using the following specifications:
Trailer: 10' long, weighs 1200 lbs. with 1/8" steel deck, 7000 lb. capacity, by Fleming Trailers, Glendale, Ariz.;
Storage Tank: 300 gallon capacity, fiberglass or poly material by Desert Sun Fiberglass, Phoenix, Ariz.;
Water Pump: Triplex piston, 3000 psi, 8 gallon/min pumping capacity, fan belt drive, by Giant Indus.;
Electric Generator: 2200 watts, 110 volts at 2700 rpm, fan belt drive by T&J Mfg. Co., Oshkosh, Wis.;
Gas Engine For Water Pump And Electric Generator: 20-25 hp., 2 cylinder gas engine, 2700 rpm constant speed, double pulley output by Kohler, Kohler, Wis.;
Oil Burner: 450,000-1,000,000 BTU depending on fuel nozzle size. A 3.50 nozzle yields 520,000 BTU's by Beckett Indus., Elirya, Ohio;
Heating Coil: 1/2" steel pipe, schedule 80, 638 150' of coil by Farley's, Siloam Springs, Ariz.;
Cyclone Sprayer: 4500 psi max, 10 gallon/min. at 250° F., 2000 rpm max, 1500 rpm operating speed, with either 18", 30" or 48" spray bar; any size nozzle from No. 2 (0.034 ID nozzle) to No. 10 (0.080 ID nozzle); nozzles oriented at 6° to 20° downward vertical angle perpendicular to spray bar longitudinal axis; No. 305 stainless steel spray bar; 4 10" rustproof standard rubber tires; T-6 aircraft grade aluminum cover and deck; mild steel handle; 7200 psi lever type shut off valve; 360° rubber rock guard around bottom of cyclone;
Reclamation Ring: 0.120 thick walls, 1" diameter mild steel tubing, about 170 1/8" D holes in a 30" diameter reclamation ring;
Vacuum Pump: 14" Hg., 280 ft. 3 air flow per minute, through 2" spined poly hoses. Pump by Suttorbuilt Div. of Garnders-Denver, Chicago, Ill.;
Gas Engine Drive For Vacuum Pump: 20-25 HP, 12 volt battery started, Kohler 2 cylinder gas engine, 2700 rpm constant speed, direct drive by Kohler, Kohler, Wis;
Vacuum Pump Silencer: 3" model D-33, Stoddard Silencers, Grayslake, Ill.;
Reclamation Tank: 170 gal. capacity; 1/2" abs plastic, by Proto Plastics, Glendale, Ariz.; 12" battery powered float operated on/off switch which is "on" when water reaches about 7" and "off" when water reaches about 3" from the bottom of tank; 1/2" one-way, spring loaded, water check valve opened by the weight of water present in the inlet of the valve;
Gas Engine Muffler: standard Chevrolet muffler;
Water Pump For Line From Filter Tank To Storage Tank: 12 volt battery powered from the gas engine battery, 6 gallon/min capacity.
The foregoing description of a preferred embodiment and best mode of the invention known to applicant at the time of filing the application has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in the light of the above teaching. The embodiment was chosen and described in order to best explain the principles of the invention and its practical application to thereby enable others skilled in the art to best utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended hereto.
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A cyclonic power wash system uses high pressure, high temperature water for selectively cleaning large, flat, concrete or asphalt surfaces. The sprayed water is reclaimed by vacuuming it through holes in the bottom of a reclamation ring attached to the underside of the mobile cyclone sprayer, filtering the vacuumed water and returning it to a storage tank for re-use by the system. The filtration tank initially filters out large matter in an inlet trough and smaller matter in a plurality of cascading chambers. A rotary union in the sprayer prevents the water, passing from the inlet of the rotary union to the discharge thereof, from leaking through or around a seal formed by pressing together a pair of hard, durable sealing surfaces, for example, silicon carbide, one of which is non-rotatably slidingly received in an upper recess of the union's fixed housing and the other, affixed to a spindle rotatably received and retained in a lower recess of the housing. The sliding fit interface of the non-rotatable seal face in the upper recessed housing is sealed by an o-ring supported at its inner bore by extended portions adjacent the central bores of the members between which it is sandwiched. Upward and rotational forces are applied to the spindle in reaction to the water exiting from nozzles affixed to a spray bar attached to the spindle.
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RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 08/464,302, filed Jun. 5, 1995, now abandoned which is a continuation-in-part application of U.S. patent application Ser. No. 08/228,243, filed Apr. 14, 1994, now abandoned.
BACKGROUND
1. The Field of the Invention.
The present invention relates generally to the field of belt, strap, or band wrenches and more particularly to side saddle type belt wrenches, and related methods, which wrenches are adjustable to fit virtually any size object to be turned, each comprising a novel turning clasp to insure low cost production, facile use without significant technical training, and which does not damage the object to be turned.
2. The Background Art.
Prior proposals for band, strap, belt or like wrenches can be classified into a number of specific types. One type consists of strap wrenches where the distal tip of a handle is required to bite against the object to be turned. Examples of such wrenches are found in U.S. Pat. Nos. 701,489, 876,469, 1,077,591, 1,161,402, 1,911,815, 2,057,949, 2,481,055, and 2,661,802.
Another category of belt, band, or strap wrenches comprise non-metallic flexible belts comprising two free ends, both of which must be pulled upon to size the loop placed around an object to be turned, following which a rachet or similar tool will turn a bite mechanism through which the two ends of the non-metallic flexible belt pass. Examples of this type of wrench are found in U.S. Pat. Nos. 3,962,936, and 4,987,804.
A third classification of such wrenches consist of single sized flexible non-metallic strap loop wrenches where both ends of the strap are fastened to a handle to be rotated, the rotation occurring either end-for-end, or around the longitudinal axis of the handle. Examples of this type of wrench are found in U.S. Pat. Nos. 3,678,788 and 4,646,593.
A fourth category of such wrenches comprise a single size steel or metal band wrench where both ends of the band are coupled to a toggle or similar mechanism which, when rotated by a wrench, cause some part of the wrench to sharply bite against the object to be rotated. Examples of such steel band wrenches are found in U.S. Pat. Nos. 3,465,622, and 5,090,274.
A fifth category of wrenches of the type in question comprise non-metallic flexible band wrenches, having an adjustable size where one belt end is anchored to a handle or like rigid member and the other belt or band end is manually displaceable and unattached. The free end passes though at least one handle slot or slot in a bracket or wrench-receiving mechanism. Examples of this type of wrench are found in U.S. Pat. No. 2,186,430, 2,787,924 and 4,750,389.
An additional category of strap wrenches includes a strap comprising two ends where both ends are enlarged to abut a handle, the strap comprising an object-engaging loop and a second hand-held loop used to vary the size of the object-engaging loop. An example of this type of wrench is found in U.S. Pat. No. 2,458,393.
A further prior proposal comprises use of two tools, one comprising a single size lid wrench comprising a wire band and a two part handle where part of one handle piece is serrated to engage and turn the lid. The second tool comprises a non-metallic flexible band wrench with the band anchored at one end and free at the other and where the distal tip of the handle was required to bite through the flexible band against the object held stationary by the second tool which the first tool turns the lid. An example of this two-tool approach is found in U.S. Pat. No. 1,299,511.
BRIEF SUMMARY AND OBJECTS OF THE INVENTION
In brief summary, the present invention comprises belt wrenches, and related methods, the wrenches being possessed of features which overcome or substantially alleviate problems associated with the prior art. The present invention comprises adjustable size, single loop belt wrenches which do not bite sharply into the side of the object to be turned and comprise a flexible, non-metallic belt, both ends of which are free and extend in substantially parallel relation through a belt biasing clasp. The clasp can be slid to an engaged position, wherein the clasp is rotated through a small angle imbalanced stiffness of one end of the belt as compared with the other. This causes a stop or wedge at one end of the belt to securingly and continuously abut the clasp at distal slot, thereby securing the belt in a restrained condition firmly around the object. The belt wrench will remain in this configuration ready for use, without further support by the user.
With the foregoing in mind, it is a primarily object of the present invention to overcome or substantially alleviate problems associated with the prior art.
Another object of importance is the provision of novel belt wrenches, and related methods, the wrenches being side-adjustable.
A further paramount object is the provision of novel belt wrenches of the side saddle type which remain in place without being supported by the hands of the user.
Another object of significance is the provision of a novel manually operable belt wrench which grasps and turns an object without sharply biting into the object.
It is a further valuable object of this invention to provide a novel belt wrench, and related methods, the wrench comprising a flexible, non-metallic belt, and a belt-receiving and tool-receiving clasp of one-piece construction.
An additional object of dominance is the provision of a novel belt wrench which comprises a belt clasp, which is turned around an axis generally parallel to but offset from the axis of the object to be turned.
Another principal object is the provision of a novel belt wrench, and related methods, the wrench comprising a single belt clasp-turning tool capable of use with one hand.
It is also an important object to provide a novel multiple size, single loop belt wrench comprising a single clasp of one-piece construction which both receive two lengths of the belt and non-rotatably accepts a turning tool for facile grasping and turning of an object to be tightened or loosened.
A further object is the provision of novel belt wrenches where each belt comprises two free ends with one end comprising a stop such that only manipulation of the belt elsewhere is required to remove slack, and rotation of a clasp with a tool biases the belt and clasp to an object for rotating the object to tighten or loosen the same.
Another significant object is the provision of a novel belt wrench comprising a stop at one end of the belt to firmly abut a one-piece clasp to accommodate transfer of force from a large surface region of the clasp to the object to be turned.
These and other object and features of the present invention will be apparent from the detailed description taken with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective representation of one belt wrench embodying the principles of the present invention, positioned to be placed over a cylindrical object to be turned to loosen or tighten the same;
FIG. 2 is an elevational view of the belt wrench of FIG. 1 positioned so that a belt loop loosely surrounds the cylindrical object to be turned;
FIG. 3 is an elevational view of the belt wrench of FIG. 1 with a belt stop firmly abutting a single clasp and the belt in contiguous, tightened relation surrounding the cylindrical object;
FIG. 4 is an elevational view of the belt wrench of FIG. 1 in contiguous, tightened relation surrounding the cylindrical object and the clasp of the wrench being rotated through slightly more than ninety degrees to tighten the wrench in preparation for rotating the cylindrical object;
FIG. 5 is a perspective representation of a second belt wrench embodying the principles of the present invention;
FIG. 6 is a perspective representation of a clasp forming part of the belt wrench of FIG. 5;
FIG. 7 is an end elevation of the clasp of FIG. 6;
FIG. 8 is a front elevation of the clasp of FIG. 6;
FIG. 9 is a top plan view of the clasp of FIG. 6;
FIG. 10 is a perspective representation of an interior liner for the clasp illustrated in FIGS. 5-7;
FIG. 11 is an end elevation of the clasp liner of FIG. 10;
FIG. 12 is a top plan view of the clasp liner of FIG. 10;
FIG. 13 is a cross-section taken along lines 13--13 of FIG. 10;
FIG. 14 is a side elevation of a third belt wrench embodying the principles of the present invention;
FIG. 15 is an enlarged side view of the third belt use of the wrench;
FIG. 16 is an enlarged side view of the third belt wrench depicted the forces around the illustrated points involved in use of the wrench;
FIG. 17 is a perspective representation of a one-piece clasp comprising part of the belt wrench of FIG. 14;
FIG. 18 is an enlarged fragmentary exploded perspective of one end of the belt of FIG. 14 comprising a clasp-engaging stop; and
FIG. 19 is a perspective view of an alternative embodiment of the clasp of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Reference is now made to the drawings wherein like numerals are used to designate like parts throughout. Particularly, initial reference is made to FIGS. 1 through 4, which illustrates a first belt wrench, generally designated 20, embodying principles of the present invention. Belt wrench 20 broadly comprises a belt 22 having two free ends a first end 24 and a second end 26. The belt 22 is illustrated as being relatively wide and thin. The belt 22 may be formed of any suitable material, for example canvas or woven synthetic fibers of any suitable synthetic resinous material, such as nylon may be used to form the belt. However, the present invention may involve use of any belt, strap, cord, or non-metallic band material in which a single loop 28 may be formed. Both lengths of the belt 22 extending away from the loop 28 pass through a single rectangular slot 30 in a clasp and turning, tool-receiving structure 32 of one-piece construction. The two lengths of the belt 22 are in substantially parallel relation as they pass through the rectangular slot 30 of the clasp 32.
The end 24 of the belt 22 comprises a stop or wedge, generally designated 35. The thickness of the wedge 34 substantially exceeds the area available in slot 30 for belt passage so that the wedge 34, when pulled form the position of FIG. 2 to the position of FIG. 3, for example, by manipulation of the free end 26, contiguously abuts the clasp surface 36 to prevent further displacement of stop 34.
In this way, wedge 34 seats against the distal edge of slot 30. Wedge 34 is thus employed to lock the second end 26 of belt 22 between the first end 24 and the distal edge of slot 30 thus securing belt 22. In this embodiment, stop 34 comprises the belt end 24 folded upon itself and side plates 38 and 40, which may be of steel, placed on opposite exposed sides of the fold and secured in position by doubled-headed rivets 42, which pass through aligned apertures in the plates 38 and 40. As will be appreciated a number of other configurations could be employed to serve the function of wedge 34. For example, the belt end may be doubled over as in FIG. 14, and stitched to form a stiff belt section with wedge 156 captured as shown.
The one pieced belt-receiving, tool-receiving, and biasing clasp 32 is, from the side, T-shaped in its configuration. It may be formed of any suitable rigid material, such as aluminum, steel, or high-strength synthetic resinous material. The clasp 32 comprises a distal edge 44, the proximal edge 36 mentioned above, a continuous flat side edge 46 for applying a well distributed force against an object 48 to be turned. While illustrated as being cylindrical, it should be apparent that other object configuration, such as polygonal shape, could be used. Surface 46 is constructed so as to avoid concentrated force transfer to the object 48, which would risk damage to the object 48.
The side of the clasp 32 opposite side 48 comprises a tool-receiving segment 50. Segment 50 comprises a base surface 52, which is flat and essentially parallel to surface 46, a front L-shaped surface 54 and a real L-shaped surface 56.
Segment 50 comprises a square socket or aperture 58, sized and shaped to receive, either permanently or removable, one leg 60 of a tool 62 tool, having a second leg 64 tool. It is to be appreciated that other tools, such as a rachet, could be used.
In operation, the size-adjustable loop 28 is positioned around the object to be turned, which can be an oil filter, the lid on a jar, or any other annular part which is placed or removed by rotation. FIG. 2 shows the loop 28 as having been loosely placed circumferentially around the object 48.
The user next typically grasps the clasp 32 in one hand, while pulling on the free end 26 of the belt 22 until the noose of loop 28 becomes firmly contiguous with the circumference with the object 28, as illustrate in FIG. 3. This manipulation causes the stop 34 at belt end 24 to firmly and impassibly abut the trailing edge 36 of the claps 32. Once the position of FIG. 3 is attained, the free end 26 of the belt 22 is manually released. Nevertheless, the belt retains its tightened position on the can due to the gripping action of the clasp. The rotational tool 62, appropriately connected to the clasp, is then grasped by the user and rotated, causing the clasp to rotate through approximately 120° for the position of FIG. 3 to that of FIG. 4. This compressively biases the loop 28 against the object 48 at surface 46, places the lower leg of the loop in tension, and causes the force of rotation to be transferred, on a distributed load basis, across the surface 46 and the belt 22 to a substantial surface area of the object 48, as illustrated in FIG. 4.
It is to be appreciated that to place the object 48 in a tightened position, the orientation of the wrench 20 around the object 48 is reversed. In other words, the segment 50 would be above rather than below belt end 26, as viewed in FIG. 2, but the operation described above would nevertheless be applied to tightening the object 48 during placement. No risk of damage is incurred, assembly is facile, and turning is accommodated by any individual, even those without much if any technical training.
Reference is now made to the second belt wrench embodiment, generally designated 80, illustrated in FIGS. 5 through 13. Belt wrench 80 comprises belt 22' substantially identical to the previously described belt 22, except end 24 comprises a modified stop 34'. Stop 34 comprises folds of the belt held together by opposed plates and rivets, whereas stop 32' comprises the end 34 merely rolled or folded upon itself and stitched or otherwise secured in the rolled or folded fashion illustrated, without the benefit of side plates and rivets or other support structure. End 34' functions as a stop abutment to impassibly engage a clasp 32' forming a part of the belt wrench 80. The belt wrench 80 is illustrated as utilizing the previously described rotating or turning tool 62, the short leg 54 thereof being illustrated in FIG. 5 as being prepared to engage the tool-receiving portion of the clasp 32' instead of the longer leg 60, as illustrated in FIG. 1.
The clasp 32' comprises an outer housing, generally designated 82, and a liner, generally designated 84, contained within the housing 82. The housing 82 is preferably formed of high molecular weight, rigid synthetic resinous material. It has an external barn-like or house-like shape comprising a plurality of flat surfaces including a top exterior flat surface 86, diagonal surface 88 and 90 extending away from surface 86, opposed side surfaces 92 and 94, each interrupted by a rectangular slot 96 which passes completely through the housing 82 from the proximal side 94 to the distal side 92, the slot 96 being sized to accommodate slidable passage therethrough of two lengths of the belt 22', as illustrated in FIG. 5.
The exterior of the housing 82 also comprises a flat bottom surface 98, which forms a large continuous area by which force is applied in a distributed fashion and not as a concentrated load across a portion of the belt 22' against the object to be turned, in the manner previously described surface 46 of the clasp 32. The housing 82 also comprises opposed flat side surfaces 100 and 102, at which the end edges 104 of the inset or liner 84 are exposed.
The housing 82 is preferably formed using conventional injection molding techniques. The liner 84 may be positioned in the mold and the housing 82 cast around it, or, in the alternative, a side-to-side aperture, square in its configuration, may be created at site 110 and the insert or liner 84, preferably formed of steel, may be driven into the aperture 110 until positioned as illustrated if FIGS. 5 through 7. One suitable liner illustrated in FIG. 10 and comprises a hollow box comprising a thin bottom wall 112, thin opposed side walls 114 and 116, parallel one to the other, and a thin top wall 118, illustrated as being parallel to bottom wall 112. Together the four walls 112, 114, 116 and 118, formed as one-piece, define a square passageway or opening 120, sized to snugly receive either end 60 or 64 of the turning tool 62 to rotate the clasp 32' in the manner described above in conjunction with clasp 32.
Walls 112, 114, and 116 are illustrated as being continuous and uninterrupted. Top wall 118 is illustrated as being interrupted by a rectangular aperture 122. A leaf spring 124, preferably formed of spring steel, is illustrated as transversing the aperture 122 and as being secured to the wall 118 as by welding at opposed ends 126 and 128. Centrally, leaf spring 124 is bowed inwardly into passageway 120, but is deflected outwardly, for example, when one end of the turning tool 62 is inserted into the opening 120. Thus, leaf spring 122 at its center 130 biases as against the inserted end of the turning tool 62 in the inserted position against inadvertent removal, while accommodating intentional manual removal.
The placement of the belt 22' around an object to be turned, the tightening of the loop of the belt 22' and the operation of the wrench 80 by the turning tool 62 using clasp 32' is essentially as described in respect to the operation of the belt wrench 20.
Reference is now made to FIGS. 14 through 18 which illustrate a further belt wrench, generally designated 150. As depicted in FIG. 14, belt wrench 150 comprises a belt 22", which in most respects is substantially similar to previously described belt 22. Accordingly, belt 22" comprises a first end 24 and a second end 26. End 24 is doubled back upon itself so as to be contiguous with an adjacent or portion of the belt. The doubled back portion of end 24 is stitched at sites 152 in its doubled back position was illustrated best in FIGS. 14 and 16. The doubled back nature of the end 24 defines an eyelet 154, which comprises a transverse opening 156, into which a pin 158 is force-fit. The eyelet 154, aperture 156, and pin 158 collectively comprises a stop, generally designated 160, the thickness of which prevents the stop 160 from passing through a clasp, generally designated 162.
Because of the double back construction of the distal end 24 of the belt 22", as explained above, three lengths of the belt 22" pass through the clasp 162 at rectangular through slot 164. The doubling back of end 24 provides a stiff portion which extends through the proximal end of slot 164. The stiff portion of end 24 of belt 22" also extends through a short radius of curvature into the loop formed in belt 22". The stiffness of belt 22" extending into loop 28' imposes a biasing stress which serves to cock loop 28' to one side as shown.
FIGS. 15 and 16 illustrate the biasing stress and associated effects in greater detail. In FIG. 15 the proximal end 26 of belt 22" having a single thickness, is depicted as it would appear when pulled tight. Pulling the proximal end 26 of belt 22" tight draws stop 160 into slot 164 which is formed by opposing sidewalls 164a and 164b. This action wedges the proximal end 26 of belt 22" between clasp 162 and stop 160, and the side of the stop opposite the proximal end of the belt 22" is wedged against the other sidewall. Thus, a wedge is formed by the engagement between the stop 160 and both sidewalls 164a and 164b defining the slot 164. This wedge acts as a lock thereby holding the belt wrench 150 in place on the object to be turned.
FIG. 16 further illustrates the forces involved in the locking action mentioned above. In instances where there is less than 45° of motion toward stop 160, clasp 162, exerts tension on stop 160 by increasing the distance from Point A to Point B by hinging over Point D. As shown, Point A is the point where the distal, doubled back, end 24 of belt 22" first contacts the object to be turned 165. Point B is the point where the doubled back end 24 begins to widen to form eyelet 154 into which pin 158 is fit to form stop 160. Stop 160 wedges into slot 164 of clasp 162 at Point B. This wedging effect exerts pressure on the proximal end 26 of belt 22" which serves to lock the belt wrench 150 in place around object 165, thus preventing movement of the proximal end of belt 22" toward Point A.
The distal end 24 of belt 22" then exerts pressure against the proximal end, single thickness portion, at Point C due to the 45° motion described above thus increasing the distance between Point A and Point B. This action creates tension at Point C which serves as an additional force binding the proximal end 26 of belt 22" against clasp 162 preventing movement toward Point A. The proximal end 26 of belt 22" at Point D is thus forced toward Point A by folding under at Point C. Point E then contacts Point F in 90 degrees of motion further binding the proximal end 24 of belt 22". Reversing the motion of clasp 162 relaxes the tension and forces exerted at Points A, B, C, and D letting the belt wrench 150 slip in the opposite direction thus creating a ratcheting effect.
The clasp 162 is preferably formed of rigid, high-strength synthetic resinous material, forced using conventional injection molding techniques. The clasp 162 is somewhat similar to clasp 32', being housed or barn-shaped, but being without a liner of insert and comprising rounded corners between flat exposed surface area. The exterior wall surface configuration of the insert 162 being substantially the same as that of clasp 32', except for dimensional differences and rounded corners, the exterior surfaces of clasp 162 have been numbered identical to the exterior surfaces of clasp 32' and no further description thereof is deemed necessary.
The depth of the belt-receiving rectangular slot 164 is slightly greater than three times the thickness of the belt 22' and slightly greater than the width of the belt 22'. A transverse, centrally disposed square opening 166 is sized so as to receive one end of a tool for rotational purposes, such as previously described tool 62. Sharp edges are provided to assist in gripping the belt when cocked to one side.
As explained earlier, the bottom surface 98 has a substantial area and, therefore, the rotational force applied by a tool such as tool 62 to the clasp 162, with the loop 28' snug, will turn the clasp through slightly greater than 90° until the bottom surface 98 is contiguous with a portion of the exterior surface of the belt 22', at the loop 28' thereof. Further turning biases the other leg of the loop 28' and generates a force against the object to be turned imposed by the bottom surface 98 through the belt 22' which is well-distributed and not concentrated, accommodating turning of the object with little if any risk that the object will be damaged in the process.
FIG. 19 illustrates an alternative embodiment of the clasp, generally designated as 162'. Clasp 162' is designed to require less material to manufacture. Clasp 162' incorporates slot 164' and square opening 166' which is sized so as to receive one end of a tool for rotational purposes.
In this embodiment, clasp 162' employs a housing 168 which employs a design requiring less material to implement the previously described embodiments. Clasp 162' employs a thin protrusion 170 in which square opening 166' is incorporated. Protrusion 170 is formed to be perpendicular to and substantially centered over slot 164'. This design results in a more streamlined clasp requiring less material for manufacture.
The invention may be embodied in other specific forms without departing from the spirit of essential characteristics thereof. The present embodiments therefore to be considered in all respects as illustrative and are not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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Adjustable size saddle type single loop belt wrenches are disclosed which do not bite sharply at a corner or the like into the side of an object comprising a flexible, non-metallic belt, both ends of which are free, but one end being equipped with a clasp-engaging stop. At least two ends of the belt pass in substantially parallel relation through the clasp which is also eyesight, in conjunction with a turning tool, to bias the belt circularly around an object to be turned. The rotation of the clasp with the tool is along an axis generally parallel to but offset from the axis of the object. Only a small angle of rotation is required whereby the stop engages the clasp and a flat or continuous surface of the clasp imposes a distributed load across the belt onto the object to be turned.
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This application is a division of Ser. No. 204,622 filed Nov. 6, 1980 which in turn is a continuation of Ser. No. 037,694 filed May 10, 1979 and now U.S. Pat. No. 4,251,977.
BACKGROUND OF THE INVENTION
This invention relates to a method of gathering a predetermined number of circular end closures for cans into a lot of cylindrical form, putting it into a paper bag, and closing the open end of the filled bag, all in automatic, high-speed operation. More particularly, the invention is concerned with a method which comprises shifting the direction of end closures for cans being fed horizontally at given intervals at a high speed, one after another, to be substantially perpendicular to a support passage extending substantially horizontally, receiving the pieces separately in the passage at a high speed and in positive way, lotting out the end closures when a predetermined number has been reached by the pieces received, compacting each such lot to a cylindrical form and putting the lot into an elongate paper bag, and then closing the open end of the bag.
As a method of packing a lot of end closures compacted to a solid cylindrical form, a practice is well known which consists of placing a cylindrical lot of a predetermined number of end closures over a spread sheet of paper, wrapping the sheet round the cylinder, and then glueing the outer end portion of the sheet to the underlying layer. However, the procedure is disadvantageous because it necessitates much time for the wrapping and glueing and fails to provide a completely closed bag. Moreover, no attempt has hitherto been made to count up exactly the number of end closures being fed at a high speed of 300 pieces a minute and divide the total on the basis of the count into lots of a predetermined number of pieces.
SUMMARY OF THE INVENTION
The present invention has for its object to provide a method which eliminates the above-mentioned disadvantages by dividing a row of end closures for cans being fed at a high speed into lots of a predetermined number of the end closures at a high speed and accurately, introducing each lot into a paper bag, and then completely closing the open end of the bag.
Many other features, advantages and additional objects of the present invention will become manifest to those versed in the art upon making reference to the detailed description which follows and the accompanying sheet of drawings.
In accordance with the invention, a method of automatically bagging end closures for cans is provided which comprises the steps of shifting the position of end closures placed horizontally on an endless belt and fed at given intervals, one after another, to be substantially perpendicular to a support passage which extends substantially horizontally and receiving the end closures in the support passage, counting the number of the end closures being fed before they are shifted to the perpendicular position and lotting out the end closures received by the support passage to form a lot of a predetermined number of pieces, introducing the lot into an elongate paper bag being supported with its open end kept wide open, and closing the bag packed with the lot of end closures by twisting the open end. In this method the step of receiving the end closures in the support passage may comprise receiving the end closures in such a way that each piece is inclined with the lower portion thereof ahead of the upper portion in the same passage, attracting by suction the forwardly inclined lower portion of the piece rearwardly and the upper portion forwardly to bring the piece rearwardly and the upper portion forwardly to bring the piece to an upright position substantially perpendicular to the support passage, and forcing such upright pieces forward through two rotating rolls. The step of lotting out the end closures to form a lot may comprise counting the number of end closures being fed at a point before they are inclined, supplying lotting pawl actuator means with a signal indicating that a predetermined number of end closures has been counted, bringing lotting pawls into contact in response to the signal, with the rearmost of a pack of end closures that has passed through the rotating rolls, moving the lotting pawls forward a sufficient distance to prevent any fall to the horizontal of the frontmost piece of the following lot as it passes through the rolls, and then moving the lot of end closures forward after the frontmost one has been stabilized against falling under the impact that the ensuing pieces receive as they pass through the rolls. The step of opening each paper bag may comprise pinching a flat, elongate paper bag, which is closed at one longitudinal end and open at the other, at the both edges of the opening parallel to the axis of the bag, and attracting by suction the superposed layers of the opening between the pinched edges apart, upward and downward, to form a round opening. The step of introducing the lot of end closures into the open paper bag may comprise inserting a hollow guide cylinder into the open portion of the bag, pressing the bag against the outer surface of the guide cylinder and thereby firmly holding the bag, and introducing the lot of end closures through the hollow of the guide cylinder into the bag so held in position. Further, the step of closing the open end of the paper bag may comprise releasing the pinch of the open end of the bag following the introduction of end closures therein and withdrawing the guide cylinder from the bag, bringing open legs of a pair of pincer-like members close to each other to squeeze the open end of the bag, further squeezing the open end while giving rotation along the longitudinal axis of the paper bag to the portion of the bag filled with the end closures, and rotating the filled portion of the bag whose opening has been further squeezed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a party broken general front view of an apparatus adapted for practicing the method of the invention;
FIG. 2 is a plan view looking in the direction of the arrows a--a of FIG. 1 (corresponding to about right-hand half of the same figure), showing sections for receiving end closures for cans, dividing them into lots, and conveying the lots;
FIG. 3 is a diagrammatic view looking in the direction of the arrows b--b of FIG. 1, showing a section for putting each lot into a paper bag and closing the bag;
FIG. 4 is a partly sectional front view of a section for receiving end closures in a support passage;
FIG. 5 is a partly broken plan view of lotting pawls and drives therefor;
FIG. 6 is a front view of the components shown in FIG. 5;
FIG. 7 is a side view of the components of FIG. 5;
FIG. 8 is a front view of auxiliary feeder section and drives for forcing a lot of end closures, already moved forward by lotting pawls, a further long step forward;
FIG. 9 is a side view showing relative position of a hollow cylinder and main feed pawl in support passage;
FIG. 10 is an explanatory view of arrangements for pulling out each of stacked flat paper bags from the bottom of the stack, showing relative position of a paper bag pusher section, conveyor belt, section for supporting the conveyed bag, and pincer-like members for pinching the opening of the bag;
FIG. 11 is a front view of a section for supporting a separate paper bag;
FIG. 12 is a front view of an upper turning section for turning the paper bag packed with a lot of end closures;
FIG. 13 is a view looking in the direction of the arrows c--c of FIG. 12;
FIG. 14 is a side view of a section for pinching the opening of the paper bag at the both edges parallel to the longitudinal axis of the bag, and then keeping the bag wide open;
FIG. 15 is a sectional view looking in the direction of the arrows d--d of FIG. 14;
FIG. 16 is a front view of a section for squeezing the opening of each paper bag;
FIG. 17 is a sectional view looking in the direction of the arrows e--e of FIG. 16; and
FIG. 18 is a side view of a section for discharging each paper bag filled and closing at the opening.
DETAILED DESCRIPTION OF THE INVENTION
The method of the present invention will now be described with reference to the drawings showing the apparatus adapted for practicing the same.
Referring now to FIGS. 1, 2 and 3, the apparatus according to the invention comprises sections A, A' where end closures for cans are received and divided into lots, auxiliary feed sections B, B' for pushing the lots of the end closures a considerable distance forward, a puller section C for pulling out paper bags, one after another, from a stack, a bag-supporting section D for supporting each paper bag pulled out into position, a section E for opening each paper bag, a closing section E' for twisting and closing the bag, a frame section F, support troughs G, G', G" which serve as passages for supporting and conducting the end closures, a transfer section J for transferring the lots of end closures from support troughs G, G' to trough G", and a guide part K for guiding the lots of end closures as they are packed in the paper bags. The apparatus also includes, although not shown, a compressed-air distribution system and drives for all the sections and parts.
The sections A, A' for receiving and lotting out end closures, which lie symmetrically in parallel with respect to the longitudinal axis of the apparatus, are constructed identically. Therefore, only the section A will be hereinafter described in detail. Turning to FIGS. 1, 2 and 4, the section A comprises a hollow cylinder 2 attached to a support plate 1 fast on a lower frame 251 and which extends substantially horizontally to form part of an end-closure support passage; a chute 3 for feeding end closures (see FIG. 4) which terminates inwardly of hollow cylinder 2, at a point away from the extremity 4 of an extended lower portion 6 at the entrance of the cylinder but short of the inner wall of the lower portion; a lower air suction port 7 which opens at a point near the lower end portion 4 of hollow cylinder 2 and communicates with evacuating means not shown via pipe 8; an upper air suction port 9 which opens at a point of the upper side of hollow cylinder 2, ahead of the upper portion of each end closure T slid down through chute 3, and in the proximity of the centerline of a roll 13 to be described below; a pair of oppositely rotatable rolls 13, 13' having peripheral surfaces partly entering the hollow 5 of cylinder 2 through windows 12 formed in the latter, at a point beyond the inner wall 6 of the cylinder, said rolls being located slightly ahead of the edge R of the lower portion P of each end closure T and made rotatable about the axes of vertical rotary shafts 11, 11a; and elastic means (not shown) biasing rolls 13, 13' toward the hollow 5. Rolls 13, 13' have vertical flutes 14, 14', respectively, formed on the peripheral surfaces in parallel with the axes thereof. The two rolls are spaced a sufficient distance for each end closure to pass, forcing the rolls apart with the diametrally opposite edges of the piece caught in vertical flutes 14, 14'.
Also, as shown in FIGS. 5, 6 and 7, the section A for receiving and lotting out end closures comprises slots 21, 21' formed axially in the upper and lower portions of hollow cylinder 2; lotting pawls 22, 22' adapted to reciprocate within slots 21, 21'; and springs 24, 24' (the latter being not shown) biasing the lotting pawls 22, 22' toward the hollow 5. The section further includes lotters 20, 20' carrying the lotting pawls at one ends; a saddle 26 having two extensions 27, 27' to which the other ends of lotters 20, 20' are attached; air cylinders 29, 30 for moving the saddle back and forth horizontally; guide rods 28, 28' for guiding the saddle during the reciprocating movement; and a connecting rod 31 which connects saddle 26 with the piston of air cylinder 30, and a rod 32 secured to the piston of the other air cylinder to push saddle 26. Tips 23, 23' of lotting pawls 22, 22' are spaced a distance slightly less than the diameter of end closures and are both projected a little into the hollow 5.
With the construction described, the section A for receiving and lotting out end closures operates in the following way. As each of end closures T for cans slides downward through chute 3 to the position indicated in FIG. 4, the lower portion P of the end closure is attracted rearward by a stream of air flowing into the lower air suction port 7, and the upper portion Q is attracted frontward by a stream of air directed to the upper air suction port 9, with the consequence that the workpiece stands upright. The piece, now in contact at the periphery with the exterior surfaces of rolls 13, 13', is held by vertical flutes 14, 14' and moved forward by the rolls running inwardly of the hollow 5. While resisting the forces with which the rolls are biased toward each other by the elastic means, the end closure extends the gap in between and passes the line X--X (FIG. 4) connecting the centers of the rolls, and then it springs out to the front of the rolls. At this point, the tips 23, 23' of lotting pawls 22, 22' are substantially on the line X--X, with the gap in between slightly smaller than the diameter of the end closure as already noted. However, the end closure, fitted in vertical flutes 14, 14' of the rolls, can force pawls 22, 22' apart and move past them frontwards.
The words "front" and "rear" as used herein mean, respectively, the left- and right-hand sides as viewed in FIG. 1. In other words, the side ahead of each end closure being handled is the front and the side behind it is the rear.
Rolls 13, 13' run so fast that the end closure that has come into contact with them is instantly forced beyond the line X--X to the front. In this manner end closure are, in succession, carried frontward past the line X--X. Before the individual end closures reach the position T in FIG. 4, the number is counted by some suitable optical counter of a well-known type. Each time a predetermined number has been counted off, the counter signals drives of air cyliners 29, 30 to actuate the cylinders. Lotters 20, 20', with tips 23, 23' of pawls 22, 22' substantially on the line X--X, are then moved frontward, conveying through the passage the predetermined number of pieces as a lot separated by pawls 22, 22' from the rest. The distance over which each lot of end closures is conveyed forward by the lotting pawls range usually from about 15 to about 30 mm. In any case the distance has only to be such that, behind the preceding lot so separated, the first piece of the next lot being fed by rolls 13, 13' is prevented from falling unsupportedly forward. When end closures have gathered in the space between lotting pawls 22, 22' in the advanced position and rolls 13, 13' to such a lot that they do not fall any longer under the impact of the ensuing pieces being driven out of the rolls (that is, after a predetermined number of end closures, which depends on the kind of material, size and other factors of the pieces, have gathered), lotters 20, 20' further advance an appropriate distance, pushing the lot of end closures accordingly. The lotters are the withdrawn at a suitable point of time by the actuation of air cylinders 29, 30 to the position where the tips 23, 23' of the lotting pawls reach substantially the line X--X.
Located between and actuated by air cylinders 29, 30, lotters 20, 20' can stop stably in proper position within a short period of time.
In sections A, A' for receiving and lotting out end closures, the pieces are counted up while they are sliding downward along chute 3, just before they reach the lower end of the passage. The counting is, therefore, easy and accurate. As soon as each piece is raised upright, it is driven forward by rolls 13, 13' running at a high speed to a point beyond the line X--X that connects the centerlines of the rolls. This facilitates the division of the row of end closures into lots by means of the lotting pawls.
As can be seen from FIG. 2, the apparatus embodying the invention includes the end closure receiving-lotting units A, A' located on both sides, symmetrically with respect to the longitudinal centerline of the apparatus. On the centerline between the two units is provided means for introducing each lot of end closures into a paper bag and closing the filled bag. The lot separated forward from the rest of end closures by lotters 20, 20' is caused to advance further through a trough 301 (or G). Next, the lot is transferred to a central trough G" in the center (FIG. 1) and moved toward a paper bag. The lots of end closures in the left and right troughs 301 (or G) and 302 (or G") are alternately shifted to central trough G" in between. The lots are moved forward within troughs 301, 302 in order to prevent the following lots of end closures gathering in those passages from coming into contact with the preceding lots prior to the transfer to central trough G".
Auxiliary feed section B for conveying the lots further frontward will now be explained with reference to FIGS. 8 and 9. It comprises brackets 51, 52 attaching the entire section to the main frame, a guide rod 53 extended between and secured at both ends to the brackets, a slide 54 movable back and forth along the guide rod, an arm 57 suspended downward from one side of slide 54 and fixed to the piston connecting rod 56 of an air cylinder 55, an arm 58 suspended downward from the other side of slide 54 and carrying a kicker 60, and a rod 59 fixed to brackets 51, 52 at both ends and kept in contact with the outer side of slide 54 to help adjust the slide direction. Kicker 60 extends obliquely downward in the direction of the center of arc of hollow cylinder 2 (FIG. 9). It has a groove 62 formed longitudinally in the upper middle portion (FIG. 8) and includes a base plate 61 secured to arm 58 by bolts 63; a small solenoid-operated valve 65 supported by a support member 64 fast on the portion of base plate 61 opposite to the side secured to arm 58; and a feed pawl 67 attached to the front end of a movable stem 66 of solenoid valve 65 and made slidable within groove 62 of base plate 61. When the lot of end closures has completed the second stage of advance under the urgings of lotters 20, 20' in the manner described, feed pawl 67 is thrusted out by the small solenoid valve through slot 45 (FIG. 4) of hollow cylinder 2 into the space behind the rearmost piece of the lot. The pawl then pushes the lot forward a sufficient distance within trough 301 to leave behind a space large enough for collection of the predetermined number of end closures to form a next lot. When the preceding lot has fully covered the distance, its rearmost end closure is at a point just beyond a detent (not shown) provided in trough 301. Since the trough is slightly inclined upward to the front, the lot will remain engaged with the detent and will not slide backward when feed pawl 67 is retracted upward from trough 301 by means of solenoid valve 65. Following the upward retraction of feed pawl 67, auxiliary feed section B is reset to the initial position on hollow cylinder 2. This sequence of movements is accomplished by air cylinder 55.
Next, transfer section J for taking out the lot of end closures from trough 301, wherein they are held in place by the detent as above stated, and transferring the lot to the central region will be described.
Turning to FIGS. 1 and 2, transfer section J comprises two parallel guide rods 401, 402 located beneath trough 301 at right angles to the direction in which end closures advance and secured to the frame F; flat plates 403, 404 lying over and bridging guide rods 401, 402; an air cylinder 405 for moving flat plate 403 from one side of the apparatus to the central region and vice versa along both guide rods 401, 402, an air cylinder 406 for similarly moving flat plate 404 from the other side to the central region and backward; a trough 303 provided above and in parallel to flat plate 403 and extending parallelly with troughs 301, 302; a trough 304 (not shown) similarly located above flat plate 404; and guide members 409, 409', 407, 407' and air cylinders 410, 410' (all not shown) for moving flat plates 403, 404 upward and downward, both flat plates 403, 404 being adapted to carry lots of end closures alternately in troughs 303, 304 from trough 301, 302 to the central region and return to the original position.
Transfer section J operates in the following way.
First, trough 303 on flat plate 403, which is on one side of the apparatus, is positioned immediately below trough 302. Next, air cyinder 408 is actuated to raise trough 303 into superposition with trough 302 which holds the lot of end closures. Trough 302 is then rolled through an angle of 180 deg., or upside down, to form a cylindrical hollow body with trough 303 and transfer the lot to the latter. Together with the lot, trough 303 descends to a predetermined level. Meanwhile, trough 302 again turns upside down to the original position to be ready for the receipt of the next lot. Flat plate 403 with trough 303 is shifted to the central region by the actuation of air cylinder 405 and stops at the point where a push rod 351 (FIG. 1) of an end closure pusher H to be described later is substantially aligned to the center of arc of trough 303. At this time, trough 304 on the other flat plate 404 begins ascending toward trough 301 and, from thence onward, acts in the same way as flat plate 403.
Push rod 351 advances to force the lot out of trough 303 into the paper bag waiting open, and then withdraws to the initial position after the lapse of a predetermined period of time to be mentioned later. Flat plate 403 is brought back to the position of FIG. 2 by means of air cylinder 405, while flat plate 404 instead shifts to the central region. These actions are repeated.
In the apparatus embodying the invention, paper bags are handled while the end closures for cans are being made ready for packing.
Handling of the paper bags starts with pulling paper bags, one by one, at puller section C.
Paper bag stacker 100 (FIG. 10) includes a stacking chamber 103 defined by both vertical side walls 101, 102 extended longitudinally and vertical front and rear walls (not shown) for enclosing therein a stack of elongate paper bags, and tabs 104, 104' 105, 105' for separating paper bags, protruding horizontally from the lower ends of vertical side walls 101, 102 toward stacking chamber 103.
The section C for pulling out, one by one, the paper bags Y from stacker 100 comprises, as shown in FIGS. 1 and 10, a suction duct 110 substantially equal in length to the paper bags in a stack and located in parallel with and beneath the bags that lie perpendicularly to the arrangements as viewed in FIG. 10; a suction port 112 formed in the upper surface 111 of the suction duct facing the bags; a lever 113 extended downward from the suction duct; a pin 114 fitted in a hole formed midway in the lever at right angles to the lever (perpendicularly to the figure); a connecting arm 115 one end of which is pivotally connected to pin 114; a pin 116 anchoring the connecting arm at the other end; a cam follower arm 117 secured at one end to pin 116; a cam follower roll 118 rotatably mounted on the other end of the cam arm; a generally triangularshaped cam plate 119 in rolling contact with the cam roll; a wheel 120 for driving cam plate 119; a bearing 121 supporting pin 116 turnably; a cam follower roll 122 rotatably carried at the other end of lever 113; a cam plate 123 having a sharp recess 124 in the lower portion; and a spring 125 stretched between the lever portion between cam follower roll 122 and pin 116 to keep cam roll 122 and cam plate 123 in contact.
This paper-bag puller section C operates as follows.
As the wheel 120, fast on a rotating shaft 126 journaled by two bearings 127 (FIG. 1), is caused to run in the direction of the arrow (FIG. 10), cam plate 119 fixedly mounted on shaft 126 turns, too, raising cam follower roll 118 in sliding contact therewith, and thereby turning connecting arm 115 clockwise with pin 116. This causes cam follower roll 122 to rise along the surface of cam plate 123 in a plane tilted upwardly to the right as viewed in FIG. 10. As a consequence, suction duct 110 is moved leftward while being raised to the point where the upper surface 111 of the duct contacts the lowermost bag of the stack in stacker 100 and attracts the left-hand portion of the bag by suction from port 112. As cam plate 119 continues to rotate, connecting arm 115 turns counter-clockwise, with the consequence that cam roll 126 moves downward along cam plate 123, and suction duct 110 descends rightward. Following the movement of the suction duct, the left end of the paper bag under suction is disengaged from separating tabs 105 etc. and then, with continued descent of the duct, the right end is released from tabs 104 etc., so that the bag is completely pulled out of the stacker. Further descent of the suction duct causes cam follower roll 122 to fall into recess 124 of cam plate 123, when the suction by duct 110 is immediately interrupted. Then, the paper bag brought down by the duct is set free onto a conveyor belt 130, as shown in FIG. 10, and is transferred, past a guide plate 170, to a separate section D for supporting the bag. This separate bag-supporting section D serves also as an assembly for holding the bag while the latter is being packed with a lot of end closures for cans. It comprises, as illustrated in FIGS. 11 and 18, a vertical flat base plate 152 extending laterally and turnably pivoted with a pin 151 to the upper end 153' (FIG. 1) of frame 253; a connecting rod 157 pivoted with a pin 156 to the opposite end 154 of base plate 152; a swingable air cylinder 155 located at the other end of connecting rod 157; a lower member 159 attached, through a bracket 158, to a portion near one end 153 of base plate 152 to widen the opening of each paper bag; a pipe 160 communicated at one end with a hollow space of lower member 159 for opening the bag (of the same construction as the hollow space of an upper member 201 for bag opening which will be referred to later) and also communicated at the other end with vacuum means (not shown); a shaft 163 rotatably supported by a bearing bracket 161 which, in turn, is attached to a portion of base plate 152 slightly nearer to the other end 154 than bracket 158 and also by another bearing bracket 162 secured near the same end 154; roll-supporting plates 164, 165 secured to the both ends of the shaft 163 so as to face each other; two turnable rods 166, 167 extended between roll-supporting plates 164, 165 (FIG. 3); a position control plate 168 for controlling the position of the paper bag placed on rods 166, 167; a guide plate 170 extending upward from position control plate 168 and carrying a horizontal plate 169 at the top; a connecting rod 173 pivotally connected by a pin 172 to an arm 171 (FIG. 18), which extends obliquely downward from one of the roll-supporting plates, 164, so that the rod can move parallelly to and turn relative to arm 171; an air cylinder 174 swingably connected to connecting rod 173; and brackets 175 pivotally supporting air cylinder 174 to permit upward, downward, and swinging motions of the cylinder.
Operation of this separate paper-bag supporting section D is as follows.
Each paper bag placed on conveyor 130 by the bag puller section C is conveyed, past horizontal plate 169 of guide plate 170, onto the turnable rods 166, 167. Next, air cylinder 155 is actuated to turn base plate 152, together with rods 166, 167, etc., about pin 151 up to a point on the extension line from central trough G (303). The two rods 166, 167 thus brought to a stop are longitudinally inclined and the paper bag thereon will slip downward unless they are pressed in position. In order to avoid the fall and open the paper bag, a section E for holding and opening the bag is provided. The section E, which functions in cooperation with lower bag-opening member 15, comprises, as shown in FIGS. 1, 2, 14 and 15, an upper bag-opening member 201; an inverted-L-shaped plate 202 which serves as a frame for suspending upper member 201; a suitable number of long bolts 205 piercing through the horizontal part 203 of suspending plate 202 and fastened to upper member 201; tension springs 208 which surround the long bolts between the upper surface 206 of upper bag-opening member 201 and the under surface 207 of horizontal plate part 203 to allow suspending plate 202 to carry upper member 201 elastically; a stop plate 209 fitted to the upper ends of long bolts 205 to set a maximum distance between upper member 201 and horizontal part 203; a pipe 211 communicated at one end with hollow space 210 of upper member 201 and at the other end with vacuum means not shown; an arm 214 turnably connected to the lower end portions of vertical part 204 of inverted-L-shaped suspending plate 202; bearings 212, 213 made fast to the side of vertical part 204 of suspending plate 202 opposite to the side where upper member 201 is suspended; a vertical guide rod 215 extended through bearings 212, 213, and a bracket 216 supporting guide rod 215 in place. The under surface of upper bag-opening member 201 is formed of an arcuate recess 220 extended in the direction where the lot of end closures is to travel and flat zones 221, 222 on both sides of recess 220. This recess 220 is shaped to one half of the circumference of the opening of each paper bag when opened wide to a round form. It has large suction ports 225, 225' and 226 formed near the adjacent flat zones and in the center and, in addition, a suitable number of smaller suction ports 227, 228 formed between ports 225 and 226 and between ports 225' and 226. The abovementioned lower bag-opening member 159 is also of the same construction and shape as upper member 201.
This bag-holding-opening section E operates in the following mamnner. Just before the paper bag slides down upon tilting of bag-supporting section D, upper bag-opening member 201 is lowered by the descent of vertically movable arm 214 until it elastically pinches the both longitudinal edges of the opening of the bag between the both flat portions of lower bag-opening member 159 and the mating flat portions of upper member 201. The pressure with which the bag is caught is the reaction force that results from the compression of springs 208. Next, after the separate bag-supporting section D has stopped in prescribed inclined position, vacuum is applied through pipe 211 of upper bag-opening member 201 and through pipe 160 of lower member 159. Of the superposed layers of the paper bag, the portions close to the pinched edges are first opened apart, upward and downward, by the suction through the large suction ports. Following this, the pinched portions of the bag (which are simply pinched by elastic means) are caused to slip off by the suction through the rest of suction ports and, in an instant, the opening of the paper bag is fully opened to the inner recessed contours of the upper and lower bag-opening members.
The bag is now fully open up to about 15 cm from the open end and is thence gradually closed toward the opposite end which is sealed, most of the bag remaining flatly closed.
After the opening of the paper bag, a hollow guide cylinder is inserted into the open portion of the bag to prepare for the introduction of a lot of end closures from the trough G" into the bag.
The guide cylinder part K for this purpose comprises, as shown in FIG. 1, a hollow guide cylinder 451; a stationary arm 452 hanging down from the rear of guide cylinder 451; a drive arm 453 for moving the guide cylinder back and forth in parallel with the direction of travel of the end closures, and support rails (not shown) for supporting the guide cylinder during its reciprocating movement. The guide cylinder has an outside diameter slightly smaller than the diameter of the rounded opening of the bag. To facilitate the insertion into the bag, the guide cylinder wall is tapered at the front end.
Operation of this guide cylinder section K is as follows. After the opening of the paper bag has been fully opened, driver arm 453 is actuated to move guide cylinder 451 forward into the open portion of the bag, to a depth of about 15 cm from the open end. Following the introduction of a lot of end closures, the cylinder is withdrawn from the bag to the original position.
At the time of introduction the lot of end closures for cans is forced deep into the bag, down to the closed end, when the bag is subjected to a pressure urging it obliquely upward. Therefore, the arrangements are so designed that, after the insertion of the guide cylinder, upper bag-opening member 201 is moved further downward to increase the pinch on the paper bag between guide cylinder 451 and recess 220 of upper member 201. After the paper bag has been pinched firmly, the lot of end closures in the central trough G" is forced through the hollow of the guide cylinder into the bag by the action of a lot-inserting feed section H which consists essentially of an air cylinder and a push rod 351 (FIG. 1) to be moved back and forth by the air cylinder.
Next, the paper bag is closed at the open end by twisting.
A section E' for twisting and closing each bag at the open end consists of a pinching part indicated in FIGS. 1, 16 and 17 and a bag-turning part in FIGS. 12 and 13. The pinching part, in turn, consists of a stationary base plate 501 fixed to a frame (not shown) and components attached to or supported by the under surface of the base plate. The components include, as shown in FIG. 16, a small motor 502; brackets 503, 504 for the motor; a drive shaft 505 extended horizontally from the motor rightwardly as viewed in the drawing; a gear 506 fixedly mounted on drive shaft 505; a driven gear 507 in mesh with gear 506; a rotating shaft 508 of driven gear 507; an inverted-U-shaped bearing 509 supporting rotating shaft 508 and secured to base plate 501; an arm 510 located within the inverted U space of bearing 509 and anchored at one end to shaft 508; an open-legged pincer-like member 511 turnably mounted on a pin set on the other end of arm 510; a spring 512 stretched between arm 510 and pincer-like member 511; a stop pin 513 provided on arm 510 to define the angle of minimum opening between arm 510 and pincer-like member 511 under the urgings of spring 512; a rotating shaft 518 located in parallel and at the same level with rotating shaft 518; and a gear 517 mounted on shaft 518 in mesh with driven gear 507. Also among the components are an arm 520, open-legged pincer-like member 521, tension spring 522, and stop pin 523 all arranged in a mirror-like symmetry with arm 510, open-legged pincer-like member 511, tension spring 512, and stop pin 513, with respect to the common tangential line Y--Y between driven gear 507 on shaft 518 and gear 517. The part further comprises cam plates 515, 525 fixed to inverted U-shaped bearing 509 to the lower portion of the U space; a cam follower roll 514 attached to the end of an upper leg of open-legged pincer-like member 511 and rotatable in contact with cam plate 515; and a cam follower roll 524 similarly attached to the open-legged pincer-like member 521 and rotatable in contact with cam plate 525. Open-legged pincer-like members 511 and 512 are staggered to pass close by each other.
On a shaft extended leftwardly of small motor 502 as viewed in the figure is fixedly mounted a sprocket 60, which is employed to drive bag-turning rolls to be described later. Referring to FIGS. 1, 12 and 13, the bag-turning part comprises a sprocket 530 to be driven by sprocket 600; a rotating shaft 531 on one end of which sprocket 530 is mounted; bearings 533, 534 suspended from and attached to a flat base plate 532 so as to support rotating shaft 531; a rotatable cam plate 535 mounted on the opposite end of rotating shaft 530; a cam follower roll 536 in rolling contact with the periphery of cam plate 535; a rocking arm 546 carrying cam follower roll 536 rotatably at one end, and rockably pivoted midway to a shaft 536, carrying arms 540, 541 turnably at the other end; bearings 537, 538 supporting shaft 539; an upper roll 550 mounted on the other end of arm 540; an upper roll 551 mounted on the other end of arm 541; an actuating arm 543 extending from arm 546 in the direction opposite to cam follower roll 536 and engaged at the end with one end of a spring 542, which serves to press cam follower roll 536 against cam plate 535; a spring holder 544 engaged with the otherend of spring 542; and a spring 545 biasing arms 540, 541 of rolls 550, 551 toward each other. With these components the bag-turning part is operatively associated with the two turnable rods 166, 167 of bag-supporting section D.
Turnable rods 166, 167 support the paper bag that holds a lot of end closures for cans and, for the turning of those rods, there are provided, as shown in FIGS. 11, 2 and 3, a small motor 180 with an output shaft 181, a gear 182 mounted on shaft 181, and gears 183, 184 mounted on rods 166, 167 in mesh with gear 182.
The section E' for twisting and closing each bag at the open end and the bag-turning part operate as follows.
As already stated, the lot of end closures pinched between guide cylinder 451 and upper bag-opening member 201 is forced into the paper bag by push rod 351. The push rod stops with its front end thrusted deep in the bag, past the mouth of the guide cylinder.
When the lot of end closures stands in the support trough without the application of any pressure, the individual pieces are not in close contact but in partial contact with one another because of their own distorsion. Consequently, the length of the loose lot is about 20 to 50% greater than that of the lot in which the pieces are fully and tighty in contact. The forceful introduction of the lot into the bag compresses the mass, decreasing the length considerably from that in the support trough. Therefore, if guide cylinder 451 and upper bag-opening member 201 release their hold on the bag, the bag will be moved forward, leaving part of the pieces exposed behind. To avoid this, open-legged pincer-like members 511, 521 on the left and right of the opening-pinching section E' draw close to each other at a point between the front end of the guide cylinder and the rearmost of the end closures as a lot in the paper bag, so as to squeeze that portion of the round-shaped paper bag. When the round-shaped portion has been reduced in size to about one half of the original, upper bag-opening member 201 rises and guide cylinder 451 recedes out of the bag to the initial position. In this way upper bag-opening member 201 and guide cylinder 451 release the bag. Since the paper bag is squeezed by open-legged pincer-like members 511, 521 only at the portion between the open end and the bag portion filled with the lot of end closures, there is no possibility of the open end of the bag passing forward through the gap formed by the both open-legged pincer-like members.
The pincer-like members are further moved closer to each other and, immediately before they pinch the bag firmly, push rod 351 is retracted out of the bag. Squeezing the bag to this degree prevents the rearmost one of the end closures from falling within the paper bag.
During the squeezing of the bag to this point, rolls 550, 551 of the bag-turning part are actuated by the rotation of cam plate 535 to press the portion of the paper bag containing the end closures on turnable rods 166, 167 of separate bag-supporting section D against the rods. In this manner the bag portion is held between turnable rods 166, 167 and rolls 550, 551. During, or before or after, the retraction of push rod 351, small motor 180 for driving rods 166, 167 secured by suitable means to roll-supporting plates 164, 165 (see FIGS. 11 and 3) starts running. Its rotational power is transmitted through the output shaft 181 of the motor, gear 182 mounted on the shaft, and gears 183, 184 meshed with gear 182 and mounted, respectively, on rods 166, 167, in the order mentioned, to turn the paper bag. As it turns, the bag is twisted relative to the portion held by pincer-like members 511, 521. With the progress of twisting the pincer-like members draw even closer to each other and close the paper bag by sufficiently twisting it about the portion where the members maintain the pinch. The bag will be closed more effectively if the bag is turned once more through an angle of about 180 deg. after the pincer-like members have been sufficiently drawn close to each other. After this, motor 180 is stopped.
Next, separate bag-supporting section D is moved downward by air cylinder 155 to the original position where the round rods and therefore the paper bag lying thereon are horizontal. Connecting rod 173 of air cylinder 174 then rises, with the result that, about shaft 163 (FIG. 18), arm 171 turnably pivoted at one end to connecting rod 173 by pin 172, roll-supporting plate 165 integral with arm 171, and turnable rods 166, 167 are all moved to the points indicated by two-dot chain lines. The paper bag now packed with the end closures is released from rods 166, 167 onto a delivery table 650. The turnable rods and associated parts are brought back by the action of air cylinder 174 to the points indicated by full lines in FIG. 18.
The embodiment of the apparatus of the present invention so far described, which includes the components described in detail and uses well-known timing means to actuate those components according to a schedule, can count up a predetermined number of end closures for cans, divide them into lots, put each lot into a paper bag, close the open end of the bag, and delivery it to the outside, all in an automatized operation. The counting and lotting are done rapidly and accurately at a handling rate of 300 pieces of end closures a minute. The bags packed with the end closures are completely closed to protect the contents.
While the embodiment of the invention has been described as including arrangements in which the sequence of counting and lotting is accomplished in two separate regions and the lots of end closures from the two regions are alternately fed to a single bagging zone for introduction into paper bags, it is not an essential requirement of the invention; the end closures may be counted up and divided into lots in one region, instead, for direct introduction into paper bags.
The method of the invention comprises novel steps and, by a combination of those steps, makes possible the automatization of rapid and accurate counting and division of end closures for cans into lots and subsequent packing of each lot into a paper bag.
It will be apparent that various changes in form and details can be made to the method of the invention without departing from the spirit and scope thereof, the forms hereinbefore described being merely preferred embodiments thereof.
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End closures for cans fed horizontally at given intervals at a high speed are shifted in direction, one after another, to be substantially perpendicular to a support passage extending substantially horizontally, received separately by the passage rapidly and positively, and lotted out when a predetermined number has been reached by the pieces received. Each lot thus compacted to a solid cylinderical form is put into an elongate paper bag, and the open end of the bag is closed.
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The present application is a continuation application of U.S. patent application Ser. No. 10/587,372 filed Jun. 12, 2008, which is a 371 International Application PCT/ES2005/070010 filed 27 Jan. 2005 entitled “METHOD OF PRODUCTION OF RECOMBINANT SUCROSE SYNTHASE, USE THEREOF IN THE MANUFACTURE OF KITS FOR DETERMINATION OF SUCROSE, PRODUCTION OF ADPGLUCOSE AND PRODUCTION OF TRANSGENIC PLANTS WHOSE LEAVES AND STORAGE ORGANS ACCUMULATE HIGH CONTENTS OF ADPGLUCOSE AND STARCH”, which was published on 18 Aug. 2005, with International Publication Number WO 2005/075649 A1, and which claims priority from Spanish Patent Application P200400257, filed 5 Feb. 2004, the content of which is incorporated herein by reference.
AREA OF INDUSTRY TO WHICH THE INVENTION RELATES
The invention relates to optimization of the production of recombinant sucrose synthase (SS) in soluble, active form employing an appropriate strain of Escherichia coli , the use of SS for making kits for determination of sucrose, design of optimized forms of SS for the synthesis of ADPglucose (ADPG), and the production of transgenic plants whose leaves and storage tissues accumulate high levels of ADPG and amylose-enriched starch as a result of overproduction of cytosolic ADPG in plants which overexpress SS.
PRIOR ART
Starch is the main storage form of carbohydrates in plants. It accumulates in large amounts in organs such as seeds (wheat, barley, maize, pea, etc.) and tubers (potato and yam among others) and is a fundamental constituent of the human diet. Furthermore, starch is widely used in the paper, cosmetic, pharmaceutical and food industries, and is also used as an essential component for the manufacture of biodegradable plastics and environment-friendly paints. Since it is made up of covalently bound glucose molecules, investigation of the processes involved in the synthesis of this polysaccharide is a top priority in various areas of industrial production.
ADPG is the universal precursor of starch biosynthesis in plants, both in heterotrophic organs ( FIG. 1A ) and in leaves ( FIG. 2A ), and it is widely assumed that its production is controlled exclusively by the enzyme ADPG pyrophosphorylase (AGPase) or ADPG synthase (EC 2.7.7.27) (Okita, T. W. (1992) Is there an alternative pathway for starch synthesis? Plant Physiol. 100, 560-56; Müller-Röber, B., Sonnewald, U. Willmitzer, L. (1992) Inhibition of the ADPglucose pyrophosphorylase in transgenic potatoes leads to sugar-storing tubers and influences tuber formation and expression of tuber storage protein genes. EMBO J. 11, 1229-1238; Stark, D. M., Timmerman, K. P., Barry, G. F., Preiss, J., Kishore, G. M. (1992) Regulation of the amount of starch in plant tissues by ADPglucose pyrophosphorylase. Science 258, 287-282; Neuhaus, E. H., Häusler, R. E., Sonnewald, U. (2005) No time to shift the paradigm on the metabolic pathway to transitory starch in leaves. Trends Plant Sci. at press). The various applications of the starch produced in a plant are based mainly on the ratio of amylose and amylopectin, which determines the structure of the starch grain, as well as its viscosity in aqueous suspensions. This ratio of amylose and amylopectin depends on, among other things, the concentration of ADPG in the plant cell (Clarke, B. R., Denyer, K., Jenner, C. F., Smith, A. M. (1999) The relationship between the rate of starch synthesis, the adenosine 5′-diphosphoglucose concentration and the amylose content of starch in developing pea embryos. Planta 209, 324-329).
SS (EC 2.4.1.13, SS) (UDP-glucose:D-fructose-2-glucosyl transferase) is a reversible enzyme that catalyses the production of UDPG and fructose from sucrose and UDP. Although, as shown in FIG. 1A , SS has classically been regarded as having the role of producing UDPG, metabolic processing of which eventually gives rise to the production of starch in heterotrophic tissues such as endosperm and tubers (Zrenner, R., Salanoubat, M., Willmitzer, L., Sonnewald, U. (1995) Evidence for the crucial role of sucrose synthase for sink strength using transgenic potato plants. Plant J. 7, 97-107; Baroja-Fernández, E., Muñoz, F. J., Saikusa, T., Rodríguez-López, M., Akazawa, T., Pozueta-Romero, J. (2003) Sucrose synthase catalyzes the de novo production of ADPglucose linked to starch biosynthesis in heterotrophic tissues of plants. Plant Cell Physiol. 44, 500-509; Pozueta-Romero, J., Muñoz, F. J., Rodríguez-López, M., Baroja-Fernández, E., Akazawa, T. (August 2003) New waves in the starch field. Lett. Plant Cell Physiol. 24-32), there are references to the potential ability of the enzyme to use other nucleotide diphosphates in vitro for the production of the corresponding sugar nucleotides (Murata, T., Sugiyama, T., Minamikawa, T., Akazawa, T. (1966) Enzymic mechanism of starch synthesis in ripening rice grains. Mechanism of the sucrose-starch conversion. Arch. Biochem. Biophys. 113, 34-44; Delmer, D. P. (1972) The purification and properties of sucrose synthase from etiolated Phaseolus aureus seedlings. J. Biol. Chem. 247, 3822-3828). Although of questionable physiological relevance (Okita, T. W. (1992) Is there an alternative pathway for starch synthesis? Plant Physiol. 100, 560-56; Müller-Röber, B., Sonnewald, U. Willmitzer, L. (1992) Inhibition of the ADPglucose pyrophosphorylase in transgenic potatoes leads to sugar-storing tubers and influences tuber formation and expression of tuber storage protein genes. EMBO J. 11, 1229-1238), it has been suggested that SS is capable of producing ADPG directly, which can be used for the production of starch both in heterotrophic tissues and in photosynthetic tissues ( FIGS. 1B and 2B ) (Pozueta-Romero, J., Perata, P., Akazawa, T. (1999) Sucrose-starch conversion in heterotrophic tissues of plants. Crit. Rev. Plant Sci. 18, 489-525; Baroja-Fernández, E., Muñoz, F. J., Akazawa, T., Pozueta-Romero, J. (2001) Reappraisal of the currently prevailing model of starch biosynthesis in photosynthetic tissues: a proposal involving the cytosolic production of ADPglucose by sucrose synthase and occurrence of cyclic turnover of starch in the chloroplast. Plant Cell Physiol. 42, 1311-1320; Baroja-Fernández, E., Muñoz, F. J., Saikusa, T., Rodríguez-López, M., Akazawa, T., Pozueta-Romero, J. (2003) Sucrose synthase catalyzes the de novo production of ADPglucose linked to starch biosynthesis in heterotrophic tissues of plants. Plant Cell Physiol. 44, 500-509; Baroja-Fernández, E., Muñoz, F. J., Zandueta-Criado, A., Morán-Zorzano, M. T., Viale, A. M., Alonso-Casajús, N., Pozueta-Romero, J. (2004) Most of ADPglucose linked to starch biosynthesis occurs outside the chloroplast in source leaves. Proc. Natl. Acad. Sci. USA 101, 13080-13085). According to this hypothesis (based solely and circumstantially on evidence of the biochemical type), SS is responsible for the synthesis of an important pool of ADPG molecules necessary for the biosynthesis of starch. This hypothesis has not, however, been demonstrated experimentally by genetic engineering or traditional crop improvement techniques, and is not consistent with the countless tests of the genetic and molecular type indicating that AGPase is the only source of ADPG in plants (Okita, T. W. (1992) Is there an alternative pathway for starch synthesis? Plant Physiol. 100, 560-56; Müller-Röber, B., Sonnewald, U. Willmitzer, L. (1992) Inhibition of the ADPglucose pyrophosphorylase in transgenic potatoes leads to sugar-storing tubers and influences tuber formation and expression of tuber storage protein genes. EMBO J. 11, 1229-1238; Neuhaus, E. H., Häusler, R. E., Sonnewald, U. (2005) No time to shift the paradigm on the metabolic pathway to transitory starch in leaves. Trends Plant Sci. at press).
Sugar nucleotides such as UDPG and ADPG are produced commercially from pyrophosphorylase reactions catalysed by enzymes such as UDPG pyrophosphorylase (UGPase) and AGPase, respectively, based on the use of an expensive substance called glucose-1-phosphate (G1P). An alternative to this practice for production of sugar nucleotides is based on the use of SS, development of which has largely been hampered by the limitations of Escherichia coli for expressing and efficiently processing a large number of eukaryotic proteins. This limitation inspired some researchers to produce recombinant SS by making use of biological factories of the eukaryotic type such as yeasts (Zervosen, A., Römer, U., Elling, L. (1998) Application of recombinant sucrose synthase-large scale synthesis of ADP-glucose. J. Mol. Catalysis B: Enzymatic 5, 25-28; Römer, U., Schrader, H., Günther, N., Nettelstroth, N., Frommer, W. B., Elling, L. (2004) Expression, purification and characterization of recombinant sucrose synthase I from Solanum tuberosum L. for carbohydrate engineering. J. Biotechnology 107, 135-149). Alternatively, SS intended for the production of sugar nucleotides has had to be purified by expensive processes of purification of proteins from plant extracts (patent DE4221595 (1993), Purified sucrose synthase enzyme useful for production of nucleotide-activated sugars or oligosaccharides). This SS obtained from plant extracts has the disadvantage that it has a predilection for UDP and very low affinity for ADP (Pressey R (1969) Potato sucrose synthase: purification, properties, and changes in activity associated with maturation. Plant Physiol. 44, 759-764; Nguyen-Quock, B., Krivitzky, M., Huber, S. C., Lecharny, A. (1990) Sucrose synthase in developing maize leaves. Plant Physiol. 94, 516-523; Morell, M., Copeland, L. (1985) Sucrose synthase of soybean nodules. Plant Physiol. 78, 149-154). Production of recombinant SS from cultures of E. coli has recently been achieved (Nakai, T., Tonouchi, N., Tsuchida, T., Mori, H., Sakai, F., Hayashi, T. (1997) “Expression and characterization of sucrose synthase from mung bean seedlings in Escherichia coli ” Biosci. Biotech. Biochem. 61, 1500-1503; Nakai, T., Konishi, T., Zhang, Z-Q., Chollet, R., Tonouchi, N., Tsuchida, T., Yoshinaga, F., Mori, H., Sakai, F., Hayashi, T. (1997) “An increase in apparent affinity for sucrose of mung bean sucrose synthase is caused by in vitro phosphorylation or directed mutagenesis of Ser11” Plant Cell Physiol. 39, 1337-1341; Barratt, D. H. P., Barber, L., Kruger, N. J., Smith, A. M., Wang, T. L., Martin, C. (2001) Multiple, distinct isoforms of sucrose synthase in pea. Plant Physiol. 127, 655-664; Christopher, B., William, B., Robert, H. “Bacterial sucrose synthase compositions and methods of use” Patent WO9803637). However, the production of SS in this prokaryotic system was associated with problems such as (1) the amount of SS produced was very low (30 micrograms/gram of bacteria, Nakai, T., Tonouchi, N., Tsuchida, T., Mori, H., Sakai, F., Hayashi, T. (1997) “Expression and characterization of sucrose synthase from mung bean seedlings in Escherichia coli ” Biosci. Biotech. Biochem. 61, 1500-1503; Li, C. R., Zhang, X. B., Hew, C. S. (2003) “Cloning, characterization and expression analysis of a sucrose synthase gene from tropical epiphytic orchid Oncidium goldiana . Physiol. Plantarum 118, 352-360), (2) the amount of active SS obtained was very low or zero (0.05-1.5 units/mg (Nakai, T., Tonouchi, N., Tsuchida, T., Mori, H., Sakai, F., Hayashi, T. (1997) “Expression and characterization of sucrose synthase from mung bean seedlings in Escherichia coli ” Biosci. Biotech. Biochem. 61, 1500-1503; Li, C. R., Zhang, X. B., Hew, C. S. (2003) “Cloning, characterization and expression analysis of a sucrose synthase gene from tropical epiphytic orchid Oncidium goldiana . Physiol. Plantarum 118, 352-360); 5.6 U/mg (Römer, U., Schrader, H., Günther, N., Nettelstroth, N., Frommer, W. B., Elling, L. (2004) Expression, purification and characterization of recombinant sucrose synthase I from Solanum tuberosum L. for carbohydrate engineering. J. Biotechnology 107, 135-149), (3) the recombinant SS had to be purified by conventional methods of purification of proteins such as chromatography, electrophoresis, isoelectric focusing, etc., which, combined, prove expensive and do not guarantee purification of the protein in a homogeneous state and (4) most of the SS is sent to inclusion bodies or is accumulated in the form of inactive aggregates as a result of the inability of the bacterium's machinery to fold the protein correctly (Miroux, B., Walker, J. E. (1996) “Over-production of proteins in Escherichia coli : mutant hosts that allow synthesis of some membrane proteins and globular proteins at high levels” J. Mol. Biol. 260, 289-298).
The present invention describes the development of a system based on the use of an appropriate strain of E. coli and on the use of a suitable expression vector that permits the large-scale production and fast and easy purification of different variants of recombinant SS in its active form. Some of these variants have greater affinity for ADP than those obtained from plant extracts and can be used both for the production of UDPG and ADPG from inexpensive substances such as sucrose, UDP and ADP.
Chromatographic techniques constitute a powerful tool for determining the sucrose content of complex samples such as plant extracts, sera, urine, fruit juice, wines, fruit and foodstuffs (D'Aoust, M-A., Yelle, S, Nguyen-Quock, B. (1999) Antisense inhibition of tomato fruit sucrose synthase decreases fruit setting and the sucrose unloading capacity of young fruit. Plant Cell 11, 2407-2418; Tang, G-Q., Sturm, A. (1999) Antisense repression of sucrose synthase in carrot affects growth rather than sucrose partitioning. Plant Mol. Biol. 41, 465-479; Frias, J., Price, K. R., Fenwich, G. R., Hedley, C. L., Sorensen, H., Vidal-Valverde, C. (1996) J. Chromatogr. A 719, 213-219). Such techniques require highly specialized technical personnel and involve a large investment in equipment. Unfortunately, alternative methods based on hydrolysis of the sucrose molecule by the action of the enzyme invertase and subsequent spectrophotometric or fluorimetric determination of the molecules of glucose and/or fructose (Sweetlove, L. J., Burrell, M. M., ap Rees, T. (1996) Starch metabolism in tubers of transgenic potato with increased ADPglucose pyrophosphorylase. Biochem. J. 320, 493-498; Stitt, M., Lilley, R. M., Gerhardt, R., Heldt, H. W. (1989) Metabolite levels in specific cells and subcellular compartments of plant leaves. Methods Enzymol. 174, 518-552; Holmes, E. W. (1997) Coupled enzymatic assay for the determination of sucrose. Anal. Biochem. 244, 103-109; Methods of Analysis (1996) Code of Practice for Evaluation of Fruit and Vegetable Juices. Association of the Industry of Juices and Nectars from Fruits and Vegetables of the European Economic Community) are subject to limitations of a technical nature such as subtraction of the measurements corresponding to the endogenous glucose and/or fructose present in the sample. The abundance of glucose and/or fructose in the sample can add background noise that hampers reliable and accurate determination of sucrose. In the vast majority of cases it is necessary to carry out exhaustive controls before issuing a reliable statement on the true sucrose content of a sample (Worrell, A. C., Bruneau, J-M., Summerfelt, K., Boersig, M., Voelker, T. A. (1991) Expression of a maize sucrose phosphate synthase in tomato alters leaf carbohydrate partitioning. Plant Cell 3, 1121-1130). Kits for determination of sucrose based on the use of invertase are available from companies such as Sigma, Biopharm GmbH and Megazyme. Alternatively, an automated method of sucrose determination has been developed, based on determination of the glucose-1-phosphate released by the action of sucrose phosphorylase of bacterial origin (Vinet, B., Panzini, B., Boucher, M., Massicotte, J. (1998) Automated enzymatic assay for the determination of sucrose in serum and urine and its use as a marker of gastric damage. Clin. Chem. 44, 2369-2371). The present invention describes the development of a simple, reliable and inexpensive alternative method for the determination of sucrose in a sample based on the use of SS and coupling enzymes which hydrolyse ADPG or UDPG.
Considerations concerning the factors governing the intracellular levels of ADPG have mainly revolved around regulation of the synthesizing enzyme, AGPase (Preiss, (1988) Biosynthesis of starch and its regulation. The Biochemistry of Plants. Vol. 14, Academic Press, New York, p. 182-249; Pozueta-Romero, J., Perata, P., Akazawa, T. (1999) Sucrose-starch conversion in heterotrophic tissues. Crit. Rev. Plant. Sci. 18, 489-525). In fact, a high proportion of the patents and scientific publications concerning the production of ADPG and the production of plants producing starches of industrial interest revolve around the use of AGPase (Stark, D. M., Timmerman, K. P., Barry, G. F., Preiss, J., Kishore, G. M. (1992) Regulation of the amount of starch in plant tissues by ADPglucose pyrophosphorylase. Science 258, 287-282; Slattery, C. J., Kavakli, H., Okita, T. W. (2000) Engineering starch for increased quantity and quality. Trends Plant Sci. 5, 291-298). However, although they are yet to be confirmed with evidence of the genetic/molecular type, recent scientific studies of a biochemical type indicate that, as shown in FIGS. 1B and 2B , SS might be involved in the direct synthesis of ADPG necessary for the biosynthesis of starch (Baroja-Fernández, E., Muñoz, F. J., Saikusa, T., Rodríguez-López, M., Akazawa, T., Pozueta-Romero, J. (2003) Sucrose synthase catalyzes the de novo production of ADPglucose linked to starch biosynthesis in heterotrophic tissues of plants. Plant Cell Physiol. 44, 500-509). This hypothesis is especially controversial, bearing in mind that (a) SS has never been linked to starch production in leaves, (b) presence of an ADPG translocator is required in the membranes of the plastids, connecting the cytosolic pool of the ADPG produced by SS to the starch synthase present inside the plastid and (c) the involvement of SS as an ADPG producing source is in direct conflict with many tests of the biochemical/genetic/molecular type which appear to show that AGPase is the only source of ADPG (Okita, T. W. (1992) Is there an alternative pathway for starch synthesis? Plant Physiol. 100, 560-56; Müller-Röber, B., Sonnewald, U. Willmitzer, L. (1992) Inhibition of the ADPglucose pyrophosphorylase in transgenic potatoes leads to sugar-storing tubers and influences tuber formation and expression of tuber storage protein genes. EMBO J. 11, 1229-1238; Stark, D. M., Timmerman, K. P., Barry, G. F., Preiss, J., Kishore, G. M. (1992) Regulation of the amount of starch in plant tissues by ADPglucose pyrophosphorylase. Science 258, 287-282; Neuhaus, E. H., Häusler, R. E., Sonnewald, U. (2005) No time to shift the paradigm on the metabolic pathway to transitory starch in leaves. Trends Plant Sci. at press). Perhaps for all these reasons, to date plants have never been designed that overexpress SS for the production of high levels of starch. However, the present invention describes, for the first time, the production of transgenic plants that overexpress SS for increasing their production of ADPG and starch. Conversely, we show that plants that are deficient in starch as a result of absence of AGPase possess normal ADPG levels. This all shows that, as shown in FIGS. 1B and 2B , SS is involved in the direct synthesis of the ADPG required for the biosynthesis of starch and is responsible for the synthesis of most of the ADPG accumulated in the plant cell.
Although based on the approach presented in FIG. 1A , according to which SS is involved in the synthesis of UDPG (but not ADPG) in storage tissues, various works have described the production of plants with reduced content of starch as a consequence of decreased activity of SS (Chourey, P. S., Nelson, O. E. (1976) The enzymatic deficiency conditioned by the shrunken-1 mutations in maize. Biochem. Genet. 14, 1041-1055; Zrenner, R., Salanoubat, M., Willmitzer, L., Sonnewald, U. (1995) Evidence for the crucial role of sucrose synthase for sink strength using transgenic potato plants. Plant J. 7, 97-107; Tang, G-Q., Sturm, A. (1999) Antisense repression of sucrose synthase in carrot ( Daucus carota L.) affects growth rather than sucrose partitioning. Plant Mol. Biol. 41, 465-479). In this sense, there is no experimental evidence that the overexpression of SS could be used for the production of plants with high starch content as a result of the increase in levels of ADPG in accordance with the metabolic schemes shown in FIGS. 1B and 2B . However, based on the ability of SS to produce the precursor molecule of the biosynthesis of cell wall polysaccharides (UDPG), works have been published and patented which describe the production of cotton plants with high fibre content or cereals with high content of celluloses as a result of overexpression of SS (Timothy, H. J., Xiamomu, N., Kanwarpal, S. “Manipulation of sucrose synthase genes to improve stalk and grain quality” Patent WO02067662; Robert, F., Danny, L., Yong-Ling, R. “Modification of sucrose synthase gene expression in plant tissue and uses therefor” Patent WO0245485; Christopher, B., William, B., Robert, H. “Bacterial sucrose synthase compositions and methods of use” Patent WO9803637).
The invention relates firstly to the development and optimization of a method of production of large amounts of recombinant SS that is soluble, can be purified easily and has high specific activity, based on the use of a suitable strain of E. coli and on the use of an expression vector that makes it possible to obtain SS with a histidine tail. The invention further relates to the procedure followed for making kits for determination of sucrose based on the use of the enzyme product with SS activity coupled to enzymes that metabolize ADPG or UDPG. It further relates to optimization of the production of sugar nucleotides such as ADPG or UDPG starting from variants of SS specially designed for this purpose. Finally, details are given of the design of transgenic plants with high content of sucrose, ADPG and starch and a high amylose/amylopectin ratio following overexpression of SS.
DETAILED DESCRIPTION OF THE INVENTION
Amplification of a cDNA that Encodes an SS
Knowing the nucleotide sequence of wild-type sucrose synthase SS4 (Fu, H., Park, W. D. (1995) Sink- and vascular-associated sucrose synthase functions are encoded by different gene classes in potato. Plant Cell 7, 1369-1385), two specific primers were created corresponding to the 5′ and 3′ ends of the gene. Using these primers, a 2418 base pair DNA fragment, designated SSX, from a potato-leaf cDNA library, was amplified by conventional PCR techniques. This PCR fragment was inserted in the pSK Bluescript plasmid (Stratagene), giving rise to the pSS construction ( FIG. 3A ), which was amplified in the host bacterium XL1 Blue.
Production of Active Recombinant SS from a Special Strain of E. coli
pSS was digested with the NcoI and NotI restriction enzymes. The fragment released (which contains the cDNA encoding SS, SSX) was cloned on the same restriction sites of the pET-28a(+) expression plasmid (Novagen) ( FIG. 3B ) which possesses a nucleotide sequence in the polylinker region that encodes a histidine-rich sequence, which becomes fused with the recombinant protein. The resulting plasmid (designated pET-SS, FIG. 3C ) was inserted by electroporation in various strains of E. coli . The E. coli strain BLR(DE3) (Novagen) transformed with pET-SS was deposited in the Spanish Type Culture Collection on 29 Oct. 2003, located in the Research Building of Valencia University, Burjassot Campus, Burjassot 46100 (Valencia, Spain) with the deposition number CECT:5850. The bacteria were incubated at 20° C. in LB medium. Overexpression of SSX was effected by addition of 1 mM isopropyl-β-D-thiogalactopyranoside (IPTG) in 100 ml of cell culture grown at 20° C. After six hours of induced culture, the bacteria were collected and resuspended in 4 ml of binding buffer (Novagen, His-bind purification kits), then sonicated and centrifuged at 40,000 g for 20 minutes. The supernatant, which contains the recombinant SS with an amino acid sequence rich in histidine residues at the N-terminal end, was passed through an affinity column of the His-bind protein purification kit from Novagen. Following the instructions with the kit, SS was eluted with 6 ml of the recommended elution buffer, which contained 200 mM of imidazole instead of 1 mol. After elution, the protein was quickly submitted to dialysis to remove any trace of imidazole, which inactivates SS irreversibly.
Production of an Isoform of SS Optimized for Production of ADPG
Using suitable primers, with pSS as template, the mutated variant SS5 was designed, giving rise to the construction pSS5. This was done using the QuikChange Site-Directed Mutagenesis kit (Stratagene). pSS5 was digested with NcoI and NotI. The fragment released (which contains SS5) was cloned on the same restriction sites of the pET-28a(+) expression plasmid giving rise to pET-SS5, which was inserted by electroporation in E. coli BLR(DE3). The E. coli strain XL1 Blue transformed with pSS5 was deposited in the Spanish Type Culture Collection on 29 Oct. 2003, located in the Research Building of Valencia University, Burjassot Campus, Burjassot 46100 (Valencia, Spain) with the deposition number CECT:5849.
Production of Transgenic Plants that Overexpress SS4
In the present invention SS was overexpressed (a) constitutively, (b) specifically in leaves and (c) specifically in storage organs such as tubers.
For the production of plants that overexpress SS constitutively, constructions were created that were controlled by the action of the 35S constitutive promoter of the tobacco mosaic virus. Successive insertion in pSS of the 35S promoter and NOS terminator in the 5′ and 3′ regions of SSX gave rise to the production of the plasmid p35S-SS-NOS, the restriction map of which is shown in FIG. 4B .
So as to be able to transfer this construction to the genome of the plants via Agrobacterium tumefaciens , it must first be cloned in a binary plasmid. For this, p35S-SS-NOS was digested successively with the enzymes NotI, T4 DNA polymerase and HindIII and was cloned within the binary plasmid pBIN20 ( FIG. 4A ) (Hennegan, K. P., Danna, K. J. (1998) pBIN20: An improved binary vector for Agrobacterium -mediated transformation. Plant Mol. Biol. Rep. 16, 129-131) which had previously been digested successively with the enzymes EcoRI, T4 DNA polymerase and HindIII. The plasmid thus obtained was designated pBIN35S-SS-NOS ( FIG. 4C ).
To overexpress SS specifically in illuminated leaves, PCR was used for amplifying the promoter region (designated RBCS) of the gene that encodes the small subunit of RUBISCO (ribulose-1,5-bisphosphate carboxylase/oxygenase) of tobacco (Barnes, S. A., Knight, J. S., Gray, J. C. (1994) Alteration of the amount of the chloroplast phosphate translocator in transgenic tobacco affects the distribution of assimilate between starch and sugar. Plant Physiol. 106, 1123-1129). This nucleotide sequence (which confers specific expression in photosynthetically active cells) was inserted in the pGEMT-easy vector (Promega), giving rise to pGEMT-RBCSprom ( FIG. 5A ). This construction was digested with HindIII and NcoI and the fragment released was cloned in the corresponding restriction sites of p35S-SS-NOS, giving rise to pRBCS-SS-NOS ( FIG. 5B ). This construction was digested successively with HindIII, T4 DNA polymerase and NotI. The fragment released was cloned in pBIN20 digested successively with HindIII, T4 DNA polymerase and EcoRI. The resulting construction was designated pBINRBCS-SS-NOS ( FIG. 5C ).
After being amplified in E. coli (XL1 Blue), both pBIN35S-SS-NOS and pBINRBCS-SS-NOS were inserted in A. tumefaciens C58:GV2260 (Debleare, R., Rytebier, B., de Greve, H., Debroeck, F., Schell, J., van Montagu, M., Leemans, J. (1985) “Efficient octopine Ti plasmid-derived vectors of Agrobacterium mediated gene transfer to plants” Nucl. Acids Res. 13, 4777-4788), which was used for transforming species such as tomato ( Lycopersicon sculentum ), tobacco ( Nicotiana tabacum ), potato ( Solanum tuberosum ) and rice by conventional techniques (Horsch, R. B., Fry, J. E., Hoffmann, N. L., Eichholtz, D., Rogers, S. G., Fraley, R. T. (1985) “A simple and general method for transferring genes into plants” Science 277, 1229-1231; Pozueta-Romero, J., Houlné, G., Schantz, R., Chamarro, J. (2001) “Enhanced regeneration of tomato and pepper seedling explants for Agrobacterium -mediated transformation” Plant Cell Tiss. Org. Cult. 67, 173-180; Hiei, Y., Ohta, S., Komari, T., Kumashiro. T. (1994) “Efficient transformation of rice ( Oryza sativa L.) mediated by Agrobacterium and sequence analysis of the boundaries of the T-DNA. Plant J. 6, 271-282). The strain of A. tumefaciens C58:GV2260 transformed with pBIN35S-SS-NOS was deposited in the Spanish Type Culture Collection on 29 Oct. 2003, located in the Research Building of Valencia University, Burjassot Campus, Burjassot 46100 (Valencia, Spain), with the deposition number CECT:5851.
Preparation of Assay Kits for Determination of Sucrose
One of the kits designed for the determination of sucrose, shown in Scheme I in FIG. 17 , which shows enzymatic reactions invoked in the kit for spectrophotometric/fluorimetric determination of sucrose based on the conversion of sucrose to a sugar nucleotide and then conversion of this to glucose-1-phosphate, glucose-6
The kit is based on the action of SS on the sucrose molecule in the presence of a nucleotide diphosphate (e.g. UDP or ADP), releasing equimolar amounts of fructose and the corresponding sugar nucleotide. If the sugar nucleotide resulting from the reaction is UDPG, this is submitted to the action of hydrolytic enzymes of UDPG such as UDPG pyrophosphatase of the Nudix type (EC 3.6.1.45) (Yagi, T., Baroja-Fernández, E., Yamamoto, R., Muñoz, F. J., Akazawa, T., Pozueta-Romero, J. (2003) Cloning, expression and characterization of a mammalian Nudix hydrolase-like enzyme that cleaves the pyrophosphate bond of UDP-glucose. Biochem. J. 370, 409-415) or UDPG hydrolase (Burns, D. M., Beacham, I. R. (1986) Nucleotide sequence and transcriptional analysis of the E. coli ushA gene, encoding periplasmic UDP-sugar hydrolase (5′-nucleotidase): regulation of the ushA gene, and the signal sequence of its encoded protein product. Nucl. Acids Res. 14, 4325-4342). The GlP released by the action of these hydrolytic enzymes is transformed by the action of phosphoglucomutase (PGM), yielding glucose-6-phosphate (G6P), which in its turn can be made to undergo a coupling reaction with NAD(P)+ by the action of the enzyme G6P dehydrogenase (G6PDH), producing 6-phosphogluconate and NAD(P)H, which can easily be determined by fluorimetry and by spectrophotometry at 340 nm. In its turn, the NAD(P)H released can be coupled to the action of FMN-oxidoreductase/luciferase, yielding light, which is quantified spectrophotometrically.
Attentively, as shown in scheme II in FIG. 8 , the UDPG produced can be coupled with UDPG dehydrogenase (EC 1.1.1.22) which, in the presence of NAD, gives rise to equimolar amounts of UDP-glucuronate and NADH, which can be determined by fluorimetry or by spectrophotometry at 340 nm. In its turn, the NADH released can be coupled to the action of FMN-oxidoreductase/luciferase, yielding light, which is quantified spectrophotometrically.
If the product of the reaction catalysed by the SS is ADPG, this is submitted to the action of hydrolytic enzymes of ADPG such as bacterial ADPG pyrophosphatase (EC 3.6.1.21) (Moreno-Bruna, B., Baroja-Fernández, E., Muñoz, F. J., Bastarrica-Berasategui, A., Zandueta-Criado, A., Rodríguez-López, M., Lasa, I., Akazawa, T., Pozueta-Romero, J. (2001) Adenosine diphosphate sugar pyrophosphatase prevents glycogen biosynthesis in Escherichia coli . Proc. Natl. Acad. Sci. USA 98, 8128-8132). The GlP released is transformed by the action of phosphoglucomutase, yielding glucose-6-phosphate (G6P), which can in turn be made to undergo a coupling reaction with NAD(P)+ by the action of the enzyme G6P dehydrogenase, producing 6-phosphogluconate and NAD(P)H, which can easily be determined by fluorimetry or spectrophotometry at 340 nm.
In any case, the schemes of enzymatic reactions coupled to the production of a sugar nucleotide mediated by SS are perfectly suitable for application to amperometric detection.
EXAMPLES OF CARRYING OUT THE INVENTION
Examples are described below, which show in detail the procedure for cloning a cDNA that encodes an isoform of SS of potato in a suitable expression vector and in a strain of E. coli optimized for the production and accumulation of the enzyme in its active form. Other examples describe the use of the recombinant SS for making assay kits for the determination of sucrose in plant samples, serum, urine, fruit juices, sweetened fruit drinks, refreshing drinks, etc. Another example describes the use of variants of SS optimized for the large-scale production of sugar nucleotides such as UDPG and ADPG. Finally, another example describes the production of plants with high content of sucrose, ADPG and starch and a high amylose/amylopectin ratio as a result of the high ADPG-producing activity in plants that overexpress SS.
Example 1
Expression, in Escherichia coli BLR (DE3), of a Recombinant SS with a Histidine Tail, which can be Purified Easily and has High Specific Activity
Knowing the nucleotide sequence of the SS4 gene that encodes an isoform of SS of potato, it was possible to create two specific primers whose sequences are, in the 5′-3′ direction, SEQ ID NO: 1 and SEQ ID NO: 2. Using these primers, a DNA fragment, designated as SSX, was amplified by conventional methods of PCR, from a potato tuber cDNA library, and this was inserted in a pSK Bluescript plasmid (Stratagene), which was amplified in the host bacterium XL1 Blue. The nucleotide sequence of SSX is SEQ ID NO: 3, which is slightly different from SS4 (GenBank accession number U24087). The amino acid sequence deducted from SEQ ID NO: 3 is slightly different from SS4 and is therefore designated SSX. The amino acid sequence deducted after expression of SEQ ID NO: 3 in the pET-28a(+) plasmid is SEQ ID NO: 4, which includes a histidine-rich sequence of 38 amino acids fused with the amino-terminal end of the amino acid sequence deducted from SEQ ID NO: 3.
Production of SSX in BL21(DE3) bacteria transformed with pET-SS was induced on adding 1 mM IPTG. After six additional hours of culture at 37° C., it was observed that the bacteria transformed with pET-SS accumulated a protein in aggregated form, the size of which corresponds to SS. However, these bacteria did not have SS activity. This failure in the expression of an active form of SS can be attributed to the problems that E. coli has in the correct folding of certain eukaryotic proteins of high molecular weight (Miroux, B., Walker, J. E. (1996) “Over-production of proteins in Escherichia coli : mutant hosts that allow synthesis of some membrane proteins and globular proteins at high levels” J. Mol. Biol. 260, 289-298). With the aim of overcoming this problem, the capacity for production of active SS in other bacterial strains and at a temperature of 20° C. was investigated. In all of them, production of SSX was induced on adding 1 mM of IPTG. After 6 hours of additional incubation, the bacteria were sonicated and centrifuged. The resulting supernatant was analysed for SS activity. In these conditions, as shown in FIG. 6 , the BLR(DE3) strain proved to be the most efficient from the standpoint of production of soluble, active SS. The E. coli strain BLR(DE3) (Novagen) transformed with pET-SS was deposited in the Spanish Type Culture Collection on 29 Oct. 2003, with the deposition number CECT:5850. The contribution of recombinant SSX in the total protein pool of CECT:5850 is approximately 20%, compared to the very low productivity of recombinant SS (30 micrograms per gram of bacteria) described in the literature (Nakai, T., Tonouchi, N., Tsuchida, T., Mori, H., Sakai, F., Hayashi, T. (1997) “Expression and characterization of sucrose synthase from mung bean seedlings in Escherichia coli ” Biosci. Biotech. Biochem. 61, 1500-1503; Li, C. R., Zhang, X. B., Hew, C. S. (2003) “Cloning, characterization and expression analysis of a sucrose synthase gene from tropical epiphytic orchid Oncidium goldiana . Physiol. Plantarum 118, 352-360). The supernatant was passed through the His-Bind affinity column (Novagen), in which the recombinant protein possessing a histidine tail is retained specifically. After eluting and dialysing the purified SS, it was incubated with 50 mM HEPES, pH 7.0/1 mM EDTA/20% polyethylene glycol/1 mM MgCl 2 /15 mM KCl/2 mM UDP. The specific activity, determined in terms of production of UDPG, was 80 units/mg of protein, much higher than the activity of 0.05-5 units/mg of recombinant SS described in the literature (Nakai, T., Tonouchi, N., Tsuchida, T., Mori, H., Sakai, F., Hayashi, T. (1997) “Expression and characterization of sucrose synthase from mung bean seedlings in Escherichia coli ” Biosci. Biotech. Biochem. 61, 1500-1503; Li, C. R., Zhang, X. B., Hew, C. S. (2003) “Cloning, characterization and expression analysis of a sucrose synthase gene from tropical epiphytic orchid Oncidium goldiana . Physiol. Plantarum 118, 352-360); Römer, U., Schrader, H., Günther, N., Nettelstroth, N., Frommer, W. B., Elling, L. (2004) Expression, purification and characterization of recombinant sucrose synthase I from Solanum tuberosum L. for carbohydrate engineering. J. Biotechnology 107, 135-149) and greater than 3 units/mg corresponding to the SS purified from plant extracts (Pressey R (1969) Potato sucrose synthase: purification, properties, and changes in activity associated with maturation. Plant Physiol. 44, 759-764. The unit is defined as the amount of enzyme that catalyses the production of one micromol of UDPG per minute. The affinity for UDP in the presence of 500 mM sucrose was Km(UDP)=0.25 mM, whereas the Km for sucrose was 30 mM in the presence of 1 mM UDP. This affinity for sucrose in the presence of UDP is significantly higher than that exhibited by the recombinant SS obtained in yeasts (Km=95 mM, Römer, U., Schrader, H., Günther, N., Nettelstroth, N., Frommer, W. B., Elling, L. (2004) Expression, purification and characterization of recombinant sucrose synthase I from Solanum tuberosum L. for carbohydrate engineering. J. Biotechnology 107, 135-149).
Example 2
Large-Scale Production of UDPG and ADPG Based on the use of Recombinant SS from E. coli
Three grams of UDPG of high purity was produced efficiently and economically after incubation for 12 hours at 37° C. of 100 milliliters of a solution containing 1 M sucrose, 50 mM HEPES, pH 7.0/1 mM EDTA/20% polyethylene glycol/1 mM MgCl 2 /15 mM KCl/100 mM UDP and 30 units of recombinant SS from potato obtained after expression of pET-SS in BLR(DE3) and subsequent purification. Reaction came to an end after heating the solution at 100° C. for 90 seconds and then centrifugation at 10,000 g for 10 minutes. The supernatant was applied to a preparative-scale HPLC chromatograph (Waters Associates) and the UDPG was purified as described in the literature (Rodríguez-López, M., Baroja-Fernández, E., Zandueta-Criado, A., Pozueta-Romero, J. (2000) Adenosine diphosphate glucose pyrophosphatase: a plastidial phosphodiesterase that prevents starch biosynthesis. Proc. Natl. Acad. Sci. USA 97, 8705-8710).
Production of ADPG required the generation of a mutated form of SS with an affinity for ADP much greater than that described for the SS extracted from plant tissues (Pressey R (1969) Potato sucrose synthase: purification, properties, and changes in activity associated with maturation. Plant Physiol. 44, 759-764; Nguyen-Quock, B., Krivitzky, M., Huber, S. C., Lecharny, A. (1990) Sucrose synthase in developing maize leaves. Plant Physiol. 94, 516-523; Morell, M., Copeland, L. (1985) Sucrose synthase of soybean nodules. Plant Physiol. 78, 149-154).
This isoform, designated SS5, was obtained by point mutagenesis of SSX using the QuikChange Site-Directed Mutagenesis kit (Stratagene) and successive use of the following pairs of primers whose sequences are [SEQ ID NO: 5, SEQ ID NO: 6], [SEQ ID NO: 7, SEQ ID NO: 8] and [SEQ ID NO: 9, SEQ ID NO: 10]. The nucleotide sequence obtained, designated SS5, is SEQ ID NO: 11. The changes in the amino acid sequence of SS5 (Susy 5) relative to SS4—Susy 4—(present in databases) are shown shaded in Table I. The amino acid sequence deducted after expression of SEQ ID NO: 11 in the pET-28a(+) plasmid is SEQ ID NO: 12, which includes a histidine-rich sequence of 38 amino acids fused with the amino-terminal end of the amino acid sequence deducted from SEQ ID NO: 11.
Table I includes said histidine-rich sequence of 38 amino acids fused to the amino-terminal portion of SS5.
TABLE I
The recombinant SS5 obtained after expression of pET-SS5 had a Vmax of 80 units/mg of protein and 65 units/mg of protein in the presence of UDP and ADP, respectively. The affinities for UDP and ADP in the presence of 500 mM sucrose were very similar (Km=0.2 mM both for ADP and for UDP), whereas the Km for sucrose was 30 mM and 100 mM in the presence of saturated concentrations of UDP and ADP, respectively. These kinetic parameters are very different from those described for the SS extracted from potato tuber and other organs of other species, according to which the Vmax of the enzyme is 10 times higher in the presence of UDP than in the presence of ADP (Presley R (1969) Potato sucrose synthase: purification, properties, and changes in activity associated with maturation. Plant Physiol. 44, 759-764; Morell, M., Copeland, L. (1985) Sucrose synthase of soybean nodules. Plant Physiol. 78, 149-154; Nguyen-Quock, B., Krivitzky, M., Huber, S. C., Lecharny, A. (1990) Sucrose synthase in developing maize leaves. Plant Physiol. 94, 516-523). The E. coli strain XL1 Blue transformed with pSS5 was deposited in the Spanish Type Culture Collection, with the deposition number CECT:5849.
Three grams of ADPG of high purity was produced efficiently and economically after incubation for 12 hours at 37° C. of 100 milliliters of a solution containing 1 M sucrose, 50 mM HEPES, pH 7.0/1 mM EDTA/20% polyethylene glycol/1 mM MgCl 2 /15 mM KCl/100 mM ADP and 30 units of recombinant SS from potato obtained after expression of pET-SS5 in BLR(DE3) and subsequent purification in a His-bind column. Reaction came to an end after heating the solution at 100° C. for 90 seconds and then centrifugation at 10,000 g for 10 minutes. The supernatant was applied to a preparative-scale HPLC chromatograph (Waters Associates) for purification of the ADPG.
Example 3
Preparation of Enzymatic Kits for Determination of Sucrose
For determination of sucrose, the following reaction cocktails were prepared with the following components and final amounts/concentrations:
1. Kits Based on the Use of Hydrolytic Enzymes of Sugar Nucleotides:
a. 2 units of SS (recombinant or not) b. 2 mM of ADP or UDP (depending on whether ADPG or UDPG is being produced, respectively) c. 2 units of ADPG pyrophosphatase or 2 units of UDPG pyrophosphatase (depending on whether it is to be included in the ADP or UDP reaction cocktail, respectively) d. 2 units of PGM e. 2 units of G6PDH f. 0.5 mM of NAD(P) g. reaction buffer: 50 mM HEPES, pH 7.0/1 mM EDTA/20% polyethylene glycol/1 mM MgCl 2 /15 mM KCl h. previously filtered test sample
2. Kit Based on the Use of UDPG Dehydrogenase
a. 2 units of SS (recombinant or not) b. 2 mM of UDP c. 2 units of UDPG dehydrogenase d. 0.5 mM of NAD e. reaction buffer: 50 mM HEPES, pH 7.0/1 mM EDTA/20% polyethylene glycol/1 mM MgCl 2 /15 mM KCl f. previously filtered test sample
Determination of the amount of sucrose present in the test sample is based on fluorimetric determination or spectrophotometric determination (at 340 nm) of the NAD(P)H produced according to the coupled reactions shown in schemes I and II.
For determining the sucrose content of barley seeds with different degrees of development ( FIG. 7 ), the reactions took place in 300-microliter wells of an ELISA plate for 3 minutes at 37° C. The volume of the test sample was 20 microliters, and the volume of the cocktail resulting from combination of reagents a-g (kit #1) and a-e (kit #2) was 280 microliters. The blanks contained all the components of the cocktail except SS. Measurement was carried out with a MultiSkan spectrophotometer. The values obtained, both with the kit of type “1” and with the kit of type “2” were found to be comparable to those determined using chromatographic techniques described in the introduction (Baroja-Fernández, E., Muñoz, F. J., Saikusa, T., Rodríguez-López, M., Akazawa, T., Pozueta-Romero, J. (2003) Sucrose synthase catalyzes the de novo production of ADPglucose linked to starch biosynthesis in heterotrophic tissues of plants. Plant Cell Physiol. 44, 500-509).
Example 4
Production of Transgenic Plants that Overexpress SS
FIGS. 8-10 present the results obtained in leaves of potato plants that overexpress SS both constitutively (35S-SS-NOS), and specifically (RBCS-SS-NOS).
As shown in FIG. 8 , the SS activity in the leaves of any of these plants is 2-10 times higher than in the same organ of a wild-type plant (WT). These leaves had the following characteristics:
1. Clear correlation between the ADPG-producing SS activity ( FIG. 8 ) and levels of starch ( FIG. 9 ) and ADPG ( FIG. 10 ). This characteristic was observed not only in leaves, but also in storage tissues such as tubers and seeds (see below). 2. High starch content ( FIG. 9 ) relative to leaves of wild-type plants. For example, the starch content of a leaf of a “wild-type” potato plant grown in a photoperiod of 8 hours light/16 hours darkness and at 20° C. is 5 micromol/gram of fresh weight, whereas a leaf of a transgenic plant that overexpresses SS is 8 micromol/gram fresh weight. The differences between wild-type and transgenic plants are accentuated when the photoperiod is long, so that the leaves of a plant that overexpresses SS contains 4 times more starch than those of a wild-type plant. 3. High ADPG content relative to the same tissue or organ of the untransformed plant ( FIG. 10 ). The average content in a leaf of a wild-type potato plant grown in a photoperiod of 8 hours light/16 hours darkness and at 20° C. is 0.35 nanomol/gram of fresh weight, whereas the leaves of the plants that overexpress SS can have a content of 2.5 nanomol/gram of fresh weight. 4. Both ADPG and starch exhibit transitory accumulation over the photoperiod ( FIG. 11 ). The rate of accumulation of both substances maintains a positive correlation with the SS activity, indicating that, contrary to what is suggested by the “classical” model of starch biosynthesis ( FIG. 2A ) and confirming the hypothesis of the “alternative” model shown in FIG. 2B , SS plays a fundamental role in the production of ADPG and in the link between sucrose metabolism and starch metabolism. 5. Normal levels of soluble sugars such as glucose and fructose. However, the levels of glucose-6-P and sucrose in transgenic leaves are higher than those observed in the wild-type potato leaves (Table 2).
TABLE 2
Levels of metabolites (expressed in nmol/g fresh weight) in leaves of control plants (WT) and 35S-
SuSy-NOS source leaves. Values significantly different from those observed in WT are shown in bold.
Control
35S-SS-NOS
WT
6
5
12
3
4
7
Glucose
848 ± 31
922 ± 29
860 ± 30
933 ± 29
881 ± 56
895 ± 32
871 ± 60
Fructose
996 ± 43
1,035 ± 57
1,094 ± 17
1,022 ± 10
1067 ± 58
1078 ± 63
817 ± 41
Sucrose
1,012 ± 27
1,529 ± 48
1,402 ± 68
1,642 ± 58
1,307 ± 35
1,317 ± 35
1,391 ± 70
Glucose-6-P
244 ± 28
309 ± 15
280 + 25
271 ± 27
355 ± 23
298 ± 12
315 ± 9.8
Glucose-1-P
22.7 ± 1.9
15.5 ± 2.1
10.3 ± 1.1
9.9 ± 1.2
9.5 ± 1.5
15.2 ± 1.9
11.4 ± 1.8
6. The external morphology of the plants that overexpress SS is not aberrant, when compared with that of the untransformed plants.
FIGS. 12-14 show the results obtained in potato tubers that overexpress SS constitutively (35S-SS-NOS). These results are essentially identical to those observed in tubers that overexpress SS under the control of a specific tuber promoter (promoter of the patatina gene).
As shown in FIG. 12 , the SS activity in the tubers of any of these plants is ??? times greater than in the same organ of a wild-type plant. These tubers had the following characteristics:
1. Clear correlation between the ADPG-producing SS activity ( FIG. 12 ) and levels of starch ( FIG. 13 ) and ADPG ( FIG. 14 ). 2. High starch content ( FIG. 13 ) relative to tubers of untransformed plants. For example, the starch content in the tuber of the “wild-type” plant is approximately 300 micromol/gram of fresh weight (equivalent to 54 mg of starch/gram of fresh weight), whereas in a tuber that overexpresses SS it is 450-600 micromol/gram fresh weight. 3. High ADPG content relative to tubers of wild-type plants ( FIG. 14 ). The average content in a wild-type tuber is 5 nanomol/gram of fresh weight, whereas the tubers that overexpress SS can have a content of 7-9 nanomol/gram of fresh weight.
The results obtained in rice seeds, tomato and tobacco leaves, as well as tomato fruits, are qualitatively similar to those shown in FIGS. 8-14 . In all cases there was an increase in the content of starch and an increase in the amylose/amylopectin ratio.
The production of plants with high content of ADPG and starch following overexpression of SS is a result that is totally unexpected according to the current ideas on the biosynthesis of starch (illustrated in FIGS. 1A and 2A ) and perhaps explains why the design of plants that overexpress SS has not previously been adopted as a strategy for increasing starch production. The results obtained on the basis of this work suggest that SS, but not AGPase, is the fundamental source of ADPG that accumulates in plants. According to the models that are still current, AGPase is the only source of ADPG. Surprisingly, however, ADPG levels have never been investigated in AGPase-deficient plants. To explore the significance of our invention, we analysed the levels of ADPG and starch in Arabidopsis and potato plants with reduced AGPase activity for the first time. As shown in FIG. 15A , the levels of starch in AGPase-deficient TL25 Arabidopsis plants (Lin, T. P., Caspar, T., Somerville, C. R., Preiss, J. (1988) Isolation and characterization of a starchless mutant of Arabidopsis thaliana lacking ADPglucose pyrophosphorylase activity. Plant Physiol. 88, 1131-1135) are lower than those observed in the WT plants. However, the levels of ADPG are normal ( FIG. 15B ). In contrast, the levels of starch in AGP62 and AGP85 potato plants (Müller-Röber, B., Sonnewald, U. Willmitzer, L. (1992) Inhibition of the ADPglucose pyrophosphorylase in transgenic potatoes leads to sugar-storing tubers and influences tuber formation and expression of tuber storage protein genes. EMBO J. 11, 1229-1238) are reduced relative to those observed in leaves of wild-type plants ( FIG. 16A ). However, the levels of ADPG are completely normal ( FIG. 16B ). Taken together, these observations (a) show that SS, and not AGPase, is the principal source of ADPG in plants and (b) highlight the significance of our invention after demonstrating that overexpression of SS gives rise to plants with high starch content.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 : Mechanisms of starch biosynthesis in heterotrophic organs. (A) “Classical” mechanism according to which SS is involved in the production of UDPG, which is eventually converted to starch after the combined action of UDPG pyrophosphorylase (UGPase), cytosolic phosphoglucomutase (PGM), plastidial phosphoglucomutase, ADPG pyrophosphorylase (AGPase) and starch synthase. (B) “Alternative” mechanism according to which SS is involved in the direct production of ADPG in the cytosol. The ADPG is then transported to the amyloplast by the action of a translocator. Once inside the amyloplast, the starch synthase utilizes the ADPG for producing starch.
FIG. 2 : Mechanisms of biosynthesis of starch in leaves. (A) “Classical” mechanism according to which the entire process of starch biosynthesis takes place inside the chloroplast. According to this view, starch metabolism and sucrose are not connected. Moreover, SS does not take part in the gluconeogenic process. (B) “Alternative” mechanism of starch biosynthesis according to which SS is involved in the direct synthesis of ADPG in the cytosol. The ADPG is then transported to the interior of the plastid where the starch synthase utilizes it as substrate for the reaction of starch synthesis.
FIG. 3 : Stages in construction of the pET-SS expression plasmid from pET-28a(+) and pSS.
FIG. 4 : Stages in construction of the pBIN35S-SS-NOS expression plasmid from pBIN20 and p35S-SS-NOS.
FIG. 5 : Stages in construction of the pRBCS-SS-NOS expression plasmid from pGEMT-RBCSprom, p35S-SS-NOS and pBIN20.
FIG. 6 : Expression of pET-SS in different strains of Escherichia coli . (A) SS activity (in milliunits (mU) per milligram of bacterial protein) in bacterial extracts transformed with pET or with pET-SS. The reaction took place in the direction of degradation of sucrose and production of ADPG. The reaction cocktail contained 50 mM HEPES (pH 7.0), 1 mM EDTA, 20% polyethylene glycol, 1 mM MgCl 2 , 15 mM of KCl and 2 mM of ADP. Reaction took place for 10 minutes at 37° C. (B) SDS-PAGE of protein extracts from the various strains of E. coli transformed with pET and with pET-SS. The position of the recombinant SSX is indicated with an asterisk.
FIG. 7 : Determination of sucrose at different stages of development of barley endosperm using the kit based on the coupled reactions of SS, ADPG (UDPG) pyrophosphatase, PGM and G6PDH. The results were identical to those obtained in parallel by use of a kit based on the coupled reactions of SS and UDPG dehydrogenase and use of high-performance chromatography (HPLC) with amperometric detection in a DX-500 Dionex system connected to a Carbo-Pac PA1 column.
Abscissa: Days after flowering Ordinate: Sucrose content (μmol/gFW)
FIG. 8 : SS activity in leaves of wild-type (WT) potato plants and potato plants that overexpress SSX following integration of the constructions 35S-SS-NOS (by the action of the strain of Agrobacterium tumefaciens CECT:5851) or RBCS-SS-NOS in their genome. Activity is expressed in milliunits (mU) per gram of fresh weight. The unit is defined as the amount of SS required for producing one micromol of ADPG per minute.
FIG. 9 : Content of starch in leaves of wild-type (WT) potato plants and potato plants that overexpress SSX following integration of the constructions 35S-SS-NOS (by the action of the strain of Agrobacterium tumefaciens CECT:5851) or RBCS-SS-NOS in their genome.
FIG. 10 : Content of ADPG in leaves of wild-type (WT) potato plants and potato plants that overexpress SSX following integration of the constructions 35S-SS-NOS (by the action of the strain of Agrobacterium tumefaciens CECT:5851) or RBCS-SS-NOS in their genome.
FIG. 11 : Transitory accumulation of (A) starch and (B) ADPG during a photoperiod of 8 hours of light and 16 hours of darkness in leaves of WT plants (●), 35S-SS-NOS (▪) and RBCS-SS-NOS (▴).
FIG. 12 : SS activity (referred to fresh weight, FW) in tubers of wild-type potato plants (WT), regeneration controls (RG) and potato plants that overexpress SSX (lines 4, 5, 6 and 12) after integration of the construction 35S-SS-NOS in their genome (by the action of the strain of Agrobacterium tumefaciens CECT:5851). The activity is expressed in milliunits (mU) per gram of fresh weight. The unit is defined as the amount of SS required for producing one micromol of ADPG per minute.
FIG. 13 : Content of starch (referred to fresh weight, FW) in tubers of wild-type potato plants (WT), regeneration controls (RG) and potato plants that overexpress SSX (lines 4, 5, 6 and 12) after integration of the construction 35S-SS-NOS in their genome (by the action of the strain of Agrobacterium tumefaciens CECT:5851).
FIG. 14 : Content of ADPG (referred to fresh weight, FW) in tubers of wild-type potato plants (WT) and potato plants that overexpress SSX after integration of the construction 35S-SS-NOS in their genome (by the action of the strain of Agrobacterium tumefaciens CECT:5851).
FIG. 15 : Content of (A) starch and (B) ADPG in leaves of AGPase-deficient Arabidopsis thaliana TL25.
FIG. 16 : Content of (A) starch and (B) ADPG in leaves of AGPase-deficient potato AGP62 and AGP85.
FIG. 17 : a scheme of enzymatic reactions for spectrophotometric/fluorimetric determination of sucrose based on the conversion of sucrose to a sugar nucleotide and then conversion of this to glucose-1-phosphate and NAD(P)H.
FIG. 18 : a scheme for coupling UDPG with UDPG dehydrogenase to give rise to UDP-glucuronate and NADH.
|
A transgenic plant that overexpresses sucrose synthase. The transgenic plant has a genetic construct that encodes a sucrose synthase peptide.
| 2 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of our pending application Ser. No. 019,020, filed Mar. 8, 1979, now abandoned which in turn is a continuation of our application Ser. No. 006,044, filed Jan. 24, 1979, which is now abandoned.
BACKGROUND OF THE INVENTION
United States Patents Nos. 3,150,136 and 3,167,537 discloses, inter alia certain pyrazoloquinazolone carboxylic acids which are useful as intermediates for the preparation of dyestuffs. German Pat. No. 1,111,505 discloses substituted 2-carboxy-pyrazolo[5,1-b]quinazolin-9(4H)-ones which are useful as photographic color developers. The references do not disclose any pharmaceutical utility for these acids, nor do they disclose the tetrazoles of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula I: ##STR1## wherein X is hydrogen, hydroxy, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, halo, trifluoromethyl, or SO n R wherein R is alkyl of from 1 to 6 carbon atoms and n is 0, 1 or 2; Y is hydrogen, hydroxy, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, or 2-tetrahydrothienyl; Z is COOH or ##STR2## and the pharmaceutically acceptable salts thereof; provided that when X and Y are hydrogen Z may not be COOH.
The invention also relates to a pharmaceutical composition comprising an anti-allergic effective amount of a compound of the formula I: ##STR3## wherein X is hydrogen, hydroxy, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, halo, trifluoromethyl, or SO n R wherein R is alkyl of from 1 to 6 carbon atoms and n is 0, 1 or 2; Y is hydrogen, hydroxy, alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 6 carbon atoms, or 2-tetrahydrothienyl; Z is COOH or ##STR4## and the pharmaceutically acceptable salts thereof.
The invention also relates to a compound of the formula II: ##STR5## wherein R' is alkyl of from 1 to 6 carbon atoms.
The invention also relates to a method of preventing the allergic response in a mammal which comprises administering to said mammal an anti-allergic effective amount of a compound of formula I and the pharmaceutically acceptable salts thereof.
DESCRIPTION OF THE INVENTION
The tetrazoles of the invention, i.e., compounds of the formula I wherein Z is ##STR6## and X and Y are as defined above may be prepared from the corresponding acids or esters by methods familiar to those skilled in the art. For example, the properly substituted carboxylic acid may be converted to the corresponding acid halide such as the chloride by treatment with thionyl chloride or oxalyl chloride and converted to the acid amide by treatment with ammonia. The amide is dehydrated by treatment with, for example, phosphorous oxychloride or p-toluenesulfonyl chloride and pyridine in dimethylformamide thereby producing the corresponding nitrile which when treated with sodium azide and ammonium chloride, for example, will yield the corresponding tetrazole. The above-described amides may also be prepared directly from the corresponding esters by treatment with, for example, gaseous ammonia by methods familiar to those skilled in the art.
Other methods and reagents for converting carboxylic acids or esters into the corresponding tetrazoles will be familiar to those skilled in the art.
The above-described 2-carboxypyrazolo[5,1-b]-quinazolin-9(4H)-ones, i.e., compounds of formula I wherein Z is COOH, may be prepared by alternate procedures, which are considered equivalent for purposes of the invention. One such procedure involves the reaction of a substituted anthranilic acid of the formula ##STR7## wherein X and Y are as defined above with phosgene to produce the corresponding isatoic anhydride of the formula ##STR8##
This reaction is conveniently carried out by adding, with cooling, a solution of phosgene in benzene to a solution of the anthranilic acid in, for example, dioxane/benzene (3:1). The isatoic anhydride is then converted to a 2-aminobenzoic acid hydrazide of the formula ##STR9## by treatment with, for example, an aqueous hydrazine hydrate solution. The hydrazide is next converted to the desired 2-carboxypyrazolo[5,1-b]quinazolin-9(4H)-ones by treatment with diethyl oxalacetate sodium salt, for example, in aqueous solution.
The alkylthio anthranilic acids of formula II which are utilized to prepare the corresponding alkylthio substituted isatoic anhydrides are novel, and may themselves be prepared by alternate procedures which are considered equivalent for purposes of the invention. One such procedure involves the steps of treating a halo-substituted 2-nitrobenzoic acid with sodium sulfide; alkylating the so produced mercaptan; followed by reduction of the nitro group thereby producing the desired alkylthio substituted anthranilic acid II. The above-described alkylated mercaptan may also be produced by treating the halo-substituted 2-nitrobenzoic acid with a mercaptide such as a sodium mercaptide. The starting halo-substituted 2-nitrobenzoic acids are either commercially available or may be prepared by methods known to those skilled in the art. For example, 5-chloro-2-nitrobenzoic acid is available from Aldrich Chemical Company, Milwaukee, Wisconsin 53233. For purposes of the invention, the preferred alkylthio anthranilic acids are represented by the following formula: ##STR10## J. Pharm. Soc. Japan, 72, 76 (1952), [C.A.: 46, 11150h (1952)] discloses ethyl 5-ethylthioanthranilate.
The compounds of the invention of formula I are acids or are acidic in nature and form pharmaceutically acceptable salts with both organic and inorganic bases such as dimethylaminoethanol, the alkali metal and alkaline earth hydroxides and the alkali metal carbonates and bicarbonates such as lithium, sodium, potassium and calcium hydroxide, and the carbonates and bicarbonates of lithium, sodium and potassium. The salts are prepared by reacting an acid or a tetrazole with the desired base in the conventional manner. The tetrazoles and acids differ from their respective salts somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective tetrazoles or acids for purposes of the invention.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
The alkylthio groups, alkoxy groups and alkyl groups contemplated by the invention comprise both straight and branched carbon chains of from 1 to 6 carbon atoms. Representative of such groups are methyl, ethyl, isopropyl, pentyl, 3-methylpentyl, methoxy, ethoxy, propoxy, 1-ethylbutoxy, pentoxy, methylthio, isopropylthio, n-butylthio and the like. The term halo is intended to include fluorine, chlorine, bromine and iodine.
The compounds of the invention of formula II are new chemical substances which are of value for preparing certain of the pharmacological agents of the invention.
The compounds of the invention of formula I are new chemical substances of value as pharmacological agents which prevent the allergic response in mammals by inhibition of the release of such allergic mediators, as histamine. The assay by which this utility was established is carried out as follows.
Rat Reaginic Passive Cutaneous Anaphylaxis (PCA).
The PCA test (D. J. Herzig, P. R. Schumann, E. J. Kusner, L. Robichaud, R. E. Giles, B. Dubnick, M. von Strandtmann, S. Klutchko, M. Cohen, and J. Shavel, Jr., "Immunopharmacology", M. E. Rosenthale and H. C. Mansmann, Eds., Spectrum Publications, Inc., New York, N.Y., 1975, pp. 103-124) involved immunization of rats with 1 mg of ovalbumin intramuscularly and approximately 10 10 B. pertussis organisms as pertussis vaccine, intraperitoneally. Fourteen days later, the rats were bled and the serum was prepared. Suitable dilutions of antiserum were injected intradermally at various sites on the back of rats 48 hrs before an intravenous injection of 1 mg of ovalbumin in 1 ml of physiological saline and 0.25% Evans Blue. Thirty minutes later the animals were killed in ether, the dorsal skin was reflected, and the means orthogonal diameter of the wheal was measured. For oral or intraperitoneal dosing, the drugs were suspended in 1% gum tragacanth in physiological saline and given 10-15 min before intravenous antigen challenge. For intravenous dosing, the compounds were dissolved in the saline/ovalbumin/Evans Blue solution and given with the antigen. If necessary, the compounds were first dissolved in a slight molar excess of sodium bicarbonate and then diluted into the antigen solution. Groups of five animals were used for all dose levels and control groups.
To quantitate the PCA test, the mean diameter of each wheal spot was graphed as a function of the relative anti-serum concentration. The line, fitted by the least-squares equation, was extrapolated to the value at "zero" antiserum concentration (base value). The following equation was then used to calculate the percent inhibition: ##EQU1##
The statistical significance of the results was determined by Student's t test (p≦0.05). An inhibition of 15% was significant.
Test results obtained for several preferred compounds of the invention are as follows:
7-methoxy-2(1H-tetrazol-5-yl)-pyrazolo[5,1-b]quinazolin-9-(4H)-one shows a 100% inhibition of allergic response when administered intraperitoneally to the rat at a dose of 5 mg/kg; 4,9-dihydro-6,7-dimethoxy-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid shows a 100 % inhibition of the allergic response when administered intravenously to the rat at a dose of 0.1 mg/kg; 4,9-dihydro-7-fluoro-9-oxopyrazolo[5,1-b]-quinazoline-2-carboxylic acid shows a 62% inhibition of the allergic response when administered intravenously to the rat at a dose of 0.1 mg/kg; 4,9-dihydro-7-(methylsulfinyl)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid shows a 76% inhibition of the allergic response when administered intraperitoneally to the rat at a dose of 5 mg/kg; 4,9-dihydro-7-(methylsulfony)9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid shows a 100% inhibition of the allergic response when administered intraperitoneally to the rat at a dose of 5 mg/kg.
The compositions of the invention can be administered in a variety of dosage forms such as tablets or capsules and liquids for oral or parenteral use. The dosage forms may contain, in addition to the active component, any of the usual compounding excipients such as flavors, colors, stabilizers and tableting materials such as binders, fillers, lubricants and the like. The dosage requirements may vary with the particular composition being employed and may depend on the severity of the symptoms being presented and the size of the mammal being treated. In general, an amount of from about 0.1 to about 10 mg/kg of the active component in single or divided doses will be sufficient to accomplish the method of the invention. The invention is illustrated by the following examples.
EXAMPLE 1
4,9-Dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid.
A mixture of 2-amino-3-methoxybenzoic acid hydrazide (23,6 g; 0.13 mole) and 90% diethyl oxalacetate, sodium salt (32.7 g; 0.14 mole) in water (400 ml) is heated under reflux for 1.5 hrs. To the resulting yellow solution is added sodium carbonate (14.8 g; 0.14 mole) and the solution is refluxed for an additional hour. The cooled reaction mixture is cautiously treated with conc. HCl (0.28 mole) and the precipitated solid is filtered off, washed with water and recrystallized from methanol (1500 ml). Yield 5.8 g; mp 271°-272° C. (d).
EXAMPLE 2 ##STR11##
The compounds below are prepared from appropriately substituted anthranilic acid hydrazides by the procedure of Example 1.
______________________________________ SOLVENT FOR RECRYSTALLI-X Y mp ZATION______________________________________(a) H H 315-320° C. (d) DMF(b) 7-Cl H 356-359° C. (d) DMF(c) 7-OCH.sub.3 H 310-320° C. DMF(d) 5-CH.sub.3 H 268-274° C. MeOH--H.sub.2 O(e) 7-CH.sub.3 H 290-295° C. DMF--Et.sub.2 O(f) 6-OCH.sub.3 7-OCH.sub.3 305-308° C. (d) DMF(g) 7-F H 300° C. DMF(h) 8-CF.sub.3 H 298-302° C. DMF--CH.sub.2 OH(i) 8-OCH.sub.3 H 293-295° C. DMF______________________________________
EXAMPLE 3
4,9-Dihydro-7-hydroxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid.
A suspension of 4,9-dihydro-7-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (2.0 g; 0.0077 mole) in 48% hydrobromic acid (30 ml) and glacial acetic acid (50 ml) is refluxed for 23 hrs. The mixture is cooled and then diluted with water (25 ml). The product, which precipitates out, is collected by filtration and recrystallized from DMF-Ether (1:1, 90 ml). Yield 1.1 g; mp 285°-286° C. (d).
EXAMPLE 4
4,9-Dihydro-5-hydroxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid.
From 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (1.04 g), 48% hydrobromic acid (25 ml) and acetic acid (25 ml), following the procedure of Example 3, there is obtained the desired product (0.75 g) as the quarter hydrate. mp 326°-330° C.
EXAMPLE 5
4,9-Dihydro-7-methylthio-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid.
A mixture of 2-amino-5-methylthiobenzoic acid hydrazide (2.5 g; 12.7 mmole) and 90% diethyloxalacetate, sodium salt (3.27 g; 14 mmole) in water (50 ml) is heated under reflux for 2 hrs. Sodium carbonate (1.5 g; 14 mmole) solution in water (15 ml) is added to the reaction mixture and the hearing is continued for another hour. The reaction mixture is cooled, carefully acidified with conc. HCl (4 ml) and the resulting yellow precipitate is filtered, washed and dried. The product is recrystallized from methanol-water, yield 1.0 g; mp 285°-9° (d).
EXAMPLE 6 ##STR12##
The compounds below are prepared from appropriately substituted anthranilic acid hydrazides by the procedure of Example 5.
______________________________________ SOLVENT FORX Y mp CRYSTALLIZATION______________________________________7-(CH.sub.3).sub.2 CHS H 275-6° DMF (d)7-CH.sub.3 (CH.sub.2).sub.3 H 270-1° DMF-MeOH (d)7-CH.sub.3 O 5-CH.sub.3 O 285-7° DMF (d).sup.1 ##STR13## 253-5° (d).sup.2 MEOH______________________________________ .sup.1 Contains 1/3 CH.sub.3 OH, 1/10 C.sub.3 H.sub.7 NO as solvent of crystallization. .sup.2 Contains 1 CH.sub.3 OH as solvent of crystallization.
EXAMPLE 7
4,9-Dihydro-7-(methylsulfinyl)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid.
A mixture of 4,9-dihydro-7-methylthio-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (5.5 g; 0.02 mole) and 1(N) sodium hydroxide solution (25 ml) in water (500 ml) is chilled to 12° and a solution of sodium metaperiodate (4.28 g, 0.02 mole) in water (150 ml) is added. The reaction mixture is stirred at room temperature for 4 hrs and the resulting solution is cooled and treated with 1(N) HCl (30 ml). The greenish precipitate is filtered, washed and recrystallized from DMF-methanol. Yield 4.4 g; mp 285°-90° (d).
EXAMPLE 8
4,9-Dihydro-7-(butylsulfinyl)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, hemihydrate.
From 4,9-dihydro-7-(butylthio)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (3.17 g, 10 mmole), 1(N) NaOH soln (10 ml) in water (150 ml) and NaIO 4 (2.14 g; 10 mmole) in water (50 ml); following the procedure of Example 7, there is obtained 4,9-dihydro-7-(butylsulfinyl)-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid, hemihydrate (2.0 g); mp 205°-210° (d) remelts at 260° (d) after crystallization from aq. methanol.
EXAMPLE 9
4,9-Dihydro-7-(methylsulfonyl)-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid.
A mixture of 4,9-dihydro-7-(methylthio)-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (1.1 g; 4 mmole), in glacial acetic acid and 30% H 2 O 2 (3 ml) is heated under reflux for 1 hr and then stirred at room temperature overnight. The tan solid is filtered off and recrystallized from DMF-ether. Yield 0.95; mp 360°-365° (d).
EXAMPLE 10
4,9-Dihydro-6,7-dihydroxy-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid, compound with dimethylformamide (1:1).
A mixture of 4,9-dihydro-6,7-dimethoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (1.0 g), 48% HBr (30 ml) and acetic acid (50 ml) is refluxed for 20 hours when the product crystallizes out as yellow solid. The reaction mixture is cooled, diluted with water (25 ml) and the product is filtered. The crude product is recrystallized from DMF (20 ml) and water (200 ml). Yield 350 mg; mp 282°-6° (d).
EXAMPLE 11
5-Methoxy-2-(1H-tetrazol-5-yl)-pyrazolo[5,1-b]quinazolin-9(4H)-one.
To a warm solution of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrile (2.98 g; 0.0124 mole) in DMF (150 ml) is added sodium azide (2.42 g; 0.0372 mole) and ammonium chloride (1.99 g; 0.0372 mole). The reaction mixture is heated at 100° C. for 22 hrs, concentrated to 1/3 volume and then poured into ice-water mixture. The mixture is acidified to pH 1.0 with 4 (N) hydrochloric acid (15 ml) and the product filtered off. The crude product is stirred with 0.5 (N) sodium hydroxide solution (600 ml) for 1.0 h, the insoluble material filtered off and the filtrate acidified with conc. HCl (30 ml). The precipitated solid is filtered, washed with water and dried; mp 300° C. when recrystallized from DMF. Yield 0.425 g.
By the same procedure starting with the corresponding 6,7-dimethoxy compound, the product obtained is 6,7-dimethoxy-2-(1H-tetrazol-5-yl)-pyrazolo[5,1-b]-quinazolin-9(4H)-one. Similarly, starting with the 7-fluoro and 8-trifluoromethyl compounds, respectively, the products obtained are the 7-fluoro- and 8-trifluoromethyl-2-(1H-tetrazol-5-yl)-pyrazolo[5,1-b]quinazolin-9(4H)-ones.
EXAMPLE 12 ##STR14##
The compounds below are prepared from appropriately substituted 4,9-dihydro-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carbonitriles by the procedure of Example 11.
______________________________________X Y mp______________________________________H H 342-345° C. (d)7-Cl H >300° C.7-OCH.sub.3 H >300° C.______________________________________
To prepare the sodium salt of the 5-methoxy compound of Example 11, the latter as the free tetrazole is dissolved with warming in an equivalent amount of 0.1 N aqueous sodium hydroxide solution, the water is evaported off and the sodium salt is dried under vacuum. The potassium, calcium and magnesium salts are prepared in the same manner.
EXAMPLE 13
5-Methylthio-2-aminobenzoic acid.
A mixture of 5-methylthio-2-nitrobenzoic acid (25.4 g; 0.119 mole), methanol (200 ml) and Raney nickel (2 g) is shaken in an atmosphere of hydrogen at 50 lb pressure when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate evaporated to dryness. The residue is recrystallized from etheriso-Pr 2 O. Yield 7.6 g; mp 145°-150°.
EXAMPLE 14
5-n-butylthio-2-aminobenzoic acid.
Catalytic hydrogenation of 5-n-butylthio-2-nitrobenzoic acid (10.6 g; 0.042 mole) in methanol (120 ml) in presence of Raney nickel (1 g) by the procedure of Example 13 gives 5-n-butylthio-2-aminobenzoic acid (8.95 g), mp 69°-72°.
EXAMPLE 15
Methyl 2-amino-3-(tetrahydro-2-thienyl)benzoate.
A solution of methyl anthranilate (75.5 g; 0.5 mole) in CH 2 Cl 2 (1.0 l) is cooled to -70° and a solution of tert-butyl hypochlorite (54 g; 0.5 mole) in CH 2 Cl 2 (150 ml) is added slowly keeping the temperature at -70°. The resultant N-chloroanthranilate solution is stirred for 1.0 hr and then tetrahydrothiophene (110 ml) is added at such a rate as to maintain the exotherm to less than 10°. The dark solution is stirred at -70° for 2.0 hr, triethylamine (125 ml) is added dropwise, and the solution is stirred for 24 hrs. The solvents are removed and the residue is diluted with CH 2 Cl 2 , washed with (1 N) NaOH solution, water and dried. Removal of solvents gives an oil. Unreacted methyl anthranilate is removed under reduced pressure (b.p. 95°-100°/0.35 mm) at bath temperature at 150°. The residue is dissolved in CH.sub. 2 Cl 2 and partially chromatographed through silica gel. The solid residue is recrystallized from methanol. Yield 27.0 g; mp 75°-9°.
PREPARATIVE EXAMPLES
PREPARATIVE EXAMPLE 1
3-Methoxy-2H-3,1-benzoxazine-2,4(1H)dione; (3-Methoxyisatoic Anhydride).
To a solution of 3-methoxy anthranilic acid (8.36 g; 0.05 mole) in dioxane (75 ml) and benzene (25 ml) is added a 12.5% solution of phosgene in benzene (46 g) with cooling in an ice bath. After the addition, the reaction mixture is stirred at room temperature overnight. The precipitated product is filtered off, washed with benzene and ether, dried and used without further purification. Yield 9.1 g (94%) mp 263°-264° C. (d).
PREPARATIVE EXAMPLE 2 ##STR15##
The compounds below are prepared from appropriately substituted anthranilic acids by the procedure of Preparative Example 1.
______________________________________X mp______________________________________3-CH.sub.3 286-288° C. (d)5-CH.sub.3 245-250° C. (d)5-OCH.sub.3 244-247° C. (d)6-OCH.sub.3 260-264° C. (d)______________________________________
PREPARATIVE EXAMPLE 3 ##STR16##
Substituted-2-aminobenzoic acid, hydrazide.
The substituted isatoic anhydride (0.14 mole) is slowly added to a cold (+5° C. to +10° C.) 18% aqueous solution of hydrazine (225 ml). During the exothermic reaction a white solid is formed. After stirring at room temperature overnight, the product is filtered off and washed with water. The hydrazide is used as is or is purified via crystallization before use.
The following compounds are prepared employing the above procedure.
______________________________________ RECRYSTALLIZATIONX mp SOLVENT______________________________________3-CH.sub.3 155-158° C. --3-OCH.sub.3 142-147° C. Benzene5-CH.sub.3 137-138° C. --5-OCH.sub.3 141-143° C. Water5-Cl 133.5-136° C. --6-CF.sub.3 120-125° C. (d) --5-F 248-251° C. CH.sub.2 Cl.sub.2 --MeOH6-OCH.sub.3 151-155° C. --______________________________________
PREPARATIVE EXAMPLE 4
4,9-Dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
A mixture of 4,9-dihydro-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carboxylic acid (5 g; 0.022 mole), thionyl chloride (250 ml) and four drops of pyridine is stirred at room temperature for 24 hrs. The reaction mixture is evaporated to dryness under reduced pressure in a water bath at 30°-40° C. The residue is treated with cold (0° C.) concentrated ammonium hydroxide solution (200 ml) and allowed to come to room temperature. The product is filtered off, washed with ether and used in the next step without further purification. Yield 3.2 g; mp 315°-325° C. An analytical sample, recrystallized from dimethylformamide, melts at 335°-340° C. By the same procedure, starting with the corresponding 7-fluoro compound, the product obtained is 4,9-dihydro-7-fluoro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
PREPARATIVE EXAMPLE 5
4,9-Dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
A mixture of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (6.6 g; 0.025 mole) and phosphorous oxychloride (100 ml) is stirred at room temperature overnight. The solid is filtered off, washed with ether, dried and treated with cold (0° C.) ammonium hydroxide solution (58%; 50 ml). After standing overnight at room temperature the product is filtered off, dried and used in the next step without further purification. Yield 5.06 g; mp 265°-270° C. By the same procedure, starting with the corresponding 6,7-dimethoxy compound, the product obtained is 4,9-dihydro-6,7-dimethoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
PREPARATIVE EXAMPLE 6 ##STR17##
The compounds below are prepared from appropriately substituted 4,9-dihydro-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acids by the procedures of the preceding preparative examples.
______________________________________ METHODX Y mp OF PREPARATIVE EXAMPLE______________________________________7-Cl H 350-360° C. 47-OCH.sub.3 H 340-355° C. 5______________________________________
PREPARATIVE EXAMPLE 7
4,9-Dihydro-5-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
To a solution of 4,9-dihydro-5-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (4.86 g; 0.02 mole) in dimethylformamide (50 ml) is added 1,1'-carbonyldiimidazole (4.86 g; 0.03 mole). The reaction mixture is heated at 100° C. for 12 min, then cooled and diluted with ether (75 ml) and methylene chloride (25 ml). The tan solid is filtered off and suspended in cold (0° C.) DMF (50 ml). Annydrous ammonia is bubbled through for 10 min and the resulting solution is allowed to stand at room temperature overnight. The dimethylformamide solution is evapoated to dryness under reduced pressure and the residue is washed with methylene chloride and ether and dried. Yield 3.0 g; mp 340°-345° C. (d). By the same procedure, starting with the corresponding 8-trifluoromethyl compound, the product obtained is 4,9-dihydro-8-trifluoromethyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
PREPARATIVE EXAMPLE 8
4,9-Dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazolinecarbonitrile.
A suspension of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide (5.05 g; 0.0195 mole) in phosphorous oxychloride (100 ml) is heated under reflux for 2 hrs. After standing two days at room temperature, excess phosphorous oxychloride is removed under reduced pressure and the residue suspended in saturated sodium bicarbonate solution (100 ml). The solid is filtered off, washed with water and dried. Yield 3.0 g; mp 292°-297° C. (d). Starting with the corresponding 7-fluoro, 8-trifluoromethyl and 6,7-dimethoxy compounds, the products obtained are, respectively, the 7-fluoro, 8-trifluoromethyl and 6,7-dimethoxy-4,9-dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitriles
PREPARATIVE EXAMPLE 9 ##STR18##
The compounds below are prepared from appropriately substituted 4,9-dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamides by the procedure of Preparative Example 8.
______________________________________ SOLVENT OFX Y mp RECRYSTALLIZATION______________________________________H H 365- 375° C. (d) DMF7-Cl H 400- 405° C. (d) DMF7-OCH.sub.3 H 343- 346° C. (d) --5-CH.sub.3 H 335- 345° C. (d) --______________________________________
PREPARATIVE EXAMPLE 10
5-Methylthio-2-nitrobenzoic acid.
5-Chloro-2-nitrobenzoic acid (100.8 g; 0.5 mole) is dissolved in water (1.0 l) and 4(N) sodium hydroxide solution (83 ml) (pH 7.5). A solution of Na 2 S.9H 2 O (132 g; 0.55 mole) in water (300 ml) is added and the mixture is heated at 50°-55° for 2.5 hrs. The reaction mixture is then treated with 20% sodium hydroxide solution (100 ml) and dimethyl sulfate (126.2 g; 1.0 mole) and is heated under reflux for 10 hrs. On cooling and acidification with (4 N) HCl (160 ml), the product precipitates out as a yellow solid (101.5 g) which is recrystallized from ether; mp 175°-8°.
PREPARATIVE EXAMPLE 11
Substituted 2-nitrobenzoic acid. ##STR19##
The compounds below are prepared from 5-chloro-2-nitrobenzoic acid, sodium sulfide and appropriate alkyl halides (R'X) by the procedure of Preparative Example 10.
______________________________________R' R'X mp______________________________________(CH.sub.3)CH-- (CH.sub.3).sub.2 CHBr 133-9°CH.sub.3 (CH.sub.2).sub.3 -- n-C.sub. 4 H.sub.9 Br 105-110°______________________________________
PREPARATIVE EXAMPLE 12
Methyl 2-amino-3,5-dimethoxybenzoate.
A mixture of methyl 3,5-dimethoxy-2-nitrobenzoate (Ger 501,609, April 2, 1927; CA. 24, 47929) (39.0 g; 0.162 mole), 5% Pd on charcoal (2.0 g), methanol (200 ml) and tetrahydrofuran (200 ml) is shaken in an atmosphere of hydrogen at 52 lb pressure for 46 h when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from methanol. Yield 28.6 g; mp 93°-5°.
PREPARATIVE EXAMPLE 13
6-Methylthio-2H-3,1-benzoxazine-2,4-(1H)-dione.
5-Methylthio-2-nitrobenzoic acid (53.25 g; 0.25 mole) is added to a solution of stannous chloride (225.6 g; 1.0 mole) in conc. HCl (340 ml) and the reaction mixture is brought to 110° and then cooled and concentrated. The concentrate is brought to pH 13 cautiously with 4(N) NaOH. The mixture is then filtered through supercel and the pH of the filtrate is adjusted to 6.7 and refiltered. The filtrate is cooled and is then treated with 12.5% phosgene in benzene solution. (400 ml). The precipitated solid is filtered, washed and dried. Yield 30.6 g; mp 216°-8°.
PREPARATIVE EXAMPLE 14
6-(isopropylthio)-2H-3,1-benzoxazine-2,4-(1H)-dione.
From 5-isopropylthio-2-nitrobenzoic acid (12.05 g), following the procedure of preparative example 13, there is obtained 5-isopropylthioisatoic anhydride (7.45 g), mp 219°-221° (d).
PREPARATIVE EXAMPLE 15
6-n-butylthio-2H-3,1-benzoxazine-2,4-(1H)-dione.
A solution of phosgene (12.5%) in benzene (40 g; 0.05 mole) is added to a cooled (5°) solution of 5-n-butylthio-anthranilic acid (8.9 g; 0.0395 mole) in dioxane (150 ml) and benzene (80 ml). The mixture is stirred at room temperature overnight and the pale green crystals are filtered off and dried. Yield 6.85 g; mp 196°-200°.
PREPARATIVE EXAMPLE 16
6,8-Dimethoxy-2H-3,1-benzoxazine-2,4-(1H)-dione.
A mixture of methyl 3,5-dimethoxy anthranilate (21.2 g; 0.1 mole) and 1(N) sodium hydroxide solution (100 ml) is refluxed for 2.0 hrs, cooled and is buffered with dry ice. The solution is treated with 12.5% phosgene in benzene (110 ml) in an ice bath. The mixture is stirred for 4.0 hrs, filtered off the product and dried in vacuo. Yield 22.0 g; mp 263°-5° (d).
PREPARATIVE EXAMPLE 17
8-(Tetrahydro-2-thienyl)-2H-3,1-benzoxazine-2,4-(1H)-dione.
From methyl 2-amino-3-(tetrahydro-2-thienyl)-benzoate (10 g; 0.042 mole), following the procedure of preparative example 16, there is obtained 8-(tetrahydro-2-thienyl)-2H-3,1-benzoxazine-2,4-(1H)-dione (6.0 g), mp 195°-9° (d).
PREPARATIVE EXAMPLE 18
5-Methylthio-2-aminobenzoic acid hydrazide.
6-methylthio-2H-3,1-benzoxazine-2,4-(1H)-dione (25.11 g; 0.72 mole) is added to a cold solution of 54.4% hydrazine (75 ml) in water (75 ml). After stirring at room temperature overnight, the while solid is filtered, washed with cold water and dried. Yield 21.3 g; mp 124°-127°.
PREPARATIVE EXAMPLE 19
Substituted-2-aminobenzoic acid hydrazide. ##STR20##
The following compounds are prepared using appropriately substituted isatoic anhydride and following the procedure of Preparative Example 18.
______________________________________X mp______________________________________5-(CH.sub.3).sub.2 CHS 110-115°5-CH.sub.3 (CH.sub.2).sub.3 S 92-95°3,5-(CH.sub.3 O).sub.2 137-141° ##STR21## 123-7°______________________________________
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Certain pyrazolo[5,1-b]quinazolin-9-(4H)-ones are disclosed. These compounds prevent the allergic response in mammals. Novel alkylthioanthranilic acids, useful as intermediates, are also disclosed.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is non-provisional application which claims priority to U.S. Provisional Application Ser. No. 61/744,525 filed on Sep. 28,2012, which is incorporated in its entirety herein.
FIELD OF THE INVENTION
[0002] The present invention generally relates to methods and devices for treatment of spinal deformity.
BACKGROUND OF THE INVENTION
[0003] Scoliosis is a spinal deformity characterized by an abnormal curvature of the spine in the coronal plane. Adolescent idiopathic scoliosis (AIS) is the most prevalent type of scoliosis which develops during adolescence in an otherwise healthy patient and typically ceases at the onset of skeletal maturity. The cause of the disease is presently unknown.
[0004] Current surgical treatment of scoliosis involves manipulation of the spinal column and attachment of corrective devices for fusion of a portion of the spine. One such system, the Cotel-Dubousset system utilizes rigid metal rods attached to the spine. The rods are manipulated during surgery in an attempt to reduce abnormal curvatures and rotations of the spinal column. Large loads are exerted on the spine for correction which risks the patient's neurological condition. Recovery from these procedures can be lengthy and painful. Also, if normal lordosis and kyphosis are not restored, a condition called “flat back syndrome” may occur causing chronic pain. Even a successful procedure rarely results in a normal spinal curvature and the patient is left with an immobile spinal section. The discs above and below the fusion zone are at risk of future degeneration due to the increased mechanical demands placed on them.
[0005] It is therefore evident that there are flaws in prior art methods and devices. Most prior art devices are part of the load path of the spinal column. For example, it is understood that the Cotel-Dubgousset system rigidly attaches stiff metal rods to the spine. A structure having two roughly parallel support members relies primarily on the stiffer of the two members for transmission of loads. Therefore, loads exerted on an instrumented spine are transferred through the implant instead of through the spine. Spinal loads can be significantly large, and the implants will not support such loads indefinitely. Fatigue failure of the implant will occur if fusion is delayed.
[0006] Therefore, there is an unaddressed need that exists to provide a new and better system for correcting spinal deformities.
SUMMARY OF THE INVENTION
[0007] The current invention describes methods and devices for treating spinal deformity which offer significant improvements over prior art methods and devices. In general terms the present invention is used to secure the distance between an ilium and the spine to either correct or maintain spinal curvature. There are many embodiments of the invention which will achieve the stated objectives, some of which will be presented in the following summary.
[0008] In one embodiment of the invention, at least one device is attached between the spine and the pelvis which incorporates at least one flexible tether. Attachment of the flexible tether to the spine and ilium involves implantation of anchoring means and then attachment of the tether to the anchoring means. For example, at least one bone screw, pedicle screw, cannulated bone screw, clamp, plate, bone anchor, or shackle might be anchored to at least one vertebra and another to a portion of the ilium and the flexible tether may be attached to both. Other means of attachment will be clear to one practiced in the art. Alternatively, a loop of material may be placed around a bony structure (e.g. spinous process, transverse process, lamina or pars) or a hole through a bony structure through which the flexible tether is passed.
[0009] It should be noted that the present invention enables manipulating the vertebral column to correct the deformity by securing the tether to a portion of the ilium and a portion of the vertebral column; the ability to correct deformity by correcting the effective length of the tether between the ilium and vertebra over time; and correcting deformity by the natural growth of the spine by allowing the tether to maintain effective length between the vertebral column and the ilium.
[0010] Adjustment of the distance between the spine and ilium is achieved by varying the location at which the tether is attached to the anchoring means. The tether does not change lengths during the adjustment process, but the distance between the attachment points does, much like adjusting a belt around your waist. Taking advantage of the inherent viscoelasticity of spinal structures, the curvature may be gradually corrected by small incremental corrections over a protracted period of time, whereby the original incision is re-opened, or a new incision next to the original incision is created and the attachment means is disengage and then reengaged at a different location along the tether. Alternatively the patient's growth may be used to achieve correction.
[0011] Alternatively, the tether may branch into multiple tethers to provide multiple attachments to the spine and/or ilium. If more than one tether is used, each can be attached to a different vertebra, or multiple tethers can be attached to the same vertebra. Tethers can be attached to either or both sides of the vertebral column and either opposing sides of ilium as needed to generate correction of the spinal deformity. A crossing pattern whereby a tether is attached to the right side of the vertebra (e.g. the right pedicle) and left ilia, or vice versa, is possible. Also, a tether may be attached to a vertebra and then passed through an eye screw or other guiding device which is attached to the ilium (or both ilia) and then attached to a second vertebra with a pedicle screw or other means. In can be envisioned by one skilled in the art that guiding devices may be utilized on a number of vertebrae or one the ilium or ilia. The tether may also originate with an attachment to the pelvis, pass through any number of guide members attached to the spine, and then terminate at the pelvis again.
[0012] These and other aspects of the present invention, will become apparent from the following description of the embodiments taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
[0013] The present invention provides an improved method of arresting a spinal deformity whereby at least one device is surgically attached between the spine and the ilium. Also, the present invention provides a system and a method for correcting a spinal deformity whereby at least one device is surgically attached between the spine and the ilium.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
[0015] FIG. 1 is an illustration of a posterior view of a deformed human spine with an implanted device according to one embodiment of the present invention;
[0016] FIG. 2 is an illustration of a posterior view of a corrected human spine with the implanted device shown in FIG. 1 ;
[0017] FIG. 3 shows a spinal anchoring means in the form of two pedicle screws and a rod onto which is secure an attachment mechanism and the tether;
[0018] FIG. 4 illustrates an attachment mechanism and the method of attaching it to the spinal anchoring mechanism;
[0019] FIG. 5 shows the anchoring mechanism of the ilium (not shown) and the method of attaching the tether to it;
[0020] FIG. 6 shows a long pair of forceps to be used for passing the tether beneath the skin;
[0021] FIG. 7 illustrates the use of the forceps of FIG. 6 in passing the tether beneath the skin;
[0022] FIG. 8 illustrates an alternative embodiment of the tether clamp and elongate rod according to the present invention;
[0023] FIG. 9 illustrates another embodiment of a clamp or anchor according to the present invention;
[0024] FIG. 10 shows a cross-sectional view of the device shown in FIG. 9 ;
[0025] FIG. 11 shows another embodiment of a clamp or anchor according to the present invention;
[0026] FIGS. 12 and 13 shows a closed head clamp according to the present invention;
[0027] FIGS. 14 and 15 shows yet another embodiment of a closed head clamp according to the present invention; and
[0028] FIGS. 16-18 illustrate various methods of coupling the tether to portions of the spine and/or ilium.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0029] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.
[0030] FIG. 1 is an illustration of a posterior view of a deformed spine 104 whereby the preferred embodiment of the device 200 is attached to an ilium 102 and a vertebra 100 . Device 200 includes a tether 204 having a free end 206 and that is configured to be attached to the ilium and a portion of the vertebra. Specifically, in one embodiment, two attachment mechanisms such as pedicle screws 300 are anchored to the vertebra of the spine by insertion into opposing pedicles, and a transverse rod 311 is attached to the pedicle screws 300 . It should be noted that although pedicle screws are provided in this particular embodiment, any other type of anchoring mechanism such as hooks may also be used. A tether clamp 310 is attached to rod 311 and the tether 204 is passed though tether clamp 310 and then passed down to the ilium 102 thereby securing a connection between the attached vertebra and the ilium. To attach the tether 204 to the ilium 102 , an ilium anchor 210 is provided. The ilium anchor 210 includes a bore 211 and is configured to be attached to the ilium by inserting the anchor 210 (threading) into a hole which has been drilled or punched through the ilium 102 . It should be noted that any other similar mechanism to attach anchor 210 to the ilium 102 may also be utilized. Tether 204 is passed through hole or bore 211 in the ilium anchor 210 and then brought back to the vertebra 100 and passed again through the tether clamp 310 . In other embodiments, the tether 204 may only be passed once through the tether clamp and ilium anchor 210 .
[0031] FIG. 2 illustrates the correction of the spine of FIG. 1 using device 200 . As illustrated in FIG. 2 , the free end 206 of tether 204 is pulled and the spine is manually manipulated during the surgery to achieve a correction of the deformity. When a satisfactory curve magnitude is achieved, tether 204 is tightened within the tether clamp, effectively locking the distance between vertebra 100 and the ilium 102 .
[0032] It should be noted that various levels of manipulation of the vertebral column can be coordinated using the device. For instance, different curvatures of the spine can be achieved by changing the position of the anchor and the clamp on the tether with respect to the vertebral column and the ilium. The locations along the tether where the clamp and anchor are attached determine an effective length of the tether, which in turn maximizes the distance that the attached vertebra may move relative to the position where the tether is attached at in the ilium. The scoliotic curve is corrected (or maintained) by adjusting the clamping and anchoring locations along the tether.
[0033] FIG. 3 shows a detailed view of pedicle screws 300 , transverse rod 311 , tether clamp 310 and tether 204 . In a preferred embodiment tether clamp 310 includes locking screw 312 which clamps tether clamp 310 onto rod 311 as well as locking the tether 204 within the clamp 310 .
[0034] FIG. 4 shows a detailed view of the tether clamp 310 coupled to the transverse rod. The tether clamp 310 is configured with a slot 501 which is provided through the tether clamp 310 and tether 204 is passed through slot 501 . It should be noted that the tether may be passed through the slot multiple times, if necessary. Locking screw 312 is used to secure the transverse rod 311 onto the tether clamp 310 and applies a compressive force upon the rod 311 onto the tether 204 , thereby clamping the tether 204 securely in place. It should be noted that although a threaded set screw is utilized in the present embodiment, any type of locking element know in the art for securing the tether within tether clamp may be used.
[0035] FIG. 5 shows a detailed view of an ilium anchor 210 . Ilium anchor 210 includes threads 212 for engagement with ilium 102 (not shown). Tether 204 is passed through bore 211 and then passed back to the vertebral column. A collar 215 is shown which keeps tether 204 adjacent to itself.
[0036] FIG. 6 shows an extra-long pair of forceps 900 . FIG. 7 shows the preferred method of passing the tether through an incision 845 and underneath skin and other soft tissues. The forceps 900 are used to pass the tether though the openings in the tether clamp and used to tension the tether to correct the deformity of the curvature in the spine.
[0037] FIG. 8 illustrates another embodiment of a tether clamp 320 according to the present invention. In this embodiment, the tether clamp 320 is configured with a through hole 322 that is configured to correspond to a through hole 324 in an elongate rod 326 that is fixated to a portion of the spinal column. A fastening element 328 such as a set screw is provided to couple the tether clamp 320 and the elongate rod 326 together. The tether clamp 320 also includes openings 330 , 332 which are dimensioned to receive and securely couple a tether 334 to the clamp 320 . The tether 334 is pulled through each of the openings 330 , 332 to securely attach the tether 334 to the clamp 320 and the elongate rod 326 .
[0038] FIGS. 9 and 10 illustrate an alternative embodiment of a clamp and/or anchor 250 that can be used to secure a tether 252 to either the vertebral column or a portion of the ilium. More specifically, the anchor 250 of FIGS. 9 and 10 may be configured and dimensioned to be attached to a portion of the vertebral column or may be configured be secure the tether to the ilium. The anchor 250 is configured as a plate 251 having at least two openings 254 , 256 to receive fasteners 258 , 260 capable of fixating the plate to bone. The plate 251 includes a middle portion 262 having an opening 264 that is capable of receiving the tether 252 . The middle portion 262 of the plate 251 is further provided with a fastening element 266 to secure the tether 252 to the plate 251 . As more clearly illustrated in FIG. 10 , the fastening element 266 may be a set screw which directly contacts the tether 252 when tightened to secure the tether 252 to the plate 251 . It should be noted that any other type of fastening element which is capable of securing the tether to the anchor may be used, such as a pin.
[0039] FIG. 11 illustrates yet another embodiment of a clamp or anchor 400 according the present invention. In this embodiment, the clamp and/or anchor 400 includes a first plate 402 and second plate 404 that are secured to one another via a fastening element 406 . The first and second plates 402 , 404 are may also include spikes 408 or similar type of features that bite into bone. Either the first or second plate 402 , 404 or both also includes an opening 410 for receiving a tether. The first and second plates 402 , 404 are positioned so that bone is in between, such as the ilium or a portion of the vertebral column. As the first and second plates 402 , 404 are compressed into bone, the tether which is positioned through the opening 410 and in between the first and second plates 402 , 404 , is also securely locked between the plates and the bone thereby securing the tether to the plates 402 , 404 . In an alternative embodiment, the tether is passed through the opening and secured to the anchor 400 by a clamp device such a belt clamp or secured by knotting the tether around the edge of the anchor 400 . It should be noted that any type of mechanical mechanism to attach the tether to the anchor may be used.
[0040] FIGS. 12-15 illustrate yet another embodiment of a clamp according to the present invention. The closed head clamp 420 as illustrated in FIGS. 12 and 13 , includes a first opening 422 extending through the clamp 420 in a first direction and a second opening 424 extending in a second direction. The first and second direction are generally perpendicular to one another. The first opening 422 is configured to receive an elongate rod 426 and the second opening 424 is configured to receive a tether 428 . The clamp 420 is further provided with a fastening element 430 that is used to secure both the rod 426 and the tether 428 . In this embodiment, FIGS. 12 and 13 also illustrates that the second opening 424 is positioned at a bottom portion of the clamp 420 , thus, as the fastening element 430 is tightened, the fastening element 430 contacts the rod 426 which is pushed against the tether 428 thereby securing the tether 428 and rod 426 within the clamp.
[0041] In an alternative embodiment of the closed head clamp as illustrated in FIGS. 14 and 15 , the closed head clamp 432 includes a first opening 434 and a second opening 436 . The first opening 434 and the second opening 436 are configured to be generally transverse to one another. The first opening 434 is dimensioned to receive an elongate rod 438 and the second opening 436 is dimensioned to receive a tether 440 . The clamp 432 also includes a fastening element 442 , such as a set screw, which when tightened secures and locks the tether 440 and the elongate rod 438 within the clamp 432 . In this particular embodiment, the second opening 436 is positioned between the fastening element 442 and the elongate rod 438 . When the fastening element 442 is tightened, the fastening element 442 directly contacts the tether 440 which contacts the elongate rod 438 thereby securely locking the tether 440 and the elongate rod 438 within the closed head clamp 432 .
[0042] FIGS. 16-18 illustrate alternative embodiments of the inventive device. Specifically, FIG. 16 illustrates the use of clamp to attach the tether to the lamina of a vertebra. As illustrated, the tether may encircle the lamina and may be tightened using a belt clamp. The other end of the tether is as shown in the earlier embodiments coupled to a portion of the ilium. Using this mechanism, the deformity of the spine may be corrected by manipulating the tether as well as the positioning of the clamp, as needed.
[0043] FIG. 17 shows a tether that includes a loop which is used to for coupling the tether to the transverse rod to fixate the tether to the transverse rod. FIG. 18 illustrates the coupling of the tether directly to the ilium using another type of tether clamp. It should be noted that in the examples provided of both anchor and clamps, these mechanical devices may be interchangeable.
[0044] It should also be noted that the tether of the present invention may be composed of fabric, polymer, such as PET, or any other biocompatible materials. The tether can be a cable and can be dimensioned to be a wide elastic band which advantageously reduce the risk of damage to tissue lacerations or injury. In some embodiments, the tether can be is between 2 and 900 mm. Also, to ensure that proper correction of deformities, a tensioner can be included as part of the system to make sure that the tether are in proper tension and tightness.
[0045] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Moreover, the improved bone screw assemblies and related methods of use need not feature all of the objects, advantages, features and aspects discussed above. Thus, for example, those skilled in the art will recognize that the invention can be embodied or carried out in a manner that achieves or optimizes one advantage or a group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein. In addition, while a number of variations of the invention have been shown and described in detail, other modifications and methods of use, which are within the scope of this invention, will be readily apparent to those of skill in the art based upon this disclosure. It is contemplated that various combinations or subcombinations of these specific features and aspects of embodiments may be made and still fall within the scope of the invention. Accordingly, it should be understood that various features and aspects of the disclosed embodiments can be combined with or substituted for one another in order to form varying modes of the discussed bone screw assemblies. Thus, it is intended that the present invention cover the modifications and variations of this invention provided that they come within the scope of the appended claims or their equivalents.
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The present invention generally relates to methods and device for treatment of spinal deformity, wherein at least one tether is utilized to maintain the distance between the spine and the an ilium to (1) prevent increase in abnormal spinal curvature, (2) slow progression of abnormal curvature, or (3) impose at least one corrective displacement and/or rotation.
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This application is a complete application of U.S. Provisional Patent Appln. Ser. No. 60/924,169, filed May 2, 2007, the contents of which are hereby incorporated in its entirety by reference.
FIELD OF THE INVENTION
The present invention relates to a bottle for dispensing medications and other fluids, such as soda, water or sports drinks, and in particular to a specialized container for dispensing fluids, semi-viscous materials, ointments, gels, creams, pastes, and the like.
BACKGROUND OF THE INVENTION
Many patients go blind even after diagnosis and treatment for the disease has been instituted. One classic example is glaucoma. The treatment of glaucoma requires the patient to instill eye drops on a daily basis in order to preserve their sight.
Studies have shown that close to 60% of patients had difficulties with self-administration of eye drops. Current means to administer topical ocular drugs requires the skill of not only administering a correct amount, but also mastering a rather difficult technique. Some of the most limiting steps to administering eye drops are inverting the bottle so as to allow fluid flow to the bottle tip, fright reaction, and bending the neck.
The problems described by patients included: raising their arms above their heads, tilting their heads, holding the inverted bottle and squeezing the bottle with the arms raised, directing the bottle on top of the eye without touching the eye, fear of hitting the eye leading the bottle to the held too high or away from the eye, involuntary blinking or closing eyes after squeezing the bottle, placing the correct number of eye drops, and poor view of the tip of the bottle. The prior art relies on squeeze-bottles, which must be inverted and positioned in an essentially up side down position for use.
In addition, patients with glaucoma frequently need to use more than one medication, which requires having two bottles. Patients tend to misplace bottles, and then sometimes only one eye drop is used, instead of the two medications needed to preserve sight. It would be therefore, an advantage to have paired medications and paired-products which allows the patient to have only one specialized container for the different eye drops.
Furthermore, delivering oral medications to patients, and in particular children requires using a pressure-based system such as a syringe or tipping the medication bottle upside down. The same occur when using ear medication in which the patient must tilt their head and the bottle is held upside down.
SUMMARY OF THE INVENTION
All of these limitations and disadvantages of the prior art are solved by the present invention. With the specialized dispenser of the present invention, the user does not have to invert the bottle and bend their neck in addition to not having to perform all of the other maneuvers described above.
The present invention relates to a bottle for dispensing products, and in particular to a container for dispensing fluids, semi-solid, ointments, gels, paste, creams, powder, and the like. In a preferred embodiment, the substances in the container are naturally fed by gravity to a dispensing portion without the need for the dispenser to be placed in a vertical position, upside down position, or inclined position in order to allow the substances to move to the tip of the dispensing portion, all the while maintaining the container in a horizontal orientation.
The substances are naturally directed to the dispensing portion by a gravity fed structure. The gravity fed structure of this invention includes an essentially slanted member in the interior of the container that is aligned with the nozzle (or opening) of the dispensing portion. Another embodiment of the invention includes a paired-product dispensing system including at least two dispensing portions, each dispensing portion facing the opposite direction of the other dispensing portion and having complimentary closure parts.
In one embodiment, the container includes a bottle having a flexible side wall which is squeezable to dispense the fluid in desired quantities using a gravity fed system. In another embodiment, the container includes at least two chambers joined to each other using a specialized configuration.
In one embodiment a fluid dispensing member, usually in the form of a cap, is mountable to the bottle and has a dispensing tip or dispensing portion (also referred herein as dispensing neck) aligned with a slanted member. The slanted member naturally forces the substance (including fluid) by gravity inside the bottle toward the dispensing portion.
The container may include an inclined member or be configured with an inclined wall or surface. The lower portion of the inclined member or the inclined wall is positioned in communication with the dispensing portion of the container to move the fluid toward the dispensing portion and prevent fluid from moving away from the dispensing portion.
One embodiment of the present invention consists of a fluid-dispensing container for eye care fluid, which dispenses medication from a horizontal position, without the need to turn the bottle upside down while simultaneously allowing the user to see the tip of the dispensing portion. The opening at the dispensing portion may include a neck as used for bottles. The nozzle (or opening) is preferably eccentrically located with respect to one end of the bottle for allowing the largest amount of fluid to be stored inside the fluid containing area. The fluid containing area is formed by the upper walls of the bottle, when the bottle is in a horizontal position, and by the slanted member inside the bottle.
The bottle has essentially two internal areas, an area for storing fluid and a second area separated by the slanted member. The second area underneath the fluid filled chamber may comprise a solid flexible part, such as plastic or be filled with air. In the embodiment of an eye drop dispenser, the dispensing tip preferably has a curved configuration, and is covered by a cap.
Upon squeezing the bottle, the pressure inside the bottle moves the fluid toward the dispensing tip. Due to the slanted member being aligned with and terminating at the nozzle (or opening), the direction of fluid is always toward the nozzle and dispensing tip.
The slanted member preferably has a round or curved configuration to force fluid from the sides to move toward the center of the slanted member. The fluid then flows from the center of the slanted member down to the dispensing tip, similar to a gutter.
Usually people with eye disorders have arthritis, and by having a gravity fed flow, less force is necessary for squeezing the bottle. The slanted member does not allow fluid to move away from the dispensing tip while forcing fluid down during squeezing. A one way valve at the tip can be used, since less force is required to squeeze the bottle because of the gravity fed system of this invention.
As fluid is used, and the amount of fluid is reduced, the slanted member forces the remaining fluid towards the neck of the bottle and with the squeezing of the bottle the fluid is dispensed at the end of the dispensing tip despite the bottle remaining in a horizontal position. The invention therefore allows a simple and low-cost structure to be utilized to store and dispense fluids while keeping the container in a horizontal position despite having very little fluid inside the container.
By keeping the bottle in the horizontal position, the user does not need to look up or bend the neck to instill eye drops. The user can look straight ahead and even use a mirror to position the dispensing tip in alignment with the conjunctival sac under direct visualization for precise placement of the eye drop. Furthermore, there is no fright reaction because the bottle is not held above the head and is not in direct line with the eyes. With the present invention the user can pull down the eyelid, and then the tip of the bottle is held horizontal and below the visual axis which prevents fright reaction.
The same advantage of this invention occurs when using ear medication allowing patients to keep their head straight. This eliminates the need for patients to tilt their heads or hold the medication bottle upside down or in an inclined position.
Any fluid can be optimally delivered with this invention. In many instances, drinking out of a can or bottle is difficult for people having neck injuries, arm injuries, stroke, or arthritis because to finish the drink they have to bend their necks, or/and hold their arms above their heads, and/or have to turn the container (such as a can or bottle) upside down. All of those maneuvers can be painful and difficult. By the present invention, can and bottles can be biologically ergonomically fit, thereby allowing all fluid to be consumed while keeping the container in a horizontal position without having to ever turn the container upside down.
Therefore, another object of the invention is to provide a container, such as a can, bottle, jar, and the like, that can be held in a horizontal position while allowing all fluid to be consumed. It is understood that other containers such as a cup, glass, mug, and the like can have the same slanted member allowing consumption of drinks, yogurts, and any other semi-solid products and the like without having to bend the neck and while maintaining the container in a horizontal position in relation to the ground. The lower end of the slanted member ends at the edge of the cup, glass, mug, and the like, and the upper end of the slanted member ends at the uppermost part of the container.
Accordingly, in one embodiment the beverage (or any fluid or substance) is dispensed from the bottle including glass bottles, without the need for squeezing the bottle, and the fluid or substance is directed to the dispensing portion by virtue of a slanted member. The slanted member does not let fluid move away from the dispensing outlet while the fluid is being dispensed. It is understood that the slanted member can be replaced by a straight member, which is angled with respect to the bottom wall of the bottle. The straight member is positioned aligned with the dispensing portion. This allows fluid to move toward the dispensing tip, while avoiding fluid to be retained inside the bottle.
A further object of the invention is to provide a dispensing apparatus that allows two or more different eye drop solutions to be held in the same containing structure while keeping the fluids separate. One of the challenges overcome by this invention is to prevent a dispensing tip of a double tip dispenser from touching the eye. Another problem with having two different fluids in the same container is that different amounts may be needed for each fluid. For example, a glaucoma patient may need on a daily basis one eye drop of a prostaglandin analog but need three drops of a carbonic anhydrase inhibitor. This would lead to one container emptying faster than the other container.
The dispenser comprised of at least two chambers is particularly useful with regard to fluids which are to be dispensed in different dosages over extended periods of time, and or products which are to be dispensed in different amounts over a certain period of time. By proportioning the two chambers so that medications are dispersed at a proportionate rate, both chambers will be emptied at the same time.
For example, the chamber requiring two drops per dose would be twice as large as a chamber requiring one drop per dose. The two chambers would thereby be emptied at the same time.
Patients commonly have to use more than one eye drop. Besides patients, doctors also have to treat patients using more than one eye drop. For example, before surgery a doctor has to apply an antibiotic and anti-inflammatory drug. With the prior art the doctor needs to carry two containers. With the present invention the doctor carries only one container which has the two drugs, and only with a flip of the dispenser the second eye drop can be administered without the risk of touching the eye. If more than one medication has to be dispensed, as occurs prior to surgery, the doctor can conveniently carry only one eye drop dispenser while dispensing at least two medications.
A two-liter bottle of a carbonated beverage demands consumption of all of the contents within a short time otherwise the carbonation is released and the beverage does not taste good. In a lot of instances, part of the contents are not used because the carbonation is lost. Therefore, it would be useful for a container, as in accordance with the invention, that allows consumption of smaller quantities while making available large amounts of beverage. This is a accomplished by the two-chamber system of the invention. One chamber which has essentially a triangular configuration holds one liter, and is anchored to the other container. The second container having an essentially triangular configuration, matches the triangular configuration of the first container. The two matching triangular configuration creates an essentially rectangular configuration or alternatively a square configuration, which is stable and well balanced.
In addition, the triangular configuration allows the use of the gravity fed system of the invention. Each container has a cap, with one cap facing one direction and the opposite cap facing an opposite direction. Preferably, one cap faces upward and the opposite cap faces downwards. Each cap has a level configuration preferably flat to allow keeping the two chamber container in a standing upright position. Preferably, the bottle has a round configuration, but it is understood that any geometric configuration can be used, or a combination of geometric configurations.
It is an object of the present invention to provide a dispenser for dispensing fluids, semisolid, solids, gels, pastes, ointments, powder, creams, and the like which solves or is an improvement over the problems and deficiencies of the art.
A further object of the present invention is to provide a fluid dispenser which remains in a horizontal position during use.
A further object of the present invention is to provide a container which is gravity fed by virtue of a slanted surface member and the container remains in a horizontal position during use.
Another object of the present invention is to provide a dispenser, which allows multiple fluids, of variable dosages, to be dispensed.
A further object of the present invention is to provide a dispenser which prevents the tip of the dispenser from touching the eye or creating fright reaction.
Another object of the present invention is to provide a dispenser with two tips which prevents any of the tips from touching the eye or creating fright reaction.
A still further object of the present invention is to provide a paired product dispenser, which allows dispensing different amounts of the product from the container.
Another object of the present invention is to provide a container that is gravity fed.
BRIEF DESCRIPTION OF THE DRAWINGS
The following drawings illustrate examples of various components of the bottle disclosed herein, and are for illustrative purposes only. Other embodiments that are substantially similar can use other components that have a different appearance.
FIG. 1 is a sectional view of a bottle according to the present invention.
FIG. 2 is a cross-sectional view taken along line 2 - 2 of FIG. 1 .
FIG. 3 is a sectional view of an alternate embodiment of the bottle shown in FIG. 1 .
FIGS. 4-6 illustrate the progressive emptying of a bottle according to FIG. 1 while the bottle is held in a horizontal orientation.
FIG. 7 illustrates a squeezable bottle having an eccentrically mounted outlet at one end of the bottle.
FIG. 8 is a sectional view of a bottle having a centrally mounted outlet at one end of the bottle.
FIG. 9 is a sectional view of an alternate embodiment having an inclined bottom wall forming the lowermost surface of the bottle.
FIG. 10 is a modified alternate embodiment illustrating a portion of the bottom wall being angled and terminating at the outlet.
FIGS. 11 and 12 illustrate eccentrically mounted outlets at one end wall of a bottle and an interior inclined wall extending from the uppermost wall and terminating at the outlet.
FIG. 13 illustrates an alternate embodiment including two bottle chambers each with an eccentrically mounted outlet located at an end wall and including a curved lowermost wall terminating at the outlet.
FIG. 14 is a sectional view, similar to FIG. 13 , having inclined, but not curved, lowermost walls terminating at a respective outlet eccentrically mounted in one end wall.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In describing a preferred embodiment of the invention illustrated in the drawings, specific terminology will be resorted to for the sake of clarity. However, the invention is not intended to be limited to the specific terms so selected, and it is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
With reference to the drawings, in general, and to FIGS. 1 and 2 , in particular, a bottle embodying the teachings of the subject invention is generally designated as 20 . With reference to its orientation in FIG. 1 , the bottle includes an upper wall 22 , a lower wall 24 , an end 26 and an end 28 .
The bottle may be cylindrical, horizontal or any other geometric shape. An outlet or dispensing nozzle 30 , having threads 32 for securing a cap thereto, is eccentrically mounted in end 28 .
Located in the interior of the bottle is an inclined wall 34 extending from end 26 at point 36 and terminating at point 38 at the lower wall 24 . Point 38 is located adjacent to the outlet 30 . Inclined wall 34 separates the contents of the bottle located in chamber 40 from a fill material 42 located below inclined wall 34 . The fill material 42 , as shown in FIG. 1 , is a solid plastic. Alternatively, as shown in FIG. 3 , the fill material 44 may be air or other fluid occupying the space below the inclined surface 34 . The purpose of the fill materials 42 , 44 is to support the inclined surface 34 so that the contents in chamber 40 are always fed by gravity to the outlet 30 .
As shown in cross section in FIG. 2 , the inclined wall 34 is also curved along its length from point 36 to point 38 . This provides a bottom channel or gutter 46 to help guide the contents of the chamber 40 to the outlet 30 . By removal of a cap or other closure mechanism from the outlet 30 , the contents of chamber 40 are fed through the outlet 30 even while the bottle 20 is maintained in the horizontal orientation shown in FIGS. 1 and 3 .
The progression of the contents in chamber 40 is shown in FIGS. 4 through 6 . The release of the contents of chamber 40 is illustrated by droplets 48 moving in the direction of arrow 50 from the full bottle 20 shown in FIG. 4 , and a partially filled bottle 20 shown in FIG. 5 , until an almost entirely empty bottle shown in FIG. 6 .
Alternatively, a bottle 52 , as shown in FIG. 7 , may have an upper wall 54 and a lower wall 56 which are squeezable towards each other in the direction of arrows 58 , 60 , respectively. An inclined wall 62 aids in transmission of the contents of chamber 64 towards the outlet 66 so that droplets 68 move in the direction of arrow 70 . Again, the orientation of the bottle 52 is horizontal so that the contents of the bottle in chamber 64 may be removed from the bottle without a tilting of the bottle.
In FIGS. 1 through 7 , the outlet or dispensing nozzle is located eccentrically in one of the two end walls. Alternatively, as shown in FIG. 8 , the dispenser nozzle 72 may be located centrally in end wall 74 . In this embodiment, to force the contents of the bottle 76 from chamber 78 , an inclined surface 80 extends from an upper portion 82 of end wall 84 and terminates at point 86 located just below an entrance to nozzle 72 .
In this embodiment, chamber 78 occupies approximately 50% of the volume of the bottle 76 . The remainder of the bottle includes fill material 88 of either solid material or air as described for FIGS. 1 and 3 . Bottle 76 appears similar to a known dispensing bottle; however, the bottle 76 takes advantage of the present invention in dispensing all of the contents of chamber 78 while maintaining a horizontal orientation of the bottle 76 .
In FIGS. 9 and 10 , bottles 90 , 92 , respectively, are shown. The bottle of FIG. 9 includes inclined wall 94 forming the lowermost wall of the bottle. Inclined wall or surface 94 takes advantage of the principles of the present invention while avoiding the need to fill a portion of the bottle with a fill material. The inclined wall 94 extends from an uppermost portion 96 located at upper wall 98 and terminates at point 100 adjacent to outlet or dispensing nozzle 102 for gravity fed release of droplets 104 .
Similarly, in FIG. 10 , the inclined surface 106 forms a portion of lower wall 108 extending from point 110 at the lower wall and terminating at point 112 adjacent to outlet or dispensing nozzle 114 for release of droplets 116 .
In this embodiment, only a portion of the lower wall includes the inclined wall portion 106 for gravity feed of the contents of chamber 118 towards the outlet 114 while maintaining a horizontal orientation of the bottle 92 . It is conceivable, in this embodiment, that the upper wall 120 and lower wall 108 may be deformable to aid in moving the contents of chamber 118 towards the inclined wall portion 106 leading to the outlet 114 .
In FIG. 11 , bottle 122 includes upper wall 124 and lower wall 126 . Inclined surface 128 , in this bottle, extends linearly from the intersection 130 of end wall 132 and upper wall 124 and terminates at point 134 adjacent to a neck 136 of a pull top dispensing mechanism 138 to allow transmission of the contents of chamber 140 to the outlet 142 . In this embodiment, the inclined surface 128 is flat and, due to the low viscosity of the liquid contents 144 of the bottle 122 , the contents 144 are rapidly evacuated from the bottle 122 upon opening of the dispensing mechanism 138 .
Similarly, in FIG. 12 , an eccentrically mounted outlet or nozzle 146 having a screw on top 148 is screwed onto threads 150 in the direction of arrow 152 to secure the contents in chamber 154 of the bottle 156 . Similarly to FIG. 11 , the inclined surface 158 is flat and extends from the intersection 160 of the end wall 162 and upper wall 164 and terminates at point 166 adjacent to the nozzle 146 . The bottom half of the bottle is filled with a solid fill material 168 in FIGS. 11 and 12 .
FIGS. 13 and 14 illustrate alternate embodiments of the present invention in which two dispensing nozzles are used to release the contents of two separated chambers contained in the single bottle.
In FIG. 13 , bottle 170 includes a chamber 172 having a curved inclined surface 174 leading to dispensing outlet or nozzle 176 for release of droplets 178 in the direction of arrow 180 . Vertically below chamber 172 is chamber 182 having curved inclined wall 184 for guiding the contents of chamber 182 to dispensing nozzle or outlet 186 for release of droplets 188 in the direction of arrow 190 . Vertically below the chamber 182 is fill material 192 to complete the volume of the bottle 170 . In this embodiment, two disparate materials may be separately stored in a single bottle and be released from the bottle while maintaining the bottle in a horizontal orientation.
FIG. 14 is similar to FIG. 13 except that, in FIG. 14 , the inclined surface 194 of chamber 196 of bottle 198 is flat. Vertically lower chamber 200 includes inclined surface 202 as its lower wall.
Inclined surface 194 leads the contents of chamber 196 to outlet nozzle or dispenser 204 , whereas the inclined wall 202 leads the contents of chamber 200 to outlet nozzle or dispenser 206 . The portion of the bottle 198 located below chamber 200 includes fill material 208 .
The foregoing description should be considered as illustrative only of the principles of the invention. Since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and, accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
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A bottle for dispensing fluids, semi-solid, ointments, gels, paste, creams, powder, and the like. The substances in the container are naturally fed by gravity to a dispensing portion without the need for the dispenser to be placed in a vertical position, upside down position, or inclined position in order to allow the substances to move to the tip of the dispensing portion, all the while maintaining the container in a horizontal orientation.
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FIELD OF INVENTION
The invention relates to the stable metal zirconium phosphates for use in colour applications. The metal zirconium phosphates according to the invention are used as colorants in ceramic compositions such as inorganic pigments, glaze, frits and glass.
BACKGROUND OF THE INVENTION
NaZr 2 (PO 4 ) 3 have a crystal structure with three-dimensional network of PO 4 tetrahedra and ZrO 6 octahedra linked by shared oxygens. A compound having such a structure is commonly refered as an NZP compound. The sodium ions are located at the interstitial sites created by the framework, but are replaced with other ions depending on the NZP analog. The NZP structure is exceptionally flexible towards ionic substitution at various lattice sites.
It is well known that ceramic materials with NZP structure have low thermal coefficient of expansion. Materials with NZP structure are used as a refractory materials, plasma powders etc. in a variety of applications.
SUMMARY OF THE INVENTION
The invention relates to novel stable metal zirconium phosphates compounds for ceramic colour applications. The metal zirconium phosphates according to the invention have the general formula X n Zr 2 (PO 4 ) 3 , in which X is a metal or combination of metals selected from Na, Mg, Ca, Co, Ni, Mn, Cu, Cd, Zn, Se, Fe, Cr, Al, Si, Sn, V; and n have a value in the range of 1.25 to 22 moles (M). These metal zirconium phosphates exhibit composite colors based on the intrinsic colors of the metals when used in ceramic composition depending upon their molar concentration in the compound. By selecting the metal or combination of metals and their molar concentration in the metal zirconium phosphate it is possible to obtain a wide range of colors in the finished goods when they are used as colorants in ceramic composition.
The invention provides a stable metal zirconium phosphate for color applications having the general formula
X n Zr 2 (PO 4 ) 3
in which, X is a metal or a combination of metals selected from Na, Mg, Ca, Co, Ni, Mn, Cu, Cd, Zn, Se, Fe, Cr, Al, Si, Sn, V; and n has a molar value in the range of 1.25 to 22.
The invention also provides a method of manufacturing a stable metal zirconium phosphate for color applications having the general formula
X n Zr 2 (PO 4 ) 3
in which, X and n are as defined above, said method comprising the steps of: mixing a metal cation solution selected from one or more metal chlorides, and/or metal nitrates, in which the metal is selected from the groups consisting Na, Mg, Ca, Co, Ni, Mn, Cu, Cd, Zn, Se, Fe, Cr, Al, Si, Sn, V; with a zirconium cation solution selected from the group consisting zirconium oxychloride and zirconium nitrate to form a metal cation solution, reacting the mixture with phosphoric acid to precipitate a gel, drying the gel to obtain a powder, sintering the powder at a temperature of 800° C. to 1000° C. for 8 to 16 hours and water washing the sintered powder followed by drying to obtain the stable metal zirconium phosphate.
DETAILED DESCRIPTION OF THE INVENTION
The materials used in the synthesis of the metal zirconium phosphates according to the invention are commercial-grade chemicals. Preferably the starting materials used are water-soluble Zirconium Oxychloride, metal chlorides and phosphoric acid with 5 to 20% concentration.
The compounds of the invention are prepared using the sol-gel technique. Preferably an aqueous metal chloride having a metal concentration in the range of 1.25 to 22.0 M is dissolved in water along with zirconium oxychloride having a concentration of 0.4 to 1.0 M Zirconium. The solution is poured in a reactor and stirred to get a homogeneous mixture. Phosphoric acid with 5 to 20% concentration is added drop by drop to the solution while stirring. Addition of phosphoric acid precipitate a gel. The resulting gel is dried to remove moisture and sintered at 800° C. to 1000° C. in a kiln for 8-16 hours. The sintered powder is then water washed to remove un-reacted metal chloride and to reduce acidity and milled to get a 300-500 mesh size fine grain of powder.
The following examples illustrate the preferred metal zirconium phosphate prepared according to the invention.
EXAMPLE 1
A metal cation solution having 3 molar concentration of Na is prepared by dissolving sodium chloride in 3 liters of water. A zirconium cation solution having 1 molar concentration of Zr is prepared by dissolving zirconium oxychloride in 2 liters of water and the two solutions are mixed thoroughly to obtain a homogeneous mixture. Phosphoric acid is dissolved in 2 liters of water to obtain 1.0 molar concentration of phosphorous in the solution. This solution is added to the homogeneous mixture of metal cation solution and zirconium cation solution dropwise while stirring to obtain a gel. The gel thus obtained is dried initially at 110° C. for 2 hours and then at 150° C. for the next 2 hours to remove moisture and then sintered at a temperature of 900° C. in a kiln for 10 hours. Metal zirconium phosphate with about 3 molar concentration of Na is obtained.
EXAMPLE 2
A metal cation solution having 1.5 molar concentration of Ni is prepared by dissolving nickel chloride in 750 ml of water and zirconium cation solution having 0.5 molar concentration of Zr is prepared by dissolving zirconium oxychloride in 1 liter of water. Phosphoric acid having 0.5 molar concentration of phosphorous is prepared by dissolving phosphoric acid in 1 liter of water. Nickel zirconium phosphate was prepared by the same steps as described in example 1. Metal zirconium phosphate with about 1.5 molar concentration of Ni is obtained.
EXAMPLE 3
The process of example 2 is repeated with metal cation solution containing 3.0 molar concentration of Co prepared by dissolving cobalt chloride in 1.5 liters of water. Metal zirconium phosphate with about 3.0 molar concentration of Co is obtained.
EXAMPLE 4
The process of example 2 is repeated with metal cation solution containing 3.0 molar concentration of Zn by dissolving sodium chloride and zinc chloride in 5 liters of water. Metal zirconium phosphate obtained has about 3 molar concentration of Na and about 3 molar concentration of Zn.
EXAMPLE 5
The process of example 2 is repeated with metal cation solution containing 5 molar concentration of Cu and 0.2 molar concentration of Co by dissolving copper chloride and cobalt chloride in 2.5 liters of water. Metal zirconium phosphate obtained has about 5 molar concentration of Cu and about 0.2 molar concentration of Co.
EXAMPLE 6
The procedure of example 2 is repeated with metal cation solution containing 1.7M of Ni and 1.0M of Mn by dissolving nickel chloride and manganese chloride in 1.3 liters of water. Metal zirconium phosphate obtained has about 1.7 molar concentration of Ni and about 1.0 molar concentration of Mn.
EXAMPLE 7
The procedure of example 2 is repeated with metal cation solution containing 1.2M Ni, 0.8M Co and 0.5 Mn by dissolving nickel chloride, cobalt chloride and manganese chloride in 1250 ml of water. Metal zirconium phosphate obtained has about 1.2 mole concentration of Ni, about 0.8 molar concentration of Co and about 0.5 molar concentration of Mn.
EXAMPLE 8
The procedure of example 2 is repeated with metal cation solution containing 0.75M Ni, 0.5M Zn and 0.5M Mn by dissolving nickel chloride, zinc chloride and manganese chloride in 820 ml of water. Metal zirconium phosphate obtained has about 0.75 molar concentration of Ni, about 0.4 molar concentration of Zn and about 0.5 molar concentration of Mn.
EXAMPLE 9
The procedure of example 2 is repeated with metal cation solution containing 4.5M of Cr and 4.0M of Fe by dissolving chromium chloride and ferric chloride in 3 liters of water. Metal zirconium phosphate obtained has about 4.5 molar concentration of Cr and about 4.0 molar concentration of Fe.
EXAMPLE 10
A metal cation solution having 3.8 molar concentration of Cr, 4 molar concentration of Fe is prepared by dissolving chromium chloride and ferric chloride in 2.9 liters of water. Zirconium cation solution with 4.0 molar concentration of Zr is prepared by dissolving zirconium oxychloride in 800 ml of water. Phosphoric acid with 0.4 molar concentration of phosphorous is prepared by dissolving phosphoric acid in 500 ml of water. Metal zirconium phosphate having about 3.8 molar concentration of Cr and about 4.0 molar concentration of Fe is obtained by the same process steps as described in example 1.
EXAMPLE 11
The procedure of example 2 is repeated with metal cation solution containing 0.2M of Cr and 1.5M of Al by dissolving chromium chloride and aluminium chloride in 500 ml of water. Metal zirconium phosphate obtained has about 0.2 molar concentration of Cr and about 1.5 molar concentration of Al.
EXAMPLE 12
The procedure of example 2 is repeated with metal cation solution containing 7.4M Fe by dissolving ferric chloride in 2.5 liters of water. Metal zirconium phosphate obtained has about 7.4 molar concentration of Fe.
EXAMPLE 13
The procedure of example 2 is repeated with metal cation solution containing 3M Co and 1.5M Cr by dissolving cobalt chloride and chromium chloride in 2 liters of water. Metal zirconium phosphate obtained has about 3 molar concentration of Co and about 1.5 molar concentration of Cr.
EXAMPLE 14
The procedure of example 2 is repeated with metal cation solution containing 8.85M Cr and 0.2M Co by dissolving chromium chloride and cobalt chloride in 3.0 liters of water. Metal zirconium phosphate obtained has about 8.85 molar concentration of Cr and about 0.2 molar concentration off Co.
The procedure of example 2 is repeated with metal cation solution containing 3.4M Sn, 0.2M Cr and 1.7M of Ca by dissolving tin chloride, chromium chloride and calcium chloride in 2.2 liters of water. Metal zirconium phosphate obtained has about 3.4 molar concentration of Sn and 0.2 molar concentration of Cr and about 1.7 molar concentration of Ca.
EXAMPLE 16
The procedure of example 2 is repeated with metal cation solution having 4.0 molar concentration of Cr, 2.0molar concentration of Fe, 0.5 molar concentration of Ni, 1.0M molar concentration of Mn and 3 molar concentration of Co by dissolving ferric chloride, nickel chloride, manganese chloride and cobalt chloride in 5 liters of water. Metal zirconium phosphate obtained has about 4.0 molar concentration of Cr, about 2.0 molar concentration of Fe, about 0.5 molar concentration of Ni, about 1.0 molar concentration of Mn and about 3 molar concentration of Co.
EXAMPLE 17
The procedure of example 2 is repeated with metal cation solution containing 0.4M Co, 0.2M Cr, 0.6M of Ni and 1.2M of Fe by dissolving cobalt chloride, chromium chloride, nickel chloride and ferric chloride in 1.3 liters of water. Metal zirconium phosphate obtained has about 0.4 molar concentration of Co, about 0.2 molar concentration of Cr, about 0.6 molar concentration of Ni and about 1.2 molar concentration of Fe.
EXAMPLE 18
The procedure of example 2 is repeated with metal cation solution containing 1.2M Ni, 0.8M Co and 0.5M of Mn by dissolving nickel chloride, cobalt chloride and manganese chloride in 1.2 liters of water. Metal zirconium phosphate obtained has about 1.2 molar concentration of Ni, about 0.8 molar concentration of Co and about 0.5 molar concentration of Mn.
The metal zirconium phosphates according to the invention exhibit composite colors based on the intrinsic colours of the metals and their proportion when used a colorant in a ceramic composition. The complex molecular structures of the metal zirconium phosphorates according to the invention accommodate additional cations of the metals based on the molar concentrations in the solution used for the preparation.
Composite colors are formed when multiple metal cations are present in different proportions in the metal zirconium phosphate according to the invention.
Desired shade and intensity of the colour can be obtained when the metal zirconium phosphate according to the invention is used as colorant in a ceramic composition by choosing the water-soluble salts of metals with differing molar proportion.
Dried gel materials with different metal compositions can be sintered together in the kiln to form the corresponding metal zirconium phosphate without any contamination from other compositions.
The metal zirconium phosphate obtained are agglomerated products and can be easily milled to less than 500 mesh, sizes.
The metal zirconium phosphate according the invention can be introduced directly into the ceramic glazes aid frits. It also eliminate or reduce the opacifier requirements in the ceramic glazes and frits due to presence of zirconium content.
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The invention provides a stable metal zirconium phosphates having formula (I), in which X is a metal or a combination of metals selected from Co, Mn, Ni, Cu, Cd, Fe, Cr, Al, Sn, V, Zn, Sc, Na, Mg, Ca and Si; and n has a molar value in the range of 1.25 to 22. These metal zirconium phosphates are prepared by sol-gel process.
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BACKGROUND OF THE INVENTION
[0001] The invention relates to a method for assisting a driver of a motor vehicle during a driving procedure to overcome a low-level obstacle at slow velocity, and also a control unit, which is designed for the purpose of executing such a method.
[0002] When driving using a motor vehicle having a conventional manual shift transmission and internal combustion engine, the driver manually controls, in cooperation with the accelerator pedal and clutch, a start procedure from a standstill over an obstacle (for example, a curbstone), such that a high torque is initially transmitted to the wheels with low clutch slip, in order to overcome the obstacle without stalling the engine. After overcoming the obstacle, the driver opens up the clutch again himself, as soon as the vehicle is set into motion, so that the traction is interrupted again and the vehicle rolls away rapidly.
[0003] In a motor vehicle having an automatic transmission with a torque converter, as a result of the characteristic of the torque converter, moderate torque is unfolded as a curbstone is overcome, so that it can be overcome in a controlled manner and with continuous, smooth forward movement of the motor vehicle.
[0004] In contrast, the start procedure using an electric vehicle over a stepped obstacle has heretofore been problematic. The driver also initially requests an elevated torque here to overcome the obstacle, by actuating the accelerator pedal. During the travel after overcoming the obstacle, the vehicle suddenly accelerates forward, since the high torque which was built up still acts on the driven wheels. Heretofore it has not been possible to control those driving situations safely and reliably in electric vehicles, in which the electric vehicle accelerates strongly from slow travel in the desired travel direction in such a manner that an excessively high velocity is reached. A relatively long time can pass until the driver has overcome the moment of surprise and reacts appropriately (for example, brakes). Therefore, the acute danger exists of a collision with another vehicle close to the obstacle, for example.
SUMMARY OF THE INVENTION
[0005] The method according to the invention for assisting a driver of a motor vehicle, in particular an electric vehicle, during a driving procedure to overcome a low-level obstacle at slow velocity has the following steps: transmitting a torque to the wheels to be driven to overcome the obstacle, recognizing that the obstacle has been overcome, and automatically decreasing the torque and/or automatically producing a braking torque to decelerate the motor vehicle immediately after the recognition.
[0006] Furthermore, a control unit for carrying out such a method is provided according to the invention.
[0007] The term “low-level obstacle” is understood to mean obstacles which, for example, extend upward from an underlying surface, for example, the ground, of a parking space with a height which is less than 40 cm, preferably less than 30 cm, particularly preferably less than 20 cm. For example, curbstones which are not sunken fall in the range of less than 20 cm. The term “low-level obstacle” also includes objects which do not extend directly upward from the ground, but rather are located above the ground up to an above-mentioned distance.
[0008] The term “electric vehicles” is to be understood to include in the wording of this text, for example, motor vehicles driven exclusively via electrical power, but also hybrid vehicles, which have combinations of electric motors with internal combustion engines or fuel cells.
[0009] The invention allows safe and reliable control of the start on an obstacle, in particular in the case of electric vehicles. The invention permits uniform and smooth forward movement of the motor vehicle as it overcomes the obstacle. The driver does not have to take any special measures for this purpose or ensure the exact cooperation of accelerator pedal and brake pedal. The above-described hazard of collisions as a result of surprising vehicle reactions is remedied. The problem that the motor vehicle is blocked in its movement path by an obstacle, whereby the drive can overheat, is also remedied. In the method according to the invention, the drive torque and therefore the power consumption of the electrical drive machine are limited. In this way, high energy loads and current spikes of the electrical drive machine are avoided during the starting and therefore a thermal overload of the electrical drive machine or its power electronics is prevented.
[0010] According to one embodiment of the method according to the invention, to recognize or register overcoming the obstacle, at least one external and/or one internal variable, such as the roadway inclination and/or statuses of the motor vehicle, such as the velocity and/or the acceleration of the motor vehicle, is registered and analyzed.
[0011] The control or regulating algorithms of a control unit which executes the method according to the invention can thus be adapted optimally to the given boundary conditions or the specific operating situation of the motor vehicle.
[0012] According to one embodiment variant of the method according to the invention, the motor vehicle is driven by an electric motor. The recognition of overcoming the obstacle is performed by analyzing a characteristic variable of the electric motor, which is characteristic in particular for a load of the electric motor.
[0013] On the basis of such characteristic variables (for example, recorded motor current), overcoming the obstacle can be recognized rapidly and reliably, so that the required vehicle reactions can be triggered in a timely manner.
[0014] In one embodiment of the method according to the invention, a pressure in a tire of the motor vehicle is analyzed to recognize overcoming the obstacle.
[0015] Tire pressure monitoring systems are known from the prior art and can be implemented simply and cost-effectively. Tire pressure monitoring systems are typically provided in any case in modern vehicles, so that the signals delivered by the tire pressure monitoring system can also be used for the present purpose. The additional required expenditure for the method according to the invention is minimal if such tire pressure monitoring systems are present.
[0016] According to one embodiment of the method according to the invention, an obstacle situation is recognized if a recognized start indication of the driver exists, an accelerator pedal gradient falls below a predefined threshold value, and, in the event of a buildup of a drive torque to a predefined upper limiting value, no acceleration of the motor vehicle in the travel direction is achieved.
[0017] The term “accelerator pedal gradient” is understood as the change of the pedal position as a function of time. The consideration of the accelerator pedal gradient is based on the finding that a driver only actuates the accelerator pedal slowly or hesitantly when controlling the motor vehicle to overcome an obstacle. By such a recognition of the obstacle situation, on the basis of the above-mentioned boundary conditions, the necessity of a start assist can be concluded and it can thus be ensured that the method according to the invention is only executed when it is also actually necessary.
[0018] For example, the position of a parking brake and/or a service brake is registered to determine the start indication.
[0019] It can thus be ensured that a registered change of the driving resistance has not occurred due to braking
[0020] In one embodiment of the method according to the invention, the position of a selection element, in particular a selection lever, which is movable into various selection positions to select various gear steps to be engaged on the transmission and/or to select various driving programs, is registered to determine the start indication.
[0021] A start indication can be reliably derived from the position of the selection lever.
[0022] According to one embodiment variant of the method according to the invention, the obstacle is recognized by means of an environmental sensor system or a telemetric unit. The environmental sensor system is embodied in particular as a camera, ultrasound, radar, and/or lidar system. By way of the possibility of the use or the combination of various sensor types, improved reliability can be achieved in the event of changing external conditions (rain, fog, etc.). For example, stepped obstacles can be identified by means of a camera image.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows a diagram having a plurality of time-dependent graphs;
[0024] FIG. 2 a shows a graph in which the motor torque of the electrical drive machine is shown when starting on the hill and on the curbstone as a function of time;
[0025] FIG. 2 b shows a graph which illustrates the time curve of the acceleration of the motor vehicle when starting on the hill and on the curbstone, and
[0026] FIG. 3 shows a flow chart of a method according to the invention.
DETAILED DESCRIPTION
[0027] FIG. 1 shows the time sequence of one embodiment of the method according to the invention.
[0028] The individual graphs 1 a ) to 1 f ) of FIG. 1 are each based on the same timescale. In each of the individual graphs, the time curve of the respective ordinate variable is shown by the dashed curve plotted in the Y-direction in the method according to the invention, in which automatic activation of the drive units and the deceleration units of an electric vehicle is performed. Correspondingly, the profile of the individual ordinate variables during conventional starting of the electric vehicle is shown by the solid lines. I.e., the driver controls the starting procedure in a conventional manner using gas pedal and brake pedal.
[0029] Graph 1 a shows the vehicle velocity as a function of time. The curve K 1 , which shows the profile of the vehicle velocity during a conventional start of the electric vehicle, has a rising section 10 , which rises steeply at moment t 1 , starting from the value 0. The curve K 1 shows a first velocity maximum V max1 , which means in other words that the initially strongly rising vehicle velocity gradually attenuates, until the vehicle velocity reaches the maximum V max1 at the moment t 2 . After passing through the maximum V max1 , the vehicle velocity falls steeply, as shown by the falling section 12 , and again reaches the value 0 at the moment t 3 .
[0030] The dashed curve K 2 in FIG. 1 a shows the time curve of the vehicle velocity in the case of the method according to the invention. A steep section 14 of the curve K 2 first runs in correspondence with the curve of the velocity in the conventional method. This correspondence can be explained in that overcoming the curbstone only occurs at the moment t 4 and before the moment t 4 , in the conventional method and in the method according to the invention, an acceleration of the electric vehicle occurs in response to the drive torque indication requested by pressing down the accelerator pedal.
[0031] As soon as the drive torque requested by the driver via an actuation of the accelerator pedal is sufficient to drive over the electric vehicle against the travel resistance of the obstacle, at the moment t 1 , the velocity rises steeply originating from the value 0, as illustrated by the rising steep section 14 . The curve K 2 passes through a second velocity maximum V max2 at the moment t 4 . After passing through the second velocity maximum V max2 , the velocity falls rapidly, as described by the falling steep section 16 , and reaches the value 0 at the moment t 5 .
[0032] FIG. 1 b shows the position of the accelerator pedal as a function of time. The curve K 3 , which shows the time curve in the conventional method, may be coarsely divided into three sections, specifically in detail into a rising section 18 , a parallel section 20 running approximately parallel to the abscissa, and a steeply falling steep section 22 .
[0033] The slight slope of the rising section 18 indicates that the driver presses down the accelerator pedal slowly. I.e., the driver recognizes the situation of starting on the curbstone and requests a corresponding drive torque by slow accelerator pedal actuation. The rising section merges continuously into the parallel section 20 . In other words, this means that from a specific moment, the accelerator pedal is not deflected further, but rather is kept constant for a while—as described by the parallel section 20 . At the moment t 6 , the driver experiences a strong acceleration of the motor vehicle and as a result suddenly releases the accelerator pedal, so that the accelerator pedal at moment t 7 again reaches its idle position.
[0034] In graph 1 c , the braking torque which decelerates the electric vehicle is plotted along the ordinate and the time is plotted along the abscissa. The curve K 4 shows the profile during the method according to the invention. Two subsections may be defined on the curve K 4 , a steeply rising steep section 24 and a parallel section 26 running approximately parallel to the x axis. At the moment t 8 , the control unit according to the invention registers by means of corresponding sensors that the curbstone has been overcome. In order to prevent undesired strong forward acceleration of the motor vehicle, the electric vehicle—as shown by the steep section 24 —is automatically decelerated immediately after overcoming the curbstone by a braking intervention, which can be provided, for example, by a brake controlled by an electronic stability program (ESP).
[0035] The profile of the braking torque in the conventional method is described by the curve K 5 . The curve K 5 corresponds with respect to the qualitative profile to the curve K 4 and again has a steeply rising steep section 28 and a parallel section 30 . The steep section 28 rises steeply at the moment t 7 , at which the reaction of the driver to the sudden acceleration of the motor vehicle after overcoming the curbstone begins and the driver rapidly presses down the brake pedal. At the same moment t 7 —as shown in FIG. 1 b —the accelerator pedal has reached its idle position, which means that the driver has changed his foot from the accelerator pedal to the brake pedal at the moment t 7 . As a result of the substantially slower reaction of the driver in comparison to the automatic braking intervention, the curve K 5 runs offset to the curve K 4 with respect to time for a specific time in the positive x direction.
[0036] The graph 1 d indicates that the gear step engaged on the transmission is continuously located at the position “D”.
[0037] In the graph 1 e , the drive torque of the motor vehicle is plotted as a function of time. The curve K 6 describes the profile of the drive torque in the method according to the invention. The curve K 6 shows a flatly increasing rising section 32 , which reaches a local maximum M max at the moment t 8 and merges into a steeply falling steep section 34 after passing through the maximum M max . This falling steep section 34 describes a rapid reduction of the drive torque initiated by the control unit implemented according to the invention immediately after recognizing the overcoming the obstacle (moment t 4 ). The drive torque transmitted to the driven wheels is adapted to the building braking force ( FIG. 1 c ), so that rapid but comfortable braking is made possible. A comparison between FIGS. 1 e and 1 c shows that the drive torque is reduced to zero upon beginning braking force, so that the brake is not excessively loaded.
[0038] The curve K 7 illustrates the profile of the drive torque in the conventional method. The curve K 7 shows a flatly increasing rising section 36 , which therefore corresponds to the rising section 32 of the curve K 6 , because in the conventional method and in the method according to the invention, the drive torque is respectively requested via the accelerator pedal actuation ( FIG. 1 b ) of the driver before overcoming the obstacle (at the moment t 4 ). The rising section 36 merges at the moment t 8 into a parallel section 38 running parallel to the abscissa, which in turn merges at the moment t 9 into a falling steep section 40 .
[0039] FIG. 1 f shows the time curve of the accelerations of the motor vehicle. The acceleration curves correspond to the first derivatives with respect to time of the velocity curves shown in FIG. 1 a . The curve K 8 illustrates the acceleration of the motor vehicle as a function of time in the method according to the invention. The curve K 8 has an upper peak section 42 similar to a parabola open at the bottom, for which all Y coordinates, i.e., the vehicle accelerations, are positive (acceleration of the electric vehicle in the stricter sense). The upper peak section 42 illustrates how the vehicle acceleration initially strongly rises to the moment t 1 and rapidly reaches a maximum value a max , to attenuate steeply and rapidly after passing through the maximum a max under the influence of the automatic braking intervention with simultaneous reduction of the drive torque, until the vehicle acceleration firstly passes through a zero crossing (in which the vehicle velocity is constant for a moment). After the zero crossing, the curve K 8 merges into a parabola-like lower peak section 44 , in which all Y values are negative (deceleration of the motor vehicle in the stricter sense). The deceleration of the motor vehicle initially strongly increases after the zero crossing, which occurs at the moment t 4 , as described by the negative steep section 46 , passes through a local minimum a min , and then gradually decreases, as illustrated by the rising section 48 . Overall, the curve K 8 shows a periodic curve profile, so that a first period duration T 1 may be defined.
[0040] The curve K 9 , which describes the time curve of the vehicle acceleration in the conventional method, shows an upper trapezoidal section 50 , which is located in the first quadrant and therefore represents accelerations of the motor vehicle in the stricter sense, and which approximately repeats with changed sign after a zero crossing, so that overall an approximately periodic profile results for the curve K 9 . Therefore, a second period duration T 2 may be defined. After the zero crossing, which occurs at the moment t 2 , the curve K 9 lies with a lower trapezoidal section 52 in the fourth quadrant, which means that the accelerations of the electric vehicle are negative at the corresponding moments. The upper trapezoidal section 50 has a steep section 54 , which corresponds to a steep section of the curve K 8 of the method according to the invention and represents an acceleration of the motor vehicle in response to the drive torque requested by pressing down the accelerator pedal. The acceleration remains constant for a specific duration at a maximum value, as described by the parallel section 56 of the curve K 9 . In other words, this means that the electric vehicle moves forward for a comparatively long time at high acceleration, which first drops steeply due to the brake actuation of the driver and has the zero crossing at the moment t 2 . In the case of such a long-lasting high acceleration of the electric vehicle, the acute hazard exists of a collision with an object, for example, a further vehicle in proximity. Furthermore, the high maximum velocity V max1 ( FIG. 1 a) is reached by the long acceleration phase, which is a multiple of the maximum velocity V max2 in the method according to the invention ( FIG. 1 a ).
[0041] The automatic vehicle reactions, in contrast, occur practically without a time delay, because the sensors deliver corresponding output signals for further processing to the control unit according to the invention directly after overcoming the obstacle. In comparison thereto, the driver reacts comparatively slowly. This different reaction behavior between the control unit according to the invention and the driver has the result, on the one hand, that the period duration T 2 of the vehicle acceleration profile in the conventional method is a multiple of the period duration T 1 of the method according to the invention (T 2 >>T 1 ).
[0042] The different reaction times also have an effect on the stopping distance of the motor vehicle. The stopping distance is determined from the distance covered during the reaction time and the actual braking distance. Since the reaction time is practically 0 in the case of the automatic controller, in this case, the stopping distance is significantly less. The time span indicated by the arrow B in FIG. 1 a is a measure of this difference of the stopping distance of the conventional method in relation to the method according to the invention.
[0043] The actuation of the accelerator pedal by the driver in the method according to the invention is apparent from FIG. 1 b . Therein, the curve K 10 shows the profile of the accelerator pedal position in the method according to the invention. After the beginning of the automatic braking or deceleration procedure (moment t 8 ), the accelerator pedal is still deflected comparatively far from the idle position. The vehicle is nonetheless decelerated ( FIG. 1 f ). This means that the control command mechanism has predominance over the manual actuation of the driver, to adapt the manual and automatic control commands to one another. After the driver experiences a deceleration of the vehicle at the moment t 4 , he slowly releases the accelerator pedal after a corresponding reaction time, to thus prevent the mechanism, which intends a deceleration of the vehicle, and the driver from working against one another. In the event of manual control command inputs and automatically generated control signals which supplement one another excessively strongly, an automatic adaptation of these control signals to one another can be performed, for example, to prevent excessively strong deceleration of the motor vehicle.
[0044] In order to initiate a situation-appropriate vehicle reaction in each case in the method according to the invention, it is preferably to be checked whether an obstacle situation actually exists, i.e., whether an obstacle is actually to be overcome, or whether a high travel resistance has other causes, for example, a start on a slope (hill start). For this purpose, FIG. 2 a shows a graph, in which the motor torque M L of the electric motor driving the electric vehicle is plotted as a function of time during a hill start (curve Bl) and a start over an obstacle (curve H 1 ). FIG. 2 b shows a further graph, in which the motor rotational acceleration (dn mot /dt) or vehicle longitudinal acceleration (a x ) during the hill start (curve B 2 ) and during the start over the obstacle (curve H 2 ) is plotted as a function of time. The two graphs 2 a and 2 b are based on the same timescale. During a hill start and during the start over the obstacle, the motor torque M L initially rises to a maximum value M Lmax , without the motor vehicle moving. The characteristic differentiating feature during the start on the curbstone, however, is the sudden reduction of the load torque when the obstacle has been overcome. This can be established, for example, by the jump of the motor torque M L described by the peak P (detectable, for example, by a sudden rotational acceleration of the rotor and/or changed power consumption of the electrical drive machine). Therefore, a way is shown in which a start on a blocking obstacle can be differentiated from a start on a slope.
[0045] FIG. 3 shows a flow chart of the method according to the invention. The method starts in step S 1 , in which a driver requests a drive torque by actuating the accelerator pedal. After step S 1 , the method progresses to step S 2 . In step S 2 , it is checked whether an obstacle situation exists, i.e., whether there is a driving situation in which a low-level obstacle is to be overcome. Such an obstacle situation is recognized if the following events or boundary conditions a) to f) are fulfilled:
[0046] a) the control unit according to the invention receives the signal “vehicle standstill”,
[0047] b) the control unit according to the invention receives the signal “parking brake not actuated”,
[0048] c) the control unit according to the invention receives the signal “service brake not actuated”,
[0049] d) the gear step engaged on the transmission is not “N” or “P”,
[0050] e) the accelerator pedal gradient falls below a predefined minimal threshold value (which means that the accelerator pedal is hesitantly actuated),
[0051] f) the drive torque corresponding to the driver indication exceeds a predefinable upper threshold value, without the motor vehicle moving.
[0052] In the case of a negative test result in step S 2 , the method is ended in ending step S 8 .
[0053] In the case of a positive test result in step S 2 , the method is continued with step S 3 . In step S 3 , it is checked whether the drive torque requested by the driver is sufficient to overcome the obstacle.
[0054] In the case of a negative test result in step S 3 (i.e., the drive torque is not sufficient to overcome the obstacle), the method progresses to step S 4 .
[0055] In step S 4 , to protect components from thermal overload after an applicable time, the drive torque is reduced in accordance with a predefinable chronological profile, for example, a ramped profile, and simultaneously a corresponding warning message is output to the driver.
[0056] After step S 4 , the method is ended in ending step S 8 .
[0057] In the case of a positive test result in step S 3 , the method is continued with step S 5 , in which it is checked whether an obstacle situation exists or an elevated travel resistance possibly has another cause, for example, a start on a hill. To avoid repetitions, reference is made to the preceding description of FIGS. 2 a and 2 b , where a possibility of how an obstacle situation can be differentiated from a hill start is described in detail.
[0058] In the decision S 5 , the method branches depending on whether or not an obstacle situation actually exists. If it is established in the decision S 5 that no obstacle situation exists, the method is ended in step S 8 .
[0059] If it is established in the decision S 5 that an obstacle situation exists, i.e., an obstacle is to be overcome, the method passes to step S 6 .
[0060] In step S 6 , it is registered by a sensor system whether the obstacle has already been overcome. If it is registered in step S 6 that the obstacle has been overcome, the method is continued with step S 7 . In step S 7 , the control unit according to the invention automatically initiates a braking intervention, which can be provided, for example, by a brake controlled by an electronic stability program. Simultaneously, the control unit according to the invention initiates a rapid reduction of the drive torque transmitted to the driven wheels in step S 7 . The drive torque is adapted to the building braking force, so that rapid but comfortable braking is made possible. After step S 7 , the method is ended in step S 8 .
[0061] If it is established in step S 6 that the obstacle has not been overcome, step S 6 is repeated until overcoming of the obstacle is established.
[0062] In summary, the invention provides a method which relieves the driver during difficult driving situations, in each of which a curbstone is to be overcome, for example, a parking procedure in a parking space or when driving out of a vehicle exit. By way of the invention, it is possible to control such driving situations safely and reliably, in particular in the case of electric vehicles.
[0063] It is obvious that the present invention can be altered in manifold ways without leaving the idea of the invention.
[0064] Thus, for example, it is conceivable that after overcoming an obstacle or a high travel resistance (for example, if a boat trailer is to be pulled out of the water or another vehicle is to be pulled out of a ditch), no reduction of the drive torque or even an increase of the acceleration is desired. A system executing the method according to the invention can be deactivated by a corresponding driver indication, which is given, for example, by actuating the ESP off button. In this case, only the above-mentioned thermal protection engages.
[0065] Furthermore, it is fundamentally possible to also use the invention in conventional motor vehicles, which are solely driven by an internal combustion engine.
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The invention relates to a method for assisting a driver of a motor vehicle, in particular of an electric vehicle, during a driving process for overcoming an obstacle which is close to the ground and has a slow speed. In this context, the method has the following steps: transmission (S 1 ) of a torque to the wheels which are to be driven in order to overcome the obstacle, detection (S 6 ) that the obstacle has been overcome, and automatic reduction in the torque and/or automatic generation (S 7 ) of a braking torque in order to decelerate the motor vehicle directly after the detection.
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BACKGROUND OF THE INVENTION
This invention relates to articles composed of resinous polymers of acrylonitrile (AN) and methacrylonitrile (MAN) and particularly to multiaxially oriented articles and more particularly to multiaxially oriented films of copolymers of arylonitrile and methacrylonitrile.
Polyacrylonitrile (PAN) has excellent barrier properties, chemical resistance, rigidity, and heat resistance. PAN, however, is not a thermoplastic, and must be dissolved in a solvent in order to be processed. The use of a solvent negatively effects the polymer's barrier properties.
Polyacrylonitrile (PAN) also has desirable barrier properties, chemical resistance, and rigidity although they are not as good as those of PAN. In contrast to PAN, PMAN is a melt processable thermoplastic, but it is prone to de-polymerization at high temperatures.
In this invention, copolymers of AN and MAN have been formed to obtain the best properties of both PAN and PMAN. A copolymer of these nitriles results in an article having excellent barrier properties, chemical resistance, rigidity and heat resistance, while desirable thermoplastic properties such as melt stability for melt processing are also obtained.
Prior to this invention, copolymers of AN and MAN were formed using only small amounts of AN, because polymers made with more than 20% by weight of polymerized acrylonitrile could not be extruded. For example, it is taught in U.S. Pat. No. 3,565,876 that up to about 20% by weight of acrylonitrile can be copolymerized with methacrylonitrile to form extrudible copolymers which can be readily oriented and possess excellent physical properties. Increasing the acrylonitrile content above 20% by weight in acrylonitrile/methacrylonitrile copolymers resulted in a resin which was unstable and not processable by any of the usual commercial techniques known today, including extrusion. Although the copolymers of the U.S. Pat. No. 3,565,876 had desirable qualities, their low AN content failed to take full advantage of AN's superior barrier characteristics.
In this art, therefore, it is desirable to have a processable, stable acrylonitrile/methacrylonitrile copolymer system wherein the acrylonitrile content is greater than 20% of the final polymer composition.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of this invention to provide an improved process for making an acrylonitrile/methacrylonitrile copolymer.
It is a further object of this invention to provide new and improved AN/MAN copolymers containing greater than 20% AN. It is a further object of this invention to provide a new and improved process for forming AN/MAN copolymers having greater than 20% AN which are melt processable and stable.
Additional objects and advantages of the invention will be set forth in part in the description which follows and in part will be obvious from the description or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out int he appended claims.
To achieve the foregoing objects and in accordance with the purpose of the invention, as embodied and broadly described herein, the process of this invention comprises forming a viscous polymer by the polymerization, of a mixture of methacrylonitrile and acrylonitrile, wherein the addition of the monomers throughout the reaction is such that the ratio of acrylonitrile to methacrylonitrile remains relatively constant throughout the reaction. This results in a relatively homogeneous final polymer composition wherein there are no long sequences of AN units or long sequences of MAN units, but a somewhat random ordering of these units in the polymer chain. Relatively constant means a ratio of monomers which achieves this somewhat random ordering.
By practicing this process, processable and stable polymers of 10 to 80 percent by weight methacrylonitrile and 20 to 90 percent by weight acrylonitrile can be formed. Preferably, the polymer is 25 to 50 percent by weight MAN and 75 to 50 percent by weight AN.
DETAILED DESCRIPTION OF THE INVENTION
While the invention will be described in connection with a preferred procedure, it will be understood that it is not intended to limit the invention to that procedure. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the spirit and scope of the invention defined by the appended claims.
In accordance with the invention, a representative polymerization procedure, comprises contacting about 0.1% to 10% by weight of a suitable emulsifier or dispersing agent in an aqueous medium, about 0.01% to 5% by weight of a molecular weight modifier, about 0.01% to 5% by weight of an initiator, and monomers. The methacrylonitrile is 5 to 80 percent by weight of the monomers and the acrylonitrile is 95 to 20 percent by weight of the monomers. The mixture is placed in a purged reaction vessel which has a means of agitation, such as stirring or shaking. Preferably, the reaction vessel and reactants are initially purged with an inert gas, more preferably the gas used is nitrogen or argon. The mixture is heated to a temperature in the range of 40° C. to 80° C., preferably about 60° C. The mixture is continuously or intermittently agitated. Preferably, the mixture is continuously agitated. Preferably, a stirrer speed of about 200 rpm is used. The agitation is continued until polymerization has proceeded to the desired extent, usually 40%-100% conversion. Preferably, the polymerization continues to at least 60% to 80% of completion.
In the foregoing polymerization reaction, the molar ratios of AN and MAN reactants must be carefully controlled throughout the reaction, because the monomers react at different rates. MAN reacts faster with propagating free radicals in this system than does AN which leads to excess MAN in the polymer and excess AN in the unreacted monomer mixture. If too great an excess of AN becomes present in the monomer mixture, long strings of acrylonitrile units may form. Long AN strings lead to unprocessable products. For this reason, in the practice of the present invention, the polymerization reaction requires either incremental or continuous addition of the reactants.
In one embodiment, the monomer reactants are added in various increments, 10% of the total monomer reactants as starting materials to initiate the reaction, and three remaining 30% portions at later periods in the reaction. Each of the additions comprises AN/MAN in amounts controlled in order to obtain the desired AN/MAN ratio in the final product. This procedure continues until all of the monomer reactants have been added. Once the final reactant addition is made, polymerization is typically complete to at least 40% to 75%. Of course, other reactant addition increments may be used.
In another embodiment, it is possible to add most of the reactants at the initiation of the reaction. As the reaction proceeds, more of the highly reactive MAN monomer is added. This technique functions to steady the resultant polymer homogeneity by maintaining the same monomer ratio throughout the reaction through matching MAN addition to the conversion rate to polymer in the proper proportion.
In the most preferred embodiment, both reactants are added based on tracking of the polymer conversion in the same amounts as they are removed from the monomer mixture by polymerization.
As can be seen from the above embodiments, the primary objective of any procedure is to maintain the desired final AN/MAN ratio throughout the entire reaction. If the ratios become too unbalanced, MAN may polymerize into long strings and become used up from the monomer mixture, and the remaining AN may polymerize into long unprocessable strings. The identified procedures function to produce melt-processable AN/MAN copolymers with excellent physical properties, by preventing the formation of long AN strings.
The free radical initiator of the present invention may be selected from the group comprising Azo compounds, peroxides, hydroperoxides, alkyl peroxides, peroxydicarbonates, peroxyesters, dialkyl peroxides, persulfates, perphosphates or another initiator known to those skilled in the art. Of course, the reaction could also be initiated by thermal means rather than the above described chemical means.
The molecular weight modifier of the present invention can be mercaptans, alcohols or any other chain transfer agent known to those of ordinary skill in the art. Mercaptans are the preferred molecular weight modifier.
At the conclusion of the reaction, the polymer of this invention may be isolated as a finely divided powder by crumb coagulation.
The crumb coagulation procedure consists of adding the product emulsion to an appropriate electrolyte solution with rapid agitation at a temperature just below the point at which the precipitated particles tend to adhere. This procedure yields a polymer in a form of granules or particles which are filtered and washed. Suitable electrolytes include sodium chloride, sodium sulfate, hydrochloric acid, phosphoric acid, calcium chloride, magnesium sulfate and aluminum which is preferred. After precipitation, the polymer is filtered and washed repeatedly with water to minimize traces of electrolyte and dispersing agent which may adhere to the particles. Washing with dilute solutions of caustic soda or ammonium hydroxide may assist in removing the last traces of dispersing agent, and at the same time yield polymers of improved heat stability. It is also beneficial to employ a final wash of an organic solvent such as a lower aliphatic alcohol (methanol or ethanol) to remove any residual soap or impurities.
Other means for isolating the polymer include spraying the solution into a heated and/or evacuated chamber where the water vapors are removed and the polymer falls to the bottom of the chamber. If the polymer is prepared with sufficiently high solids content it can be isolated as a granular powder by filtration or centrifugation. The polymer may also be isolated by cooling eh dispersion below the freezing point of the aqueous medium or by the addition of a large volume of a lower aliphatic alcohol such as methanol or ethanol.
if desirable, lubricants, dyes, bleaching agents, plasticizers or pseudoplasticizers, pigments, stabilizers, antioxidants, reinforcing agents (including fillers and fibers) and antistatic agents may be incorporated into a polymer of this invention.
The polymers of this invention can be formed into films having extremely good barrier properties. Particularly, the oxygen transmission rate of films of this invention are generally below 0.30 (cc mil/100 in 2 atm--24 hr.). Preferably, the oxygen transmission rate is below 0.10 (cc mil/100 in 2 atm--24 hr.). Most preferably the oxygen transmission rate is below 0.05 (cc mil/100 in 2 atm--24 hr.). The water vapor transmission rate is generally below 3.25 (g--mil/100 in 2 --24 hr.). Preferably, the water vapor transmission rate is below 2.00 (g--mil/100 in 2 --24 hr.). Most preferably, the water vapor transmission rate is below 1.00 (g--mil/100 in 2 --24 hr.).
The films of this invention may be prepared by solvent casting or preferably by a thermal forming procedure such an extrusion, injection molding, compression molding or calendering, however, for economic reasons and for ease in processing it is most preferred that the polymer be extruded. The polymers of this invention may be extruded for any conventional type extruder at a temperature of about 160° C. to 250° C. Preferably, the extrusion is at about 200° C. to 220° C. A screw-type extruder employing an annular die to form a thin walled polymer cylinder or sheet die to form a continuous sheet may be used.
The polymers of this invention are also suitable for forming fibers. This can be accomplished by solution spinning by procedures known to those skilled in the art.
Because the copolymer AN/MAN is thermoplastic, it can be oriented as a solvent-free material. This is an advantage because the presence of any solvent int he polymer makes orientation difficult and adversely affects the barrier properties of the polymer.
EXAMPLES
Copolymers of methacrylonitrile/acrylonitrile were prepared by means of emulsion polymerization according to the following general procedure.
A two liter reactor containing 900 g of deionized water was used. 9 g of GAFAC RE-610 1 was dissolved int he water overnight. Acrylonitrile and methacrylonitrile totaling 300 g (the specific ratio dependent on the final product desired) were added. An initiator (generically 2,2'-azobis (2,4-dimethylvaleronitrile), specifically Vazo® 52 polymerization initiator made by DuPont Company) and N-dodecyl mercaptan were added to the reactants. The reactants and reactor were nitrogen purged. The reaction temperature was 60° C. with a stirrer speed of 200 rpm. At the end of the reaction time, (40-80% conversion of monomers to polymers) the products were isolated by crumb-coagulation in an aluminum sulfate solution at 77° C., water washed, methanol soaked, filtered, and fluid bed dried. The oxygen transmission rate and water vapor transmission rate results of films having different AN:MAN ratios can be seen in Table 1.
EXAMPLE 1
211.0 grams of acrylonitrile and 89.0 grams of methacrylonitrile were added as follows: 10% of the monomers were charged to the reactor before addition of the initiator; 30% of the monomers were added in each of three 90 minute periods; 6 g of N-dodecyl mercaptan were added in three 2 g installments, just prior to each of the three 90 minutes monomer addition periods. 1.5 g of Vazo® 52 polymerization initiator were added to the reactor when the reaction mass reached 60° C. The monomers resulted in a polymer composition of 72.4 mole percent acrylonitrile and 27.6 mole percent methacrylonitrile.
EXAMPLE 2
231.4 grams of AN and 68.6 grams of MAN were added at the beginning of the reaction. Additional MAN (13.6 grams) was added in each of three 90 minute stages of the reaction to compensate for its higher conversion rate and maintain the initial monomer feed ratio in the reactor. 6 g of N-dodecyl mercaptan were added in three 2 g installments, just prior to each of the three 90 minute monomer addition periods. 1.5 g of Vazo® 52 polymerization initiator were added to the reactor when the reaction mass reached 60° C. The reaction resulted in a polymer composition of 65.1 mole percent AN and 34.9 mole percent MAN.
EXAMPLE 3
183.9 grams of AN and 116.1 grams of MAN were charged to the reactor at the beginning of the reaction. Additional MAN (16.4 grams) was added in each of three 90 minute states of the reaction to compensate for its higher conversion rate and maintain the initial monomer feed ratio in the reactor. 6 g of N-dodecyl mercaptan were added in three 2 g installments, just prior to each of the three 90 minute monomer addition periods. 1.5 g of Vazo® 52 polymerization initiator were added to the reactor when the reaction mass reached 60° C. The reaction resulted in a polymer composition of 50.7 mole percent AN and 49.3 mole percent MAN.
EXAMPLE 4
126.6 grams of AN and 173.4 grams of MAN were added as follows: 10% of the monomers were charged to the reactor before addition of the initiator; 30% of the monomers were added in each of three 90 minute periods; 6 g of N-dodecyl mercaptan were added in three 2 g installments, just prior to each of the three 90 minute monomer addition periods. 1.5 g of Vazo® 52 polymerization initiator were added to the reactor when the reaction mass reached 60° C. The polymer composition consisted of 38.7 mole percent AN and 61.3 mole percent MAN.
PMAN
300 grams of MAN were added as follows: 10% of the monomer was charged to the reactor before addition of the initiator; 30% of the monomer was added in each of three 90 minute periods; 6 g of N-dodecyl mercaptan were added in three 2 g installments, just prior to each of the three 90 minute monomer addition periods. 1.5 g of Vazo® 52 polymerization initiator were added to the reactor when the reaction mass reached 60° C. The polymer was 100% MAN.
TABLE 1______________________________________ AN/MAN Oxygen Transmis- Water Vapor Trans- Ratio sion Rate (cc mil/ mission Rate (g-mil/Example (Mole %) 100 in.sup.2 atm-24 hr) 100 in.sup.2 - 24 hr)______________________________________1 72.4/27.6 0.03 0.622 65.1/34.9 0.03 1.743 50.7/49.3 0.05 2.274 38.7/61.3 0.28 3.18PMAN 0/100 0.33 2.52______________________________________
Each of the examples showed a good melt processability. Particularly, Brabendering at 235° C. showed torques of 400 to 2000 metergrams.
Thus is apparent that there has been provided, in accordance with the invention, new and improved copolymer compositions that fully satisfy the objects, aims and advantages set forth above. While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modification, and variations will be apparent to those skilled int he art in light of the foregoing description. Accordingly, the invention is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims.
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A process for forming a stable and processable polymer comprised of methacrylonitrile (10 to 80 percent) and acrylonitrile (20 to 90 percent) by controlling the ratio of the monomers in the reaction mixture.
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CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 08/305,184, filed Sep. 13, 1994 (abandoned), which is a continuation-in-part of application Ser. No. 8/108,067, filed Aug. 17, 1993 (abandoned).
BACKGROUND OF THE INVENTION
The present invention relates generally to mechanical presses or to any press with a sealed drive piston, and in particular, to an oil mist eliminator in an oil control system which prevents lubricating oil from leaking onto and contaminating the product stamped by the press die.
Mechanical presses, for example, straight side and gap frame stamping and drawing presses, comprise a frame having a crown and bed and a slide supported within the frame for motion toward and away from the bed. Between the slide and bed is located the press die within which a product is stamped or drawn. The slide is driven by a crankshaft having a connecting arm connected to the slide. Such mechanical presses are widely used for stamping and drawing operations and vary substantially in size and available tonnage depending upon the intended use.
In most cases, lubricating oil within the press drive, through gravity and open areas in the press crown, moves down onto the slide and ultimately migrates toward the press die. This oil can find its way to the product being worked upon in the press. If the workpiece becomes contaminated with oil, it may be rejected and scrapped, thereby increasing production costs. This is an important issue in industries dealing with food and beverage containers.
Certain prior art presses have been designed with pistons which protrude from the bottom of the crown. The slide is attached to these pistons which are in turn connected to the press drive for reciprocation. Seals installed about these pistons seal the oil within the crown and keep it from contaminating the workpieces. This oil control means is passive, and works only while the seal maintains its integrity. Seal damage due to installation, contamination, corrosion, or seal compression either occur rapidly or eventually, degrading the seals' ability to retain oil within the crown. Eventually, an oil leak occurs that allows oil to reach the stamped workpieces, thus ruining the product and increasing production costs.
Other prior art oil control systems utilize a filter upstream of the pump suction port. A disadvantage of this arrangement is that since the filter is on the vacuum side of the pump, the filter cannot be drained while the pump is in operation. The oil control system must be shut off to discharge the pump because ambient air simply runs up the filter drain, if any, and prevents the oil from draining out of the filter.
SUMMARY OF THE INVENTION
The present invention overcomes the disadvantages inherent in prior art oil control systems by providing an oil mist eliminator filter downstream of the jet pump exhaust flow.
The oil control system used for a machine press provides a seal about the drive piston of the slide to prevent migration of lubrication oil from the press crown to the slide or to the product worked on by the press. The oil control system operates to vacuum oil, that has leaked past the drive piston seal, away from the drive piston to an oil sump or reservoir.
In one form of the oil control system, a vacuum housing having an annular drain port is attached below the oil seal. This drain port is placed under vacuum to pull any oil leaking from the seal, and a certain amount of ambient air, away from the drive piston. A vacuum generator, comprising an air driven ejector or jet pump, creates the oil displacing vacuum within the drain port. By varying the input air to the ejector, the amount of vacuum created in the drain port is controlled.
An oil mist eliminator filter is used to control vapor emissions from the ejector. The oil mist eliminator filters have not been marketed to press manufacturers. An oil mist eliminator filter operates on the same principle as a high line pressure coalescing filter commonly utilized on fluid power devices but the oil mist eliminator filter operates at a much lower back pressure, normally less than 2 psi. A typical high line pressure coalescing filter will not allow an oil control system to function due to the high input pressure required at the coalescing filter and the low output pressure of the jet pump.
The oil mist eliminator filter includes a drain port which allows coalesced oil to return to the press sump. The oil mist eliminator filter element separates the oil from the air exhaust allowing the air to escape directly to the ambient atmosphere.
An advantage of the oil mist eliminator of the present invention is that the unit is downstream of the jet pump so that the press reservoir is not required to be pressurized thus eliminating a cause of oil leaks at the reservoir. The oil mist eliminator filter operates under a slight positive pressure (from the jet pump exhaust) which promotes filtration and drainage from the filter.
A further advantage of the oil mist eliminator of the present invention is that the oil is constantly coalesced and drained off while the oil control system is in operation thus eliminating the need to stop or shut off the oil control system in order to drain the filter. The oil is reclaimed and routed to the press oil reservoir eliminating the need to replace lost oil.
A still further advantage of the oil mist eliminator of the present invention is that up to 99.97% of the oil particles of 0.3 microns and larger are extracted from the oil laden jet pump exhaust by the oil mist eliminator filter thus eliminating leaks and drips from oil laden air collecting at the press reservoir vents or the oil mist eliminator filter exhaust port.
Another advantage of the oil control system of the present invention is that control of leaked oil is accomplished as long as there is a supply of air. Control and capture of oil no longer depends on the total integrity of the seal.
Yet another advantage of the oil control system of the present invention is that removal of oil from the piston is performed after the seal has used it. The oil removal function of the present invention does not increase the friction and heat on the piston, thereby assuring stable parallelism of the slide to the bolster.
Another advantage of the oil control system of the present invention is that control of leaked oil does not depend on the design of the seal. Various seals and geometries of presses may be utilized with the invention.
A further advantage of the oil control system of the present invention is that the amount of air flow transporting the leaked oil can be adjusted depending on the oil leakage rate.
Yet another advantage of the oil control system of the present invention is that oil or cleaning fluid can be evacuated from the seal area to clean the seal housing before service personnel open the press for repair.
The invention, in one form thereof, provides a press having a frame structure with a crown and a bed. A slide, having a drive piston, is guided by the frame structure for reciprocating movement in opposed relationship to the press bed. A drive mechanism is attached to the frame structure to reciprocate the slide. Oil is used to lubricate the moving parts and may collect into an oil sump. A seal is located about the drive piston to prevent oil from a portion above the slide, such as the drive piston, from migrating to the slide or workpiece. An oil control mechanism is arranged about the seal, the mechanism having a vacuum induced air flow to vacuum oil leaking from the seal away from the drive piston, the oil entrained within the air flow. The oil laden air flow passes through an oil mist filter to coalesce the entrained oil to substantially eliminate oil from the air flow.
BRIEF DESCRIPTION OF THE DRAWINGS
The above-mentioned and other features and advantages of this invention, and the manner of attaining them, will become more apparent and the invention will be better understood by reference to the following description of an embodiment of the invention taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is a front elevational view of a mechanical press incorporating the vacuum-induced oil control device of the present invention;
FIG. 2 is a sectional view of the oil seal and drain housing of the mechanical press;
FIG. 3 is a sectional view of the oil mist eliminator filter;
FIG. 4 is a pneumatic and vacuum schematic of one form of the system.
Corresponding reference characters indicate corresponding parts throughout the several views. The exemplification set out herein illustrates one preferred embodiment of the invention, in one form, and such exemplification is not to be construed as limiting the scope of the invention in any manner.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, mechanical press 10 comprises a crown portion 12, a bed portion 14 having a bolster assembly 16 connected thereto and uprights 18 connecting crown portion 12 with bed portion 14. Uprights 18 are connected to or integral with the underside of crown 12 and the upper side of bed 14. Tie rods (not shown) extend through crown 12, uprights 18 and bed portion 14 and are attached at each end with tie rod nuts. Leg members 24 are formed as an extension of bed 14 and are generally mounted on the shop floor 26 by means of shock absorbing pads 28.
A slide 30 is disposed between press uprights 18 as shown in FIG. 1. Slide 30 reciprocates within press 10 by the action of main drive motor 32 attached to the top portion of crown 12. Connected to main drive motor 32 by means of a belt (not shown) is a hydraulic combination clutch/brake (not shown) as known in the art for controlling the applied torque from motor 32 to slide 30. The hydraulic combination clutch/brake is attached to slide 30 by means of a crankshaft 38 connected to a connecting rod 36 attached to drive piston 34.
The word "piston" utilized in this application identifies generally any member that slides or reciprocates within another. Specifically, the term "drive piston" relates to the portions of slide 30 that are parallel with slide movement and attached to connecting rod 36.
In the prior art, a seal member has been utilized to seal about the drive piston to retain or divert low pressurized lubricating oil possibly flowing from the press crown. As shown in FIG. 2, drive piston 34 is disposed for reciprocation within piston housing 42. Piston housing 42 is normally attached to crown 12. Located between piston housing 42 and drive piston 34 is a guide bushing 43 to maintain adequate clearance between drive piston 34 and piston housing 42, with a seal 40 sealing between drive piston 34 and a piston seal housing 44. Seal 40 is seated in a seal groove 37. A plurality of secondary seals 45 are interfit between metal-to-metal interfaces of press 10 as shown in FIG. 2.
The present invention, in one form thereof, comprises an oil control system 39 generating a vacuum about drive piston 34 near seal 40 to capture any oil that passes past seal 40. As shown in FIG. 2, an additional piston vacuum housing 46 is attached to piston seal housing 44 by screws 48. An annular drain port 47 is located in bore 52 of piston vacuum housing 46 about drive piston 34. It is this drain port 47 that initially catches leaking oil by virtue of a vacuum created therein.
Located within piston vacuum housing 46 is a conduit 50 that attaches between drain port 47 and the vacuum producing mechanism to be described below. As shown in FIG. 2, bore 52 through which drive piston 42 reciprocates, may include a chamfer 54 to ensure an adequate flow of ambient air is available so oil, leaking past seal 40, will be more easily vacuumed into conduit 50 and the rest of the system.
Bore 52, between drain port 47 and the bottom edge of piston vacuum housing 46 or chamfer 54, is particularly sized to create the correct conditions for vacuuming leaking oil away from seal 40 and drive piston 34. At this location, bore 52 has approximately an 0.008" to 0.012" diametral clearance about drive piston 34. The preferred diametral clearance of approximately 0.010" has been found to create the most uniform vacuum induced air flow around piston 34 and upward toward drain port 47. The oil control system, as designed, operates effectively at one (1) inch or more of mercury vacuum level.
Between seal groove 37 and drain port 47 is a plurality of vent ports 51 permitting fluid communication therebetween. Vent port 51 operates to help seal 40 seat in seal groove 37 by allowing air trapped in groove 37 to escape. The vacuum created in drain port 47 also reduces the pressure within groove 37, thereby pulling the heel of seal 40 closer to the bottom of groove 37. Oil may also be pulled through vent port 51 to improve seal stability and seating. During a seal leak, leaking oil will be vacuumed into drain port 47.
Oil and air vacuumed into conduit 50 proceeds to the vacuum generator 60 and press oil reservoir 56 as shown in FIG. 4. The vacuum-induced air flowing through conduit 50 can be generated by any device as is known in the art, but in the particular embodiment shown in FIG. 4, it has been found to be most reliably and efficiently generated by a device known as an ejector or jet pump 60.
Ejector 60 utilizes compressed air, from a source 62 (FIG. 4), flowing through a compressed air inlet 64 into a passageway 66, having the general configuration and shape of a nozzle, to create a venturi effect. Ejector 60 further includes an inlet 68 that connects to a conduit 50 associated with a particular drive piston 34. Preferably, two conduits 50 are connected to each drain port 47.
Compressed air at a low pressure of approximately 1 to 60 pounds per square inch is introduced through inlet 64 of ejector 60. The venturi design of ejector 60 creates a vacuum pressure area within side inlet 68. This vacuum draws air and oil from drain port 47 through conduit 50 and into ejector 60. The combined flow of oil and air (an oil aerosol), from air inlet 68 exits ejector 60 through exit tube 72 at a pressure lower than at inlet 68, but higher than atmospheric pressure. As shown in FIG. 4 two ejectors 60 empty into a common exit tube 72.
Air and oil, exiting exit tube 72 flow into the bottom of an oil mist eliminator filter 110 of the present invention. Filter 110 comprises a housing 112 in which is disposed an annular filter element 114 to separate the oil from the air. An oil reservoir 56 is connected to filter drain tube 116 by an oil conduit 75 (FIG. 4) to drain collected oil from filter 110. After the oil has been substantially removed from the oil aerosol by the oil mist eliminator filter element 114, the remaining air is expelled as exhaust air out of an air outlet port 118.
As more clearly shown in FIG. 3, oil mist eliminator filter 110 includes an annular oil filter element 114 disposed within housing 112. Housing 112 includes a centrally located support bracket 120 which is constructed so as to allow passage of the oil aerosol. A removable circular lid 124 is attached by means of a wingnut 126 to support bracket 120 to contain filter element 114 within housing 112. An O ring 128 is disposed between the lid 124 and housing 112 to form a seal there between. Filter element 114 may be constructed from fiberglass or activated charcoal pads to filter the air/oil exhaust. The oil mist eliminator filter 110 is commercially available from Solberg Manufacturing, Inc. of Itasca, Ill. having a Serial No. PCSL-FG848-150HC with a replaceable filter element FG848. When lid 124 is open via unscrewing wingnut 126 insignificant amounts of oil will be lost out of 112 since the entire amount of oil within housing 112 drains away through drain tube 116 as soon as it is collected. The preferred oil mist eliminator filter 110 further enables use of a low back pressure pump such as jet injector 60.
FIG. 4 shows a schematic diagram of the present system utilized by two drive pistons 34. To most reliably and efficiently operate this invention, one ejector 60 vacuum generating device must be connected to each drive piston 34 of press 10 to ensure that oil is drawn off when an oil leak occurs. By utilizing one ejector 60 per drive piston 34, the system can be constructed so that air flow will not be diverted to a point of less resistance, such as a drain housing, if a seal 40 does not leak. This maintains the correct flow of air within the system.
By drawing off oil at several points on drain port 47, an oil leak is kept under control for all rates of possible leakage.
The air flow from source 62 utilized by vacuum ejector 60 is preferably kept on at all times, even while the press 10 is not running, so as to constantly evacuate any lubricating oil leaking from about seal 40.
As shown in the schematic drawing of FIG. 4, compressed air source 62 is attached to a valve 82 to shut off the air flow from source 62 entering oil control system 39. From valve 82, an air hose 84 connects to an air filter 86 and from there another air hose 88 is connected to pressure regulators 90 (FIG. 4). Pressure regulator 90 is of a known type, to permit the operator to vary the air pressure through the oil control system. The press operator is allowed to monitor the compressed air pressure by an optional air pressure gauge 92 connected in line with pressure regulator 90 by means of an air hose 94. Through air hose 94, compressed air flows to air hose 96 and on into air inlet 64 of ejector 60.
As shown in FIG. 4, air hose 88 may attach to a branch portion 98 that can communicate compressed air to other ejectors 60.
In operation, the oil control system 39, in one form thereof, operates as follows. During press 10 operation, power from motor 32 will be conducted to crankshaft 38 shown schematically in FIG. 4. Rotation of crankshaft 38 will cause connecting rod 36 to change rotational motion of crankshaft 38 to rectilinear reciprocating motion of drive piston 34. Seal 40 seals between reciprocating drive piston 34 and housings 44 and 46.
Any oil escaping down past seal 40 along drive piston 34 will be caught in annular drain port 47 connected to conduit 50. Compressed air from air source 62, passing through valve 82, filter 86 and regulator 90, will be injected into ejector 60. Through a venturi effect created in ejector 60, a low pressure area will be developed in conduit 50 connected to ejector 60 through air inlets 68. A combination of air and oil drawn through conduit 50 is now caused to flow through exit tube 72.
The oil, entrained within the air in exit tube 72, will drop out upon contact with the filter element 114. The air, now substantially free from entrained oil, is allowed to pass through air exhaust tube 118, back to the ambient atmosphere.
As shown in FIG. 4, an optional vacuum gauge 100 may be placed in communication with conduit 50 to measure the vacuum developed by ejector 60.
The amount of air flow transporting the oil can be adjusted for various leakage rates of seals 40 by opening and closing regulator 90. Further, oil control is accomplished as long as there is a supply of compressed air. Oil control of the present invention does not depend on 100% integrity of the seal or the intervention of the press operator.
Further due to particular products operated on by press 10, it may be necessary to install air filters within chamfer 54 or within conduits 50 to prevent contamination from the die or slide 30 to be drawn into press oil reservoir 56.
The present invention, as shown in the previous embodiment, is not limited to oil control mechanisms located within the crown of a press. Depending upon the size of press 10, the required tonnage and different operating mechanisms, different locations for oil control system 39 are possible.
While this invention has been described as having a preferred design, the present invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.
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An oil mist eliminator filter used with a dynamic oil control mechanism consisting of a vacuum-inducing jet-pump to vacuum oil leaking from about an oil seal, an oil seal located around the drive piston on the press slide, a drain port located about the housing in which the drive piston reciprocates. The oil mist eliminator filter, downstream of the jet pump, separates the oil from the air with 99.97% efficiency allowing the cleaned air to escape freely to atmosphere without causing pressurization of the press reservoir and leaks at the press reservoir, and allowing the oil to constantly recirculate back to the press reservoir thus permitting use of the oil control system without the need to shut the oil control system off to drain accumulated leakage oil.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable
FEDERALLY SPONSORED RESEARCH
Not Applicable
SEQUENCE LISTING OR PROGRAM
Not Applicable
BACKGROUND OF THE INVENTION
FIELD OF INVENTION
This invention relates to biomedical implants and, more importantly, to a system for monitoring the strength of a healing, bone, joint, or ligament union while an orthopedic fixation device such as a plate, pin, or screw is in place.
BACKGROUND OF THE INVENTION
Bone fractures heal in progressive, complex, sequential steps at the cellular level. The healing process produces osteoid, the precursor of new bone, which eventually undergoes calcification and new bone formation. As healing progresses, the strength of the healing area increases. This same process occurs when physicians operatively stabilize a bone fracture by implanting a bone fixation device such as a plate, pin, or screw. Physicians use similar bone fixation devices after resecting diseased bone and tissue. Another option is to substitute a portion of cadaver bone for the resected bone using an implanted bone fixation device to stabilize the bone junction until healing occurs.
Bone healing takes months for completion, depending on many variables, some of which are unknown and uncontrollable. During the healing process, the repaired area is subject to injury by excessive load applied to the area; yet, studies show that some load to the area promotes healing. Currently, physicians most often monitor bone healing by observing the increase in tissue density and calcification in a series of x-rays. X-rays are subjectively interpreted, frequently inconclusive, and tell little about the strength of the healing repair. Similar limitations apply to special imaging studies such as dual energy x-ray absorptiometry and peripheral quantitative computed tomography. Therefore, physicians must depend on clinical judgment and personal experience when advising patients on safe levels of activity, including movement and weight bearing, involving the repaired site.
Physicians need an objective measure of the degree of healing and strength of the union stabilized by the bone fixation device. Only then may physicians confidently advise patients on what level of effort by the patient the repair can safely bear. Equally important, physicians will avoid needlessly restricting patient activity because the safe level of activity is unknown, hoping to avoid injury to the repaired area. Detailed information on strength of healing not now available would significantly improve patient care and quality of life. Improvements in the cost of medical care would be significant but are beyond the scope of this patent application.
Several methods to measure bone strain received U.S. patents. The device of Yen, et al. described in U.S. Pat. No. 5,456,724 (1995) appears useful during surgery to install bone grafts but is not implantable for strain measurements during healing. The device of Orsak, et al. described in U.S. Pat. No. 5,695,496 (1997) measures light transmission through an optical fiber attached to an external bone fixation apparatus. This method is not applicable to commonly used implanted bone fixation procedures.
The system of Elvin, et al. described in U.S. Pat. No. 6,034,296 (2000) utilizes an implantable bone strain sensing system mounted on or in the bone fixation hardware. Some components must be hermetically sealed and mounted by adhesives to the bone fixation device. Eliminating the need for adhesives and seals and making the sensor system an integral part of the bone fixation device would improve reliability of operation. Vigorous manipulation sometimes necessary during surgical installation of the bone fixation device subjects all parts mounted on the bone fixation hardware to risk of damage during surgery. Also the added mass of foreign material introduced in the body comprising the mounted sensing system adds to the risk of complications during surgery and later recovery. Variations in the physical properties, such as density, of the attached materials comprising the sensing system compared to the properties of the bone fixation device increase the risk of implant failure. An ideal sensing system would be an integral part of the bone fixation device with no measurable increase in mass of foreign materials introduced into the body or variation in physical properties from the fixation device.
Morgan, et al. in U.S. Pat. App. No. 20060052782 described a monitoring system employing one or more sensors and microchips attached to a bone-fixation device. These attachments are subject to failure of adhesion to the fixation device, failure of seals protecting the components, and the danger of damage during surgical installation of the fixation device. Pressure and strain measurements from the discreet focus of the sensing site may not apply to the implant as a unit. Focal changes such as swelling or shrinkage of tissue during normal healing may confound readings intended to reflect forces on the entire fixation device. Sensor readings depend on radio frequency transmission, which is subject to interference and distortion in many environments. The ideal monitoring system would provide direct readings of strain on the fixation device as a single, bone-stabilizing unit with a sensing system integral to the fixation device.
The physical properties and electrical conduction characteristics of carbon nanotubes make them well suited to provide the basis for measuring the strength of healing of bone repairs. Since carbon nanotubes are molecular structures, they do not add any significant foreign mass to a bone fixation device. Carbon nanotubes may even add strength to a bone fixation device.
The diameter of a nanotube is on the order of a few nanometers (approximately 50,000 times smaller than the width of a human hair), while they can be up to several millimeters in length thus exhibiting a very high aspect ratio, referring to the ratio of length to width. The tubes occur naturally in random orientations and can be imbedded in or on various materials. Changes in tube length and/or orientation by even a micron or less alter the effective electrical resistance of the nanotube network. This alteration in electrical resistance is measured by current flow and indicates the stress and strain on the implant. Stress is the application of force per unit area on the implant; strain is the ratio of extension in length when loaded, to the original length of the implant.
BACKGROUND OF THE INVENTION
Objects and Advantages
Accordingly, the objects and advantages of the present invention are:
(a) to provide a method of obtaining objective data to indicate the magnitude of load a surgically repaired part can bear; (b) to provide a healing indicator system that generates real-time data while a load is applied to the site of repair; (c) to provide a healing indicator system that will allow physician and patient to determine maximum, safe load for the site of repair; (d) to provide a healing indicator system without any significant additional foreign material inserted into the patient; (e) to provide a healing indicator system that is an integral component of the bone fixation device without requiring special adhesives or seals; and (f) to provide a healing indicator system that is not subject to damage during surgical installation.
Further objects and advantages will be apparent after considering the ensuing description and drawings.
SUMMARY
The present invention comprises a method to measure the strength of healing bone, joint, or ligament repairs when an orthopedic fixation device is used to stabilize the defective area.
DRAWINGS—FIGURES
FIG. 1 depicts a bone repair stabilized by an implanted bone fixation plate.
FIG. 2 depicts an extremity with a bone repair stabilized by an implanted bone fixation plate.
FIG. 3 depicts the testing cuff and connections.
FIG. 4 depicts the testing cuff externally encircling an extremity with a bone repair stabilized by an implanted bone fixation plate.
DRAWINGS -- REFERENCE NUMERALS
10
Proximal healthy bone segment
11
Distal bone segment
12
Healing area between bone segments
13
Skin surface
14
Bone fixation plate
15
Attachment screw
16
Testing cuff
16a
Active coil
16b
Passive coil
16c
Power source connector
16d
Analyzer connector
17
Electric current source
18
Analyzer
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 illustrates, in longitudinal cross-section, implanted bone fixation plate 14 bridging a defect between proximal healthy bone segment 10 and distal bone segment 11 . The unique property of bone fixation plate 14 is a component of carbon nanotubes.
FIG. 2 depicts the bone repair of FIG. 1 located within the body, as in an extremity covered by skin surface 13 .
FIG. 3 illustrates testing cuff 16 comprising two sets of electric coils. Active coil 16 a and passive coil 16 b both encircle the area of bone fixation plate 14 similar to a blood pressure cuff. Power source 17 attaches to active coil 16 a via power source connector 16 c . Analyzer 18 attaches to passive coil 16 b via analyzer connector 16 d.
FIG. 4 illustrates testing cuff 16 surrounding an extremity with a repaired bone as used for measuring the strength of healing area between bone segments 12 .
Operation
Bone fixation plate 14 is implanted using a plurality of anchors such as attachment screw 15 , as usually performed by surgeons skilled in the art. The bone healing process begins promptly, as described above. When the physician wishes to monitor the strength of healing area between bone segments 12 , testing cuff 16 is placed around the extremity encompassing the site of healing area between bone segments 12 . Connections are made to power source 17 and to analyzer 18 . When power source 17 is activated, electric current pulses through active coil 16 a , causing an induced electric current to flow in bone fixation plate 14 . The induced electric current in bone fixation plate 14 produces a corresponding secondary induced current in passive coil 16 b . Analyzer 18 measures the secondary induced current.
A reading from analyzer 18 is made while patient is at rest. A series of additional readings is made with increasing loads placed on healing area between bone segments 12 . If loads increase to the point that analyzer 18 indicates strain on bone fixation plate 14 , testing ceases. Analyzer 18 detects strain on bone fixation plate 14 by indicating a decrease in the secondary induced current in passive coil 16 b compared to the resting state reading. This decrease in the secondary induced current results from the reduction in current flow through bone fixation plate 14 , a property of its carbon nanotube component in response to strain from the applied load. The indication of strain shows that healing has not occurred sufficient to bear the load applied. The physician will then advise patient to engage only in activities producing a lesser load on bone fixation plate 14 . Active patients would greatly appreciate knowing this limit. Additionally, the physician can encourage patient to engage in activities at a level that is safe as determined by the load applied prior to evidence of strain on bone fixation plate 14 .
As healing area between bone segments 12 becomes stronger, the greater the load it can bear without causing strain on bone fixation plate 14 . Bone healing may be considered complete when the maximum load supported by healing area between bone segments 12 is equal to the load that can be borne by the corresponding opposite side of the patient's body. Alternatively, healing may be considered complete when the maximum load not causing strain on bone fixation plate 14 approximates the load bearing capacity by similar, closely matched individuals. Such studies on normal individuals are commonly performed in medical research. At this point, physicians will know that the bone fixation device may be removed, if medically desirable.
Implanted bone fixation devices are subject to failure from breaking. This method will detect early evidence of loss of integrity of a bone fixation device. Any disruption of the carbon nanotube component of bone fixation plate 14 by even a partial break will cause an increase in electrical resistance at rest compared to past readings by analyzer 18 . Similarly a loosened attachment screw 15 , also having a component of carbon nanotubes, will cause an increase in electrical resistance to current flow in bone fixation plate 14 . Prompt medical intervention and surgical revision of the repair will prevent extensive injury from an unexpected break of bone fixation plate 14 .
Additional Embodiments
Bone fixation devices other than plates include rods, screws, nails, wires, clamps, prostheses, and others, any of which may incorporate carbon nanotubes or other high-aspect ratio, electrical conducting nano-particles, allow this method to measure the strength of healing.
Carbon nanotubes may be incorporated into resins such as polymethylmethacrylate described by Pienkowski, et al. in U.S. Pat. No. 6,872,403 (2005). Such resins may be used to stabilize repaired areas, allowing this invention to measure the strength of healing.
Some materials other than carbon form nanotubes that exhibit the electric current conduction properties in response to strain. These other materials may substitute for carbon and this invention will measure strength of healing.
The preferred embodiment emphasizes physicians and patients, but veterinary applications are obvious. Because test results are based on objective measurements of electric current changes through the bone fixation device, no response is required from the test subject.
Analyzer 18 may display the test result and sound an alarm when a load indicates strain on the bone fixation device. This will prevent injury from overloading the repaired area during testing.
Analyzer 18 may transmit test results to other external devices by direct or wireless communication permitting remote monitoring.
This method of measuring strength of healing may be used on patients not aware of pain due to treatment, medication, or illness. Pain sometimes provides a signal that a safe load limit has been reached or exceeded, but pain is unreliable for preventing further injury from overloading. Conversely, excessive fear of pain or fear of further injury may inhibit the patient from performing actions that are safe and beneficial to healing. This method for measuring strength of healing adds important information that will give confidence and encouragement to proper use of the repaired area during healing.
This method permits continuous monitoring for strain on bone fixation plate 14 by wearing testing cuff 16 while performing predetermined actions. An alarm on analyzer 18 can be made to sound when activity unexpectedly causes strain on the bone fixation device. Thus, advising patients on permissible activities and warning against excessively strenuous activities are based on objective, real-time test results.
This method is readily adaptable to external bone fixation devices. A carbon nanotube component incorporated in the rigid external bone fixation device permits testing for strain on the device with load bearing by direct contacts to an electric current source and to analyzer 18 .
Similarly, direct measurement of electric current changes caused by strain as described for this method may be performed when bone fixation devices are implanted in sites where a detection cuff is not usable or the bone fixation device is very short. Electric leads attached to the ends of the bone fixation device may be brought to skin surface 13 where direct contact can be made for appropriate studies as described above. To reduce infection risk contact leads may remain below the skin surface where electrical contact can be made using sterile needles during testing. This is similar to the principle of implanting vascular access devices beneath the skin to minimize infection risk for patients receiving chemotherapy or renal dialysis.
When bone, ligament, or joint repairs require use of bone adhesives, the adhesives may be compounded to include carbon nanotubes as described by Pienkowski, et al. in U.S. Pat. No. 6,872,403 (2005). This method can then measure the strength of healing bone, ligament, joint, and related tissues.
This invention will measure bone strength in areas at high risk for fracture, such as brittle bones, by using limited surgery to attach a carbon nanotube-containing rigid rod to the bone in order to measure the limit of load capacity. This will allow the patient to know the safe level of activity similar to repaired bone areas.
It is feasible to inject carbon nanotube containing materials to stabilize weak areas of bones and ligaments. The present invention can be used to measure safe loads for these treated areas.
SUMMARY
The present invention permits non-invasive measurement of strength of healing at the site of bone repair by using rigid materials incorporating carbon nanotubes to stabilize the repair. This device can, with some modification, provide a means to measure bone healing in any area of the body. The present method will assess healing of joints or ligaments that have been repaired by rigid materials similar to bone fractures or resections. This device is safe since only graduated loads on the repaired area are used, thus minimizing risk of injury during testing. This device provides objective information not available by any method to measure healing of bone and related structures. The measurements by this device are important to patients who require guidance on limiting activities that may cause injury, as well as encouragement to engage in safe activities with confidence that injury will not occur. Thus, debilitating muscle atrophy from prolonged disuse during healing can be minimized. This invention provides real-time display of results on a continuous or episodic basis using appropriate alarm warnings when injurious loads are approached.
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A method of measuring healing strength of bone includes a bone fixation plate ( 14 ) implanted at the healing area between bone segments ( 12 ). The bone fixation plate ( 14 ) includes high aspect ratio material with electric current conduction properties responsive to strain. This method causes an induced, or directly applied, electric current to pass through the high aspect ratio material. Analysis of the change in this current by a series of increasing loads placed on the healing body part indicates what level of load produces strain on the bone fixation plate ( 14 ). As healing strength increases, evidence of strain on the bone fixation plate ( 14 ) occurs at a greater load. Physicians determine thereby the strength of bone healing and safe levels of activity for patients while bone healing progresses.
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This is a division of application Ser. No. 09/477,238, filed Jan. 4, 2000, now U.S. Pat. No. 6,135,165.
BACKGROUND
This invention relates to a method and a system to allow for the preparation of a pressurized water borne paint formulation at the point of retail sale to the ultimate end user.
One of the most significant developments in the field of paints and other protective coatings in the last thirty years has been the rapid growth and widespread acceptance of water-based paints. Since they were first introduced in the later forties as an interior wall finish composed of a water-based styrene-butadiene latex, there has been a great increase in the sale of these paints. The paints are practically odorless during their application and dry rapidly.
Latex wall paints produce a low sheen or gloss finish which has good washability within a short period after application. In cases of scratches, mars or dirt pick-up during this period, it is only necessary to touch up the wall with the original paint. In some cases, however, this has become impracticable because the necessity to save some of the original paint or it becomes inconvenient and time consuming to prepare and clean up the equipment such as brushes and rollers. A convenient solution would be the availability of an aerosol can containing an exact match of the original paint. Unfortunately, however, prepackaged water based aerosols are unstable and have a short shelf life, making them impractical as a retail product. Our invention, as described below, solves this problem.
Since the introduction of the aerosol surface coatings, major steps have been taken to improve the formulation of these materials. Acceptable aerosol dispensed paints must have sufficient mechanical stability to withstand the mechanical shearing forces which aerosol water based paint compositions normally experience as they are dispensed from conventional aerosol containers. Insufficient stability results in mechanical shearing of polymeric components of the composition. Agglomerated bits of the composition can clog the narrow orifices of the aerosol valve outlet and interfere with the even disbursement of paint. Agglomerated bits can also break away for the orifice and be delivered onto the surface of the substrate being painted, thereby marring the paint film thereon.
Mechanical stability of paint formulations is depended in a large measure upon maintaining a solution of the polymer in the aerosolized formulation. Proper mechanical stability and low viscosity have been achieved in solvent based systems employing hydrocarbons, alcohols and other solvents. The volatility of the solvent causes rapid thickening of the paint as the aerosolized composition is dispensed and applied to a substrate. The rapid thickening of the aerosol paint during and after it is dispensed is essential to commercial solvent based paint formulations which must be capable of adhering to vertical surfaces without running. That property of a paint composition is referred to herein as vertical cling.
Although organic solvent based aerosol systems have been developed which have good mechanical stability and vertical cling properties, the solvents employed in such systems (e.g., hydrocarbons or alcohols) are flammable, toxic and environmentally undesirable. Thus, it was deemed desirable to develop a water based paint composition which would possess the degree of mechanical stability necessary for it to be dispensed with a minimum of breakup from a conventional aerosol valve, while at the same time possessing a high degree of vertical cling when the composition is sprayed onto a vertical substrate.
In light of the environmental hazards associated with aerosol propellants such as the fluorocarbon propellants, it is also important to employ a propellant which is environmentally friendly, and possesses a low degree of flammability when used as a propellant for water based concentrate. One such propellant is dimethyl ether, which possesses very low flammability in aqueous systems.
Another problem with solvents in water based paint systems is that over time they begin to react adversely with the paint formulation destroying the desirable properties, such as vertical cling. Accordingly, it is an object of this invention to provide methods and a system whereby a stable aerosol water based paint product can be prepared at the point of retail sale to the person who will ultimately use the paint.
It is another object of this invention to provide an aerosol water based paint composition which employs an environmentally safe and acceptable propellant, while at the same time possessing the key attributes desired in an aerosol dispensed, water based paint, i.e., mechanical stability, the ability to provide a foam-free durable coherent film on the substrate to which the paint is applied, the ability of the composition to cling to vertical surfaces without running, as well as the ability to provide finished paint films having a wide range of gloss. In particular, it is an object of this invention to provide a convenient system whereby a consumer at the retail level can obtain an aerosol can of water borne paint composition that matches a previously purchased paint product.
Yet another object is to provide a system and a method of formulating an aerosol paint composition at the point of retail sale that is stable and ready for immediate use by a consumer. Because the final paint formulation is prepared at the point of retail sale, the contact of the propellant with the water borne paint formulation is significantly minimized, thus avoiding the deleterious degradation of the paint formulation. This results in a stable product with excellent performance characteristics.
Although aerosol water based paints are disclosed by the patent literature (see e.g., Page et al. U.S. Pat. Nos. 4,384,661, 4,265,797, 4,250,253, and 5,071,900; Suk U.S. Pat. Nos. 4,265,797 and 4,450,253; Brouillette et al. U.S. Pat. No. 4,518,734; and Rapaport et al. U.S. Pat. No. 4,482,662), these prior art formulations require that the paint compositions must be specifically formulated to allow them to be aerosolized. However, in our invention, unlike the dimethyl ether propelled compositions of the prior art, we provide a method and system for developing a pressurized can which is capable of accepting water based coatings which are not manufactured specifically to be aerosolized. One advantage of our invention is that it accepts nearly any latex paint without stability problems and prevents agglomeration and gloss loss. It also provides coatings that are environmentally safe, non-flammable and may be cleaned up easily with water.
SUMMARY
The present invention provides a method of preparing a aerosol container of water borne paint comprising of a pressurized container having a filling opening and containing a solvent mixture of a volatile propellant, such as dimethyl ether, stabilizers, water and an emulsion. After the selection of a waterborne formulation, for example to match a previously applied paint, it is injected into the pressurized container through the filling opening to form an aerosol container of water borne paint. The present invention provides a method of adding the water borne paint as a last step at the point of retail sale to a mixture of propellant, water, emulsion and stabilizers to allow for flexibility in choice of latex paint used, to ensure stability and to prevent agglomeration.
BRIEF DESCRIPTION OF THE DRAWING
The Invention may take form in various parts and arrangement of parts. The drawing is only for purposes of illustrating a preferred embodiment and is not to be construed as limiting the invention.
FIG. 1 shows a can filling machine and pressurized container according to our invention.
DETAILED DESCRIPTION
A critical aspect of this invention is the preparation of pressurized container containing paint additives that can be supplied to retail establishments whereby, as a last step, a water borne paint formulation is added immediately prior to the purchase by the user of the aerosolized paint. A necessary component of this invention is the inclusion of a propellant, one particularly preferred propellant is dimethyl ether which has been used in water based aerosol products such as hair sprays, perfumes, air fresheners, insecticides and spray polishes. Dimethyl ether (DME), which is water soluble, has also been successfully used in water based aerosol paints. It has been found useful, not only as a major portion of the propellant phase essential to efficient atomization of the aerosol paint for application purpose, but also because it provides excellent co-solvency with water. The use of dimethyl ether as a propellant/co-solvent overcomes the foaming problems encountered with other aerosol coating containing water. It also overcomes any need for aromatic hydrocarbons or halogenated hydrocarbons in the formulations.
DME is a commercially available liquefiable gas having a boiling point of −23° C. at one atmosphere, and is soluble in water to the extent of about 35% by weight at 24° C. at about 5 atmospheres of pressure. Although any commercially available DME can be used in the present invention, one commercial supplier of DME is DuPont®. Although DME is a preferred propellant, other propellants may be used alone or in addition to DME, for example, propane, carbon dioxide, and nitrous oxide.
In addition to the propellant ingredient, our invention requires the addition of several other components in order to obtain the ultimate desired coating. Preferably, a solution comprising water, an emulsion, and stabilizers are also introduced into the container preferably before the addition of the propellant. By adding the propellant last, the propellant can be used to pressurize the container. Alternatively, the solution of water, emulsion and stabilizers can be added in conjunction with the propellant to the-container and sealed and pressurized accordingly.
The emulsion agent, also referred to as a resin, applicable for this invention consist of those rendered water soluble by neutralization of acidic or basic sites thereon which render the emulsion dispersible in molecular or near molecular dimensions, resulting in a single liquid A phase. The emulsion agent used can be polyurethane, acrylics, epoxy, styrene, butadiene and any mixture thereof although this group is not limiting. Indeed, other resin examples include styrene acrylics, urethanes, polyesters, and silicone polymers. Water soluble emulsions are commercially available through several different suppliers. One example of a commercially available acrylic latex emulsion suitable for use herein is one obtained from S.C. Johnson Polymer, namely Joncryl 537. The addition of certain acrylic emulsions to the latex system serves to prevent gloss loss, to prevent agglomeration and to prevent stability problems with nearly any latex paint.
The stabilizers used in the invention are selected are from the group consisting of surfactants, plastizers, antifoam agents, alcohols, pH buffers and mixtures thereof. In particular fluoro surfactants are preferred, specifically FC120 manufactured by 3M. The stabilizers are necessary to insure that the water borne paint formulation, in particular the pH of the concentrate, will not have a corrosive effect on the container. Suitable pH buffers include ammonia, and amines such as triethanol amine. Other suitable stabilizers include AMNP-95.
Once the pressurized container of propellant, emulsion, water and stabilizers is prepared, the product is ready for sale at the retail level. Immediately prior to the sale the ultimate end user selects a water borne paint formulation to be added to added to the pressurized container. Typically, the paint formulation selected is to match an existing color or type of paint previously used. A water borne paint formulation is any water soluble paint composition, preferably latex based paints. Other water borne paint formulations include water reducible alkyls and water, based polyurethanes. After selection, the water borne paint composition is injected into the pressurized container through the filling opening in the container to form the aerosol container of water borne paint.
In order to match exist paint colors, a tint base can be added to non-pigmented formulations to form a tinted water borne paint formulation of choice. The choice of tint bases, colors that are used to match a particular paint swatch, depends upon the characteristics and color desired of the coating. Any pigment commonly used in paint compositions can be employed in the present invention. Examples of useful pigments include titanium dioxide, carbon black, phthalocyanimes, molybdates, perlenes, flavanthrones, quinacridones, iron oxide and other known paint tint bases.
Product enhancers, such as thickeners, corrosion inhibitors and flow modifiers, may be added to the composition without departing from the spirit of the disclosure for the scope of the appended claims. Total miscellaneous paint enhancers will generally constitute less than about 5% by weight of the total aerosol can content. These are preferably added during the preparation of the aerosolized container of paint additives prior to the addition of the water borne paint formulation. Thickeners are employed as an ingredient because of their marked increase in the viscosity of the composition which prevents the occurrence of undesirable “running” of the wet paint film when it is sprayed onto a slanted or vertical surface. A wide variety of acrylic emulsion thickening agents are commercially available. One example is Kings PUR 60. An example of a commercially available corrosion inhibitor is AMP-95 and example of a commercially available flow modifier is any fluorosurfactant.
Introduction of the water borne paint formulation into the pressurized can is accomplished using known means, preferably using a can filling machine. The can filling machine can be any apparatus that is known in the art such as a pneumatically controlled aerosol can filling machine disclosed in U.S. Pat. No. 4,938,260 (Hirz), the teachings of which are incorporated herein by reference. FIG. 1 illustrates one embodiment of the can filling machine 10 having placed therein for filling pressurized container 20 . The propellant and the solvent mixture can be placed in the container to be utilized as an aerosol spray paint before the cap is crimped thereon and the paint can be forced through a filling valve by a pneumatically operated can filling machine.
The method of this invention includes adding the water borne paint formulation last to avoid agglomeration of the paint particles as a result of prolonged exposure to the propellant. Agglomeration can occur because the propellant, being a solvent, softens most latex polymers, and it being present at very high concentration at the dip tube opening. For example, a mixture of dimethyl ether and water is added to a standard pressurized spray paint container along with certain acrylic emulsions and stabilizers. The water acts as a dilutent for the dimethyl ether, which prevents the resin agglomeration at the dip tube. The water borne paint composition is injected into the pressurized container at the point of retail sale, immediately prior to its ultimate use by a consumer. Because there is only a short period of time between the relatively final addition of the water borne paint formulation and end use of the pressurized paint composition, the deleterious side effects of the propellant do not manifest themselves.
It should be understood that the embodiments and examples disclosed herein are presented for illustrative purposes only and that many other combinations and articles that embody the methods, formulations and systems will be suggested to persons skilled in the art and, therefore, the invention is to be given its broadest interpretation within the terms of the following claims:
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A pressurized package of paint, additives is prepared by mixing water emulsion, stabilizers and a propellant in a pressurizable container. This pressurized container is then sold to retail stores where a water borne paint composition is injected into the pressurized container and sold directly to the end user.
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This application is a continuation-in-part of U.S. application Ser. No. 08/780,504 filed on Jan. 8, 1997, now U.S. Pat. No. 5,823,238.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a machine for clearing land, and more particularly to an environment friendly attachment mounted on an excavator which grinds trees, shrubs, concrete, tree stumps and roots, and to a method of grinding standing large trees.
2. Description of the Related Art
In the past, land has been cleared for many purposes by removing tree stumps and tree roots. Large tractors have been used to remove tree stumps and roots from the ground. After removal from the ground, tree stumps and roots have been piled for burning, or they have been hauled away for disposal. Disposal at a remote location has been by burial, or by burning.
Environmental concerns, government requirements and cost have made it necessary to find other methods for clearing land. One method for land clearing is to grind tree stumps and roots into a mulch and leave the mulch in the ground where the tree stumps and roots were originally. This procedure eliminates transportation costs and disposal costs. Leaving such shredded wood and fiber mulch on the ground improves soil fertility.
Tree stump grinders have been used to grind tree stumps following the removal of a tree from areas near buildings or other areas where it is desirable to minimize disturbance of the surface.
Known stump machines generally comminute the portion of a stump that is above the ground and the portions which are near the surface. These stump grinding machines though do not operate on standing trees, only on stumps on which the majority of the standing tree portion has been previously removed. They grind up sufficient material to allow soil to cover the remaining stump and for grass to be planted. Such stump grinders generally do not remove all of a stump or tree roots. Stump grinders designed to grind the portion of a stump that is close to the surface are relatively slow. Additionally, such grinding machines have been oriented for horizontal rotation, not vertical rotation.
SUMMARY OF THE INVENTION
The invention includes a frame movable from tree to tree, a drum and a drum support rotatably mounting the drum to the frame. The drum support rotates or swivels 360 degrees relative to the frame via a swivel motor. A hydraulic motor is attached to the drum support with a first drive pulley attached to the motor and a second drive pulley connected to the drum. A plurality of drive belts connects the first drive pulley to the second drive pulley so the hydraulic motor may rotate the drum.
The invention comprises, in one form thereof, a grinder for grinding items, such as trees, having a frame movable from location to location tree, a drum, and a drum support rotatably mounting the drum to the frame. The drum support is swivelably mounted to the frame. A drum motor is attached to the drum support while a first drive pulley is attached to the drum motor and a second drive pulley is connected to the drum. A plurality of drive belts drivingly connect the first drive pulley to the second drive pulley. In one particular embodiment, the drum support is swivelable 360 degrees.
An advantage of the present invention is that it is adaptable for grinding and shredding standing trees. The vertical orientation of the rotating drum permits the grinder to control the placement and ejection of shredded material. Further, the vertical orientation of the rotating drum and anchor assembly permit more options on grinding of trees independent of the workplace angle or grade. The system is able to collapse a tree and grind it while preventing the tree from falling on the operator.
A further advantage of the present invention is that the entire grinding system is balanced both statically and dynamically. By the use of V-belts as a drive member, in case of wear or need of replacement, no rebalancing of the system is necessary.
Yet another advantage of the present invention is that it may utilize a number of different type cutting or grinding bits depending on the material to be ground. Diamond tipped bits, flail bits attached by a pivoting connection, knife edge bits, and others may be utilized by attachment to the rotatable drum.
BRIEF DESCRIPTION OF THE DRAWINGS
The above-mentioned and other features and advantages of this invention, and the manner of attaining them, will become more apparent and the invention will be better understood by reference to the following description of an embodiment of the invention taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is an elevational view of the grinder and backhoe of the present invention with the drum shown in a vertical orientation;
FIG. 2 is a side elevational view of the grinder;
FIG. 3, is a front elevational view of the grinder and backhoe stick;
FIG. 4 is a front elevational view of the grinder module of the present invention;
FIG. 5 is a side elevational view of the grinder of the present invention; and
FIG. 6 is a side sectional view of the grinder of the present invention showing the plurality of drive belts.
Corresponding reference characters indicate corresponding parts throughout the several views. The exemplification set out herein illustrates one preferred embodiment of the invention, in one form, and such exemplification is not to be construed as limiting the scope of the invention in any manner.
DETAILED DESCRIPTION OF THE INVENTION
The tree stump grinder 10 is mounted on the stick 12 of an excavator or backhoe 14. The excavator 14, a portion of which is shown in FIG. 1, includes a base frame 16. The base frame 16 is supported by a pair of track assemblies 18. A swing frame 20 is connected to the base from 16 by a trunnion which allows the swing frame 20 to pivot about a generally vertical axis relative to the base frame 16. An operator's cab 22 is mounted on one side of the swing frame 20. An engine compartment 24 is also mounted on the swing frame 20. The engine compartment 24 houses an internal combustion engine. The internal combustion engine drives hydraulic oil pumps which drive the tracks and provide power to perform all the other standard excavator functions. Valves for directing hydraulic oil are controlled from the operator's cab 22.
A typical boom 26 is pivotally attached to the swing frame 20. A pair of hydraulic boom cylinders 28 are connected to the swing frame 20 by pins 30 and to the boom 26 by support pins 32. The operator can direct hydraulic oil to and from the double acting hydraulic boom cylinders 28 to pivot the boom 26 about the axis of its attachment to swing frame 20 to raise and lower the free end of the boom.
A stick 12 is pivotally attached to the free end of the boom 26 by a pivot pin 34. A double acting hydraulic stick cylinder 36 is connected to boom 26 by a pin 38 and to the stick 12 by a pin 40. A valve controlled from the operator's cab can direct oil to and from the hydraulic stick cylinder 46 to pivot the stick 12 relative to the boom 26 about the axis of the pivot pin 34.
Referring to FIG. 2, the tree stump grinder 10 of the present invention includes a drum support such as a yoke assembly 42. Yoke assembly 42 is swivelably attached to hydraulic swivel 43. Hydraulic swivel 43 permits yoke assembly 42 to swivel 360 degrees about the axis of the stick 12. Mounting plates 45 are affixed to hydraulic swivel 43. Mounting plates 45 are pivotally attached to stick 12 by pivot pin 44. A double acting hydraulic grinder swing cylinder 46 is attached to stick 12 by a pin 48. The hydraulic grinder swing cylinder 46 is also attached to a pair of links 50 and links 52 by a pin 54. The links 50 are attached to stick 12 by pin 55. The links 52 are attached to mounting plates 45 by a pin 56. Oil can be directed by a valve, controlled from the operator's cab, to and from the hydraulic grind swing cylinder 46 to pivot the yoke assembly 42 about the axis of the pivot pin 44. The links 50 and 52 increase the range of movement of the yoke assembly 42 about the axis of the pivot pin 44 and increase the force available to pivot the yoke assembly 42 in some portions of the yoke's range of movement. The hydraulic grinder swing cylinder 46, the links 50, and the links 52 are standard parts of a excavator 44 that normally control a bucket attached to the stick 12 during use of the support vehicle as an excavator.
Referring to FIG. 3, hydraulic swivel 43 houses swivel motor 47. Swivel motor 47 is a hydraulic motor with hydraulic oil supplied to it through oil supply line 49. During operation, swivel motor 47 powers the 360 degree swivel action of yoke assembly 42. Alternatively, an electric motor may be used in place of a hydraulic motor to actuate swivel action of yoke assembly 42. An operator can control the swivel action of yoke assembly 42 by directing the flow of hydraulic oil 47 through oil supply 49.
During the operation of the present invention, hydraulic swivel 43 is stationary relative to swiveling yoke assembly 42. Alternatively, hydraulic swivel 43 may swivel along with yoke assembly 42 about the axis of stick 12.
The drum support, i.e., yoke assembly 42, as shown in FIGS. 4-6, has a main portion 58 and a pair of arms 60 and 62. Hydraulic swivel 43 is swivelly attached to the main portion 58 of the yoke assembly 42. A pair of mounting plates 45 are rigidly secured to hydraulic swivel 43. The mounting plates 45 are used to attach the yoke 42 to the links 50 and stick 12.
A rotatable grinder drum 66 includes a shaft 68 therethrough. The ends of shaft 68 pass through bores in both arms 60 and 62 and connect with bearings 70 and 72 mounted thereon, respectively. The end of shaft 68 extending toward bearing 72, extends therethrough. Drum 66 has an axis for rotation that is oriented vertically during operation. Such vertical orientation permits the safe grinding of entire standing trees and stumps.
A hydraulic drum motor 74 is secured to a portion of yoke assembly 42, preferably to main portion 58. Hydraulic motor 74 is in fluid communication with a source of pressurized hydraulic fluid, such as an auxiliary hydraulic pump operated by a secondary internal combustion engine 76 located within engine compartment 24 or at least on the frame portion of backhoe 14. The hydraulic fluid applied to hydraulic drum motor 74 is controlled by the equipment operator using valves to control the pressure and direction of fluid flow to hydraulic motor 74. By reversing direction of hydraulic fluid, a reversal in the direction of rotation of hydraulic drum motor 74 is accomplished.
Extending from hydraulic drum motor 74 is a shaft 78 on which is attached a first drive pulley 80. On the section of drum shaft 68 that passes through bearing 72 is attached a second drive pulley 82. The preferred type of pulley 80 and 82 is that of a multi V-belt pulley able to mount at least six, but possible more, high strength V-belts 84 thereon. Other types of belts may be utilized. A plurality of V-belts 84 are used to drivingly connect first drive pulley 80 with second drive pulley 82. Use of these belts 84 reduces shock loading of hydraulic drum motor 74 during use, thereby increasing its operational life. If desired, additional gearing of hydraulic drum motor 74 may be utilized.
A plurality of grinding, cutting or shredding bit assemblies 86 are secured to the outside surface of the grinder drum 66. Such bit assemblies may include carbide tipped bits, flail type bits and hammer bits attached for pivotable connection to the grinder drum 66.
The flow of hydraulic oil to and from the hydraulic motor 74 can be stopped to prevent the grinder drum 66 from rotating.
The hydraulic boom cylinders 28, the hydraulic stick cylinder 36, and the hydraulic grinder swing cylinder 46, are all connected to the hydraulic system that is standard on the excavator 14. No modifications are required in the hydraulic system to control these cylinders.
While this invention has been described as having a preferred design, the present invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.
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A tree grinder movable from tree to tree. The tree grinder includes a frame movable from tree to tree, a drum and a drum support rotatably mounting the drum to the frame. The drum support rotates or swivels relative to the frame via a swivel motor. A hydraulic motor is attached to the drum support with a first drive pulley attached to the hydraulic motor and a second drive pulley connected to the drum. A plurality of drive belts connects said first drive pulley to said second drive pulley so the hydraulic motor may rotate the drum.
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TECHNICAL FIELD
[0001] This invention relates to a series of new pyrazolopyrimidinone derivatives (1A and 1B), processes for their preparation, and pharmaceutical compositions containing them. The compounds have potent inhibitory activities against type V phosphodiesterase (PDE5), therefore they are useful for treating erectile dysfunction and other cardiovascular dysfunction.
BACKGROUND
[0002] International application WO94/28902 disclosed the use of pyrazolo[4,3-d]pyrimidine-7-one as selective cGMP PDE inhibitor for erectile dysfunction, and then WO02/27848 disclosed another series of pyrazolo[4,3-d]pyrimidine-7-one derivates, which also have potent inhibitory activity against PDE5.
[0003] The level of cGMP in the smooth muscle cell will increase once the PDE5 in smooth muscle cells are inhibited, cGMP activates protein kinase G (PKG), which subsequently phosphorylates the target protein including smooth muscle myosin, and resulting in the relaxation of smooth muscle and vasodilation. Therefore PDE5 inhibitors are useful in the treatment of a variety of cardiovascular diseases.
[0004] Sildenafil, the first launched PDE5 inhibitor, is used for male erectile dysfunction in clinic, which also demonstrates clinical effect in female sexual dysfunction and hyperpietic. The PDE5 inhibitor under development is also used for the treatment of alimentary canal in the diabetic, insulin resistance and hyperlipemia.
[0005] Despite its effectiveness, Sildenafil has shown clinically significant adverse reactions such as headache, flushing, dyspepsia, snuffle, dimness of vision, photosensitive, and other visual disturbances, which may be linked to insufficient selectivity versus the other PDE isoforms and the dosage. Therefore, both potencies toward PDE5 and selectivities against other PDEs, especially PDE6 are the goal for the successful development of new PDE5 inhibitors.
SUMMARY
[0006] It is an object of the present invention to provide a series of new pyrazolopyrimidinone derivatives (1A and 1B).
It is another object of the present invention to provide the processes for the preparation of compounds of formula 1A and 1B.
It is still another object of the present invention to provide the pharmaceutical compositions containing the compounds of formula 1A and/or 1B.
[0007] The inventors designed and synthesized a series of novel pyrazolopyrimidinone derivatives (1A and 1B), most of which have higher inhibitory activity towards PDE5 and better selectivity against PDE6 distributing in retina than Sildenafil. Therefore, the compound provided by this invention will demonstrate better safety and efficacy, and has a good prospect in clinical application.
[0000]
[0000] wherein:
R 1 represents H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halo or C3-C6 cycloalkyl;
R 2 represents C2-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halo or C3-C6 cycloalkyl;
R 3 represents C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halo, C1-C3 alkoxyl C3-C6 cycloalkyl;
Wherein formula 1A,
m=1-6; n=0-6;
p=1-5; q=1-5;
r1, r2, r3 and r4 independently represent H or C1-C3 alkyl, r1 and r2, r3 and r4 together with the carbon which they are attached to, form Het;
[0008] R 4 and R 5 independently represent H, C1-C6 alkyl, (CH 2 ) u Ar, (CH 2 ) v Het, COR 9 , SO 2 R 9 , C1-C3 alkyl substituted by NR 10 R 11 or C1-C3 alkyl; in case of n=0, R 5 doesn't represent H; in case of R 1 represents methyl; R 2 represents propyl, R 3 represents ethyl, m=1, n=1, p=q=2, r1, r2, r3 and r4 all represent H, R 4 and R 5 don't represent H at same time.
[0009] R 9 represents H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by C 1 -C 3 alkoxyl or NR 12 R 13 , (CH 2 ) u Ar or (CH 2 ) v Het;
[0010] R 10 and R 11 independently represent H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by C 1 -C 3 alkoxyl or NR 12 R 13 , or R 10 and R 11 together with the nitrogen which they are attached to, form Het;
[0011] R 12 and R 13 independently represent H, C 1 -C 6 alkyl;
[0012] Wherein formula (1B)
[0013] t=1-5;
[0014] R 6 represents C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C3 alkoxyl, phenyl, pyridyl, furanyl, pyridazinyl, pyrazinyl, imidazolyl, C 1 -C 3 substituted with hydroxyl, C 1 -C 3 alkoxyl, acetoxyl, phenyl, pyridyl, furanyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl; the above phenyl, pyridyl, furanyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl optionally substituted with one or more substituents selected from halo, C1-C3 alkyl, C1-C3 alkoxyl;
[0015] R 7 and R 8 independently represent H, C 1 -C 6 alkyl, C3-C6 cycloalkyl, C 1 -C 3 haloalkyl, C 1 -C 6 alkoxyl, C1-C3 alkyl substituted with hydroxyl, acetoxyl, C 1 -C 3 alkoxyl, or R 7 and R 8 together with the nitrogen which they are attached to, form four-membered to eight-membered heterocyclic ring, including morpholine, piperidine, pyrrole, piperazine; the above heterocyclic ring optionally substituted with one or more substituents selected from halo, C1-C3 alkyl, C3-C6 cycloalkyl, C 1 -C 3 haloalkyl, C1-C3 alkoxyl;
[0016] Wherein u, v=0, 1 or 2;
[0017] Ar represents phenyl or phenyl substituted by one to two substituents selected from halo, NH2, C1-C3 alkyl, C1-C3 alkoxy, CONH 2 , CN, SO 2 NH 2 ;
[0018] Het represents a four-membered and six-membered heterocyclic ring substituted with one or two substituents selected from halo, C1-C3 alkyl, C1-C3 alkoxy, the heterocyclic contains one to four heteroatoms selected from nitrogen, sulfur, oxygen.
[0019] As previously defined, no particular explanation, alkyl with there or more carbon wherein said may be straight or branched chain. Halo represents fluorine, chlorine, bromine or iodine
[0020] The compound of formula 1A and 1B may have one or more chiral center, therefore, the compound may exist stereomer, that's to say, enantiomer, diastereomer or their mixture. The invention includes within its scope all the possible isomers, stereomers and their mixture of formulae 1A and 1B.
[0021] The compounds of formula 1A and 1B may have stereomers and this invention includes all the possible isomers, stereomers and their mixtures thereof.
[0022] The invention includes within its all the possible prodrugs of formula 1A and 1B.
[0023] The invention includes the pharmaceutically acceptable salts of formula 1A and 1B, preferred salts are hydrochloride and methanesulfonate.
[0024] The invention still includes the pharmaceutically acceptable solvates of formula 1A and 1B (e.g. hydrates).
[0025] The invention also includes the pharmaceutically oxide of formula 1A and 1B.
[0026] Preferred compounds of IA and IB include those wherein:
[0000] R 1 represents C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
R 2 represents C 2 -C 4 alkyl or C3-C6 cycloalkyl;
R 3 represents C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted with C 1 -C 3 alkoxyl;
m=1-2; n=0-2;
p=2-4; q=2-4;
r1, r2, r3 and r4 independently represent H or methyl;
R 4 and R 5 independently represent H, C 1 -C 3 alkyl, phenyl, pyridimethyl 4-piperidyl, COR 9 , C 1 -C 3 alkyl substituted by NR 10 R 11 ; in case of n=0, R 5 doesn't represent H; in case of R 1 represents methyl, R 2 represents propyl, R 3 represents ethyl, m=1, n=1, p=q=2, r1, r2, r3 and r4 all represent H, R 4 and R 5 don't represent H at same time
[0028] R 9 represents C 1 -C4 alkyl, phenyl or pyridyl;
[0029] R 10 and R 11 independently represent H, C 1 -C 3 alkyl; or R 10 and R 11 together with the nitrogen which they are attached to, form a heterocyclic ring, including morpholine, piperazine, piperidine, pyrrole;
[0030] Wherein IB:
[0031] t=2-3;
[0032] R 6 represents C 1 -C 3 alkyl, phenyl, pyridyl, benzyl or C 1 -C 3 substituted with hydroxyl, C 1 -C 3 alkoxyl, acetoxyl, phenyl, pyridyl;
[0033] R 7 and R 8 together with the nitrogen which they are attached to, form a morpholine, piperidine or pyrrole heterocyclic ring;
[0034] Particularly preferred compounds of IA and IB include those wherein:
[0035] R 1 represents methyl or ethyl;
[0036] R 2 represents ethyl and n-propyl;
[0037] R 3 represents ethyl, n-propyl or methyloxyethyl;
[0038] Wherein IA,
[0039] m=1; n=0-1;
[0040] p=2-3; q=2-3;
[0041] r1, r2, r3 and r4 represent H;
[0000] R 4 and R 5 independently represent H, methyl, ethyl or COR 9 ; C 1 -C 3 alkyl substituted by NR 10 R 11 ; in case of n=0, R 5 doesn't represent H; in case of R 1 represents methyl, R 2 represents propyl, R 3 represents ethyl, m=1, n=1, p=q=2, r1, r2, r3 and r4 all represent H, R 4 and R 5 don't represent H at same time;
R 9 represents methyl or pyridyl;
[0042] Wherein IB,
[0043] t=2-3
[0044] R 6 represents methyl, ethyl, benzyl, pyridylmethyl, or C 1 -C 3 substituted with hydroxyl, C 1 -C 3 alkoxyl, acetoxyl;
[0045] The preferable compounds of the present invention are:
1-methyl-5-{2-propyloxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 1) 1-methyl-5-{2-propyloxy-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 2) 1-methyl-5-{2-propoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 3) 1-methyl-5-{2-ethoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 4) 1-methyl-5-{2-ethoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 5) 1-methyl-5-{2-ethoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 6) 1-methyl-5-{2-ethoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 7) 1-methyl-5-{2-propoxy-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 8) 1-methyl-5-{2-methoxyethyl-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 9) 1-methyl-5-{2-methoxyethyl-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 10) 1-methyl-5-{2-ethoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 13) 1-methyl-5-{2-propoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 14) 1-methyl-5-{2-ethoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 16) 1-ethyl-5-{2-ethoxy-5-{[1-ethyl-1-[2-(1-ethyl-1-(2-acetoxyethyl))amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 19) 1-methyl-5-{2-ethoxy-5-{[1-methyl-1-[2-(1-methyl-1-(2-hydroxyethyl))amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 21) 1-methyl-5-{2-propoxy-5-{[1-methyl-1-[2-(1-methyl-1-(2-hydroxyethyl))amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 23) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 24) 1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 25) 1-methyl-5-{2-methoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 26) 1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 27) 1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 28) 1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 29) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 31) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 33) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 35) 1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 36) 1-methyl-5-{2-propoxy-5-[bis(3-hydroxypropyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 37) 1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 38) 1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethoxyethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 39) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 41) 1-methyl-5-{2-propoxy-5-[bis(2-hydroxypropyl)amidosulfonyl]phenyl}-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 42) 1-methyl-5-{2-ethoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 43) 1-methyl-5-{2-ethoxy-5-[bis(3-hydroxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 44) 1-methyl-5-{2-ethoxy-5-[bis(2-hydroxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 45) 1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 46) 1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 47) 1-methyl-5-{2-ethoxy-5-[[1-ethyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 51) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 52) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 53) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 54) 1-methyl-5-{2-propoxy-5-[[1-(4-fluorobenzyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 56) 1-methyl-5-{2-propoxy-5-[[1-(2-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 60) 1-methyl-5-{2-ethoxy-5-[[1-(3-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 61) 1-methyl-5-{2-propoxy-5-[[1-(3-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 62) 1-methyl-5-{2-propoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 63) 1-methyl-5-{2-ethoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 64) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 65) 1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 66) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 68) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 70) 1-methyl-5-{2-propoxy-5-[[1-(2-furanylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 72) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 78) 1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 79) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 80) 1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 81) 1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 82) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 83) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 84) 1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 85) 1-methyl-5-{2-propoxy-5-[[1-(2-pyridylmethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 87) 1-methyl-5-{2-ethoxy-5-[[1-(2-pyridylmethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 88) 1-methyl-5-{2-propoxy-5-[[1-(3-pyridylmethyl)-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 89) 1-methyl-5-{2-ethoxy-5-[[1-(3-pyridylmethyl)-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 90) 1-methyl-5-{2-propoxy-5-[[1-(2-acetoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 91) 1-methyl-5-{2-propoxy-5-[[1-(3-acetoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 92) 1-methyl-5-{2-propoxy-5-[bis(3-acetoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 93) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 94) 1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 95) 1-methyl-5-{2-propoxy-5-[[1-(2-acetoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 96) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-acetoxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 97) 1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 98) 1-methyl-5-{2-propoxy-5-[[1-(methoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 99) 1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 100) 1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 101) 1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 102) 1-methyl-5-{2-propoxy-5-[bis(3-methoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 103) 1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 104) 1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 105) 1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 106) 1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 107) 1-methyl-5-{2-ethoxy-5-[bis(3-acetoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 108) 1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 109) 1-methyl-5-{2-propoxy-5-[[1-methyl-1-(3-dimethylaminopropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 110) 1-methyl-5-{2-propoxy-5-[[1-(2-ethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 111) 1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-morpholin-1-yl)propyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 112) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(3-morpholin-1-yl)propyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 113) 1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 114) 1-methyl-5-{2-ethoxy-5-[[1-(3-acetoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 115) 1-methyl-5-{2-propoxy-5-[[1-(3-ethoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 116) 1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(4-morpholin-1-yl)butyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 117) 1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(3-acetoxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (compound of example 118)
[0137] The present invention also provides the processes for the preparation of compounds of formula 1A and 1B.
[0138] There are two different types of preparation methods according to their structure features.
[0139] Type 1, some of the compounds of formula 1A (both R 4 and R 5 are not H) and formula 1B may be prepared from 2A and 2B. The scheme is as follows
[0000]
[0140] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , r 1 , r 2 , r 3 , r 4 , m, n, p, q and t are as previously defined for formula 1A and 1B, but R 4 , R 5 are not H.
[0141] This step was achieved by the existing cyclization method for pyrimidinone compounds. The reaction is usually carried out in the presence of a suitable base and a suitable solvent at temperatures at a range from 50 to 200° C. Preferred bases include metal alkoxides (e.g. potassium tertbutoxide, sodium ethoxide), alkaline earth metal or hydrides of alkali metal, amine (e.g. triethylamine), metal salts of ammonia, hydroxides (e.g. sodium hydroxide), carbonates and bicarbonates. Preferred solvents include alcohols (e.g. t-butanol, methanol, ethanol, isopropanol, glycol, 2-methoxyethanol), aromatic hydrocarbons (e.g. benzene, toluene, chlorobenzene), pyridine, halogenated hydrocarbon, acetonitrile, tetrahydrofuran, dioxane, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidin-2-one.
[0142] Type 2, some of the compounds of formula 1A containing hydroxyl group at the ending chain may be prepared form the hydrolysis of their corresponding ester derivates, which is to say that when at least one of R 4 and R 5 is H (e.g. 1A-1), the hydroxyl derivates may be prepared through hydrolysis reaction. The scheme is as follows:
[0000]
[0143] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , r 1 , r 2 , r 3 , r 4 , m, n, p, q and t are as previously defined for formulae 1A and 1B.
[0144] The compounds of formula (2A) and (2B) are usually prepared by reacting the compounds of formula (3A) and (3B) with the compounds of formula 4 respectively. The scheme is as follows
[0000]
[0145] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , r 1 , r 2 , r 3 , r 4 , m, n, p, q and t are as previously defined for formulae IA and IB, but R 4 , R 5 are not H.
[0146] Method 1, the carboxyl group in the compounds of formula (3A) or (3B) was transformed into acyl chloride or mixed anhydride by using thionyl chloride, oxalyl chloride or ethyl chlorformate, then the mixture was reacted with the compounds of formula 4 to get the corresponding acid amide (2A) or (2B). The acidylation reaction is usually carried out in the presence of a suitable deacidification reagent and a common solvent. Preferred deacidification reagents include organic bases (preferred triethylamine, N,N-diisopropylethylamine, pyridine) and inorganic bases (preferred hydroxides, carbonates). Preferred solvents include diolefines (preferred petroleum, n-hexane, cyclohexane), halohydrocarbon (preferred dichlormethane, chloroform), ethers (preferred tetrahydrofuran, dioxane, ether), aromatic solvents (preferred toluene) and alcohols (preferred t-butanol, isopropanol).
[0147] Method 2, carboxylic acid was reacted with amine derivates directly to get the formula (2A) and (2B). The reaction is usually carried out in the anhydrous solvent with the presence of activating agent or dehydrating agent.
[0000] Preferred activating agents or dehydrating agents include DCC, EDCI, EEDQ, CDI, HOBt. Preferred solvents include halogenated hydrocarbons (e.g. dichlormethane, dichlormethane), ethers (e.g. tetrahydrofuran, dioxane, ether), aromatic hydrocarbons (e.g. benzene, toluene), polarity aprotic solvent (dimethylsulfoxide, N,N-dimethylformamide), or their mixture.
[0148] The compounds of formula 3A, 3B and 4 can be prepared according to literatures or supplied commercially.
[0149] In addition, the present invention provides the pharmaceutical compositions containing the compounds of formula 1A and/or 1B.
[0000] The above mentioned compositions contain one or more compounds of formula 1A and/or 1B (or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates) and at least one kind of pharmaceutical excipient. The pharmaceutical excipient, which is used according the administration route and their functional properties, are normally fillers, diluents, adhesives, moistening agent, disintegrants, emulsifier, suspending agent, etc.
The compositions according to the invention can be administrated by any suitable route, for example by oral, parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical administration. Oral administration is the preferred route.
The compounds of formula 1A and/or 1B should preferably be presented in the above mentioned pharmaceutical compositions in a concentration of about 0.1 to 99.9%, preferably 1 to 99% by weight of the total mixture.
[0150] The present invention also provides processes for the preparation of the pharmaceutical compositions containing the compounds of formula IA and/or IB. The compounds of formulae IA and/or IB can be mixed with pharmaceutical excipient or excipients and made into dosage forms according the administration route in the conventional method. The dosage forms include tablets, capsules, granules, pills, solutions, solutions, emulsion, emulsions, membranes, creams, aerosols, injection and suppositories etc. Tablets and capsules are preferred.
[0000] Tablets and capsules can contain one or more compounds of formula of IA and/or IB in addition to one or more conventional excipients, such as (a) fillers, for example starches, sucrose, lactose, glucose, microcrystalline cellulose, and mannitol, (b) binders, for example carboxymethylcellulose, gelatine, alginates and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrating agents, for example agar-agar, ethyl cellulose, sodium starch glycolate and calcium carbonate (e) lubricants, for example magnesiumstearate, talc, and polyethylene glycols.
The dosages of the compounds of the invention are generally 1 to 500 mg per day, preferably 10 to 100 mg, taken once or several times. However, it may be necessary to properly deviate from the dosages mentioned. The optimal dosages, which may be determined by specialist with their professional knowledge, depend on the severity of the disease, the individual response towards the medicament, the characteristics of the formulation, and the administration routes.
Moreover, the invention provides the compounds of formulae IA and/or IB, or the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable solvate of either entity, or the pharmaceutical composition containing any of the foregoing, for use as a human medicament.
[0151] The invention further provides the use of the compounds of formulae IA and/or IB, or the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable solvate of either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated.
[0152] Still further, the invention provides the use of the compounds of formulae IA and/or IB, or the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable solvate containing either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of male erectile dysfunction, benign prostatic hyperplasia (BPH), female sexual dysfunction, premature labour, dysmenorrhoea, bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, kidney failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by disorders of gut motility (e.g. irritable bowel syndrome, IBS).
DETAILED DESCRIPTION OF EMBODIMENTS
Example
[0153] The following examples serve to explain the compounds in this invention and the methods for the intermediates, but without limiting it.
[0154] 1 H NMR spectra were determined on a Mercury 400 NMR spectrometer or Mercury 400 NMR spectrometer (Varian Company). The conventional abbreviation was as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak.
Example 1 1-methyl-5-{2-propyloxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
Step 1: Preparation of 4-{2-propoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]benzoylamino}-1-methyl-3-n-propylpyrazolo-5-carboxamine
[0155]
[0156] 2-propoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]benzoic acid (0.43 g, 1 mmol) was dissolved in CH 2 Cl 2 (20 mL), Carbonyldiimidazole (CDI, 3 mmol) was added to the solution and stirred at room temperature for 0.5 hours, then 4-amino-3-propylpyrazolo-5-carboxamine (0.18 g, 1 mmol) was added and stirred another 1-6 h, the stopping point was detected by TLC. When the reaction was finished, the reaction mixture was washed with the ammonium chloride solution and brine, the CH 2 Cl 2 layer was dried over anhydrous magnesium sulfate and the solvent was concentrated to dryness under reduced pressure, the resulting residue was recrystallized from alcohol to get white powder (0.51 g), yield 86%.
Step 2: Preparation of 1-methyl-5-{2-propoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0157]
[0158] Potassium tert-butoxide (0.06 g, 0.55 mmol) and the product of step 1 (0.3 g, 0.5 mmol) were added to tert-butyl alcohol (15 ml) successively, and the mixture was heated to reflux for 30 minutes to produce a clear solution. The solution was refluxed for another 10 hours, then cooled to room temperature and water (20 ml) was added. The resulted solution was adjusted to neutral by adding 4% acetic acid. cooled to 5-10° C. and a white solid was precipitated. The white solid was collected by filtration, washed with cold water (3×10 ml) and dried. The solid was recrystallized from MeOH/EtOAc to afford the title compound (0.22 g), yield 76%. 1 H NMR (CDCl 3 ) δ: 10.83 (1H, s), 8.87 (1H, d), 7.90 (1H, dd), 7.14 (1H, d), 4.27 (3H, s), 4.25 (6H, m), 3.49 (4H, t), 2.93 (2H, t), 2.04 (2H, m), 2.03 (6H, s), 1.86 (2H, m), 1.17 (3H, t), 1.02 (3H, t).
Example 2 1-methyl-5-{2-propyloxy-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0159]
[0160] To the solution alcohol (5 ml), water (10 ml) and potassium carbonate (0.1 g, 0.7 mmol), the compound of example 1 (0.12 g, 0.2 mmol) was added and the solution was heated to reflux, the stopping point was detected by TLC. When the reaction was finished, the PH value of the solution was adjusted to neutral by dilute hydrochloric acid and a white solid was precipitated, the solid was collected by filtration, washed with water and dried to get crude product. The crude product was recrystallized from dichloromethane and n-hexane to afford the title compound (0.06 g), yield 61%. 1 H NMR (CDCl 3 ) δ: 10.82 (1H, s), 8.84 (1H, d), 7.91 (1H, dd), 7.14 (1H, d), 4.26 (3H, s), 4.25 (2H, t), 3.88 (4H, t), 3.49 (2H, s), 3.38 (4H, t), 2.92 (2H, t), 2.02 (2H, m), 1.84 (2H, m), 1.17 (3H, t), 1.02 (3H, t).
Example 3˜120
[0161] The example 3˜120 was prepared from different substitute start materials following the procedure of example 1 and example 2 (unless otherwise noted, NMR spectra were determined in CDCl 3 solution)
[0000]
Example
Structure
Name and 1 H-NMR (δ)
3
1-methyl-5-{2-propoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one11.08 (1 H, s), 8.92 (2 H, s), 8.75 (3 H, m), 8.21 (2 H,d), 7.90 (1 H, dd), 7.32 (2 H, dd), 7.01 (1 H, d), 4.56(4 H, t), 4.27 (3 H, s), 4.11 (2 H, t), 3.77 (4 H, t), 2.91(2 H, t), 1.97 (2 H, m), 1.84 (2 H, m), 1.15 (3 H, t),1.00 (3 H, t)
4
1-methyl-5-{2-ethoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.87 (1 H, d), 7.90 (1 H, dd), 7.14 (1 H,d), 4.37 (2 H, q), 4.25 (4 H, m), 4.24(3 H, s), 3.50 (4 H,m), 2.94 (2 H, t), 2.02 (6 H, s), 1.88(2 H, m), 1.63 (3 H,t), 1.01 (3 H, t)
5
1-methyl-5-{2-ethoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one11.05 (1 H, s), 8.93 (2 H, d), 8.76 (m, 3 H), 8.22 (2 H,m), 7.92 (1 H, dd), 7.32 (2 H, m), 7.01 (1 H, d),4.57 (4 H, t), 4.27 (3 H, s), 4.24(2 H, m), 3.76 (t, 4 H),2.90 (2 H, t), 1.80 (2 H, m), 1.56 (3 H, t), 1.00 (3 H, t)
6
1-methyl-5-{2-ethoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.81 (1 H, s), 8.87 (1 H, d), 7.89 (1 H, dd), 7.14(1 H, d), 4.37 (2 H, q), 4.27 (3 H, s), 4.25 (4 H, t),3.50 (4 H, t), 2.98 (2 H, q), 2.02 (6 H, s), 1.63 (3 H,t), 1.41 (3 H, t)
7
1-methyl-5-{2-ethoxy-5-[bis(2-nicotinoyloxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one11.05 (1 H, s), 8.93 (2 H, s), 8.75 (3 H, m), 8.21 (2 H,ddd), 7.90 (1 H, dd), 7.33 (2 H, ddd), 7.00 (1 H, d),4.56 (4 H, t), 4.27 (3 H, s), 4.21 (2 H, q), 3.77 (4 H,t), 2.96 (2 H, q), 1.58 (3 H, t), 1.39 (3 H, t)
8
1-methyl-5-{2-propoxy-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.79 (1 H, s), 8.85 (1 H, d), 7.92 (1 H, dd), 7.15(1 H, d), 4.37 (2 H, q), 4.27 (3 H, s), 3.89 (4 H, t),3.39 (4 H, t), 2.98 (2 H, q), 1.66 (3 H, t), 1.40 (3 H, t)
9
1-methyl-5-{2-methoxyethoxy-5-[bis(2-acetoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one11.07 (1 H, s), 8.78 (1 H, d), 7.90 (1 H, dd), 7.12(1 H, d), 4.42 (2 H, t), 4.27 (3 H, s), 4.24 (4 H, t),3.88 (2 H, t), 3.60 (3 H, s), 3.49 (4 H, t), 2.92 (2 H, t),2.03 (6 H s), 1.86 (2 H, m), 1.02 (3 H, t)
10
1-methyl-5-{2-methoxyethoxy-5-[bis(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one11.07 (1 H, s), 8.75 (1 H, d), 7.91 (1 H, dd), 7.13(1 H, d), 4.42 (2 H, t), 4.27 (3 H, s), 3.87 (6 H m),3.59 (3 H, s), 3.49 (2 H, s), 3.38 (4 H, t), 2.91 (2 H, t),1.84 (2 H, m), 1.02 (3 H, t)
11
1-methyl-5-{2-ethoxy-5-[[1-(2-diethylaminoethyl)-1-(2-methoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one7.97 (1 H, d), 7.89 (1 H, dd), 7.32 (1 H, d), 4.19 (m,2 H), 4.11 (3 H, s),3.30 (2 H, t), 3.20 (3 H, s), 3.14 (2 H,t), 2.76 (2 H, t), 2.50 (2 H, t), 2.42 (4 H, m), 1.34 (3 H,t), 1.26 (2 H, m), 0.80 (9 H, m) (DMSO).
12
1-methyl-5-{2-ethoxy-5-[[1-(2-diethylaminoethyl)-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.88 (1 H, d), 7.91 (1 H, dd), 7.12(1 H, d), 4.39 (2 H, q), 4.26 (3 H, s), 4.23 (2 H, t), 3.482 H, t), 3.30 (2 H, t), 2.92 (2 H, t), 2.70 (2 H,m), 2.58 (4 H, q), 2.04 (3 H, s), 1.83 (2 H, m), 1.63(3 H, t), 1.01 (9 H, m)
13
1-methyl-5-{2-ethoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.87 ( 1 H, d),7.89 (1 H, dd), 7.14 (1 H,d), 4.37 (2 H, m), 4.27 (3 H, s), 3.81 (2 H, t), 3.25(4 H, m), 2.93 (2 H, t), 2.86 (2 H, t), 2.61 (4 H, t),1.86 (2 H, m), 1.64 (3 H, t), 1.11 (6 H, t), 1.03 (3 H, t).
14
1-methyl-5-{2-propoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.87 (1 H, d), 7.88 (1 H, dd), 7.15 (1 H,d), 4.29 (2 H, q), 4.27 (3 H, s), 3.67 (2 H, t), 3.34(2 H, t), 3.24 (2 H, q), 2.93 (2 H, t), 2.61 (2 H, t),2.56 (2 H, t), 2.53 (2 H, t), 2.03 (2 H, m), 1.85 (2 H,m), 1.18 (3 H, t), 1.11 (3 H, t), 1.01 (6 H, t).
15
1-methyl-5-{2-ethoxy-5-[1-(2-diethylaminoethyl)-1-(2-acetoxyethoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.88 (1 H, d), 7.92 (1 H, dd), 7.13 (1 H,d), 4.37 (2 H, q), 4.27 (3 H, s), 4.14 (2 H, t), 3.67 (2 H,t), 3.62 (2 H, q), 3.43 (2 H, t), 3.33 (2 H, t), 2.92 (2 H,t), 2.72 (2 H, m), 2.57 (4 H, q), 2.05 (3 H, s), 1.85(3 H, m), 1.66 (3 H, t), 1.00 (9 H, m)
16
1-methyl-5-{2-ethoxy-5-[1-(2-diethylaminoethyl)-1-(2-hydroxyethoxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one12.17 (1 H, s), 7.97 (1 H, d), 7.92 (1 H, dd), 7.33 (1 H,d), 4.20 (2 H, m), 4.16 (3 H, s), 3.53 (2 H, t), 3.44(2 H, t), 3.39 (2 H, t), 3.30 (2 H, t), 3.17 (2 H, t), 2.77(2 H, t), 2.55 (2 H, t), 2.44 (4 H, m), 1.74 (2 H, m),1.33 (3 H, t), 0.92 (9 H, m) (DMSO)
17
1-methyl-5-{2-ethoxy-5-{[1-ethyl-1-[2-[1-ethyl-1-(2-acetoxyethyl)]amino]ethyl]amidosulfonyl]}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.88 (1 H, d), 7.91 (1 H, dd), 7.12 (1 H,d), 4.36 (2 H, q),4.33 (3 H, S), 4.07 (2 H, t), 3.32 (2 H,q), 3.20 (2 H, t), 2.92 (2 H, t),2.73 (4 H, m), 2.58 (2 H,q), 2.02 (3 H, s), 1.85 (2 H, m),1.64 (3 H, t), 1.21 (3 H,t), 1.01 (6 H, m)
18
1-methyl-5-{2-ethoxy-5-{[1-ethyl-1-[2-[1-ethyl-1-(2-hydroxyethyl)]amino]ethyl]amidosulfonyl]}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.87 (1 H, d) , 7.91 (1 H, dd), 7.13(1 H, d), 4.37 (2 H, m), 4.27 (3 H, s), 3.55 (2 H, t),3.31 (2 H, q), 3.24 (2 H, q), 2.92 (2 H, t), 2.74 (2 H,t), 2.64 (2 H, t), 2.62 (2 H, t), 1.85 (2 H, m), 1.64(3 H, t), 1.17 (3 H, t), 1.03 (6 H, m)
19
1-ethyl-5-{2-ethoxy-5-{[1-ethyl-1-[2-[1-ethyl-1-(2-acetoxyethyl)]amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.89 (1 H, d), 7.91 (1 H, dd), 7.13 (1 H,d), 4.64 (2 H, q),4.37 (2 H, q), 4.09 (2 H, t), 3.32 (2 H,q), 3.26 (2 H, t), 2.98 (2 H, q),2.75 (4 H, q), 2.62 (2 H,q), 2.05 (3 H, s), 1.65 (3 H, t), 1.52 (3 H, t), 1.41 (3 H,t), 1.18 (3 H, t), 1.03 (3 H, t)
20
1-methyl-5-{2-ethoxy-5-{[1-ethyl-1-[2-[1-ethyl-1-(2-hydroxyethoxyethyl)]amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.85 (1 H, d) , 7.91 (1 H, dd), 7.12(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 3.66 (2 H, m),3.57 (4 H, m), 3.31 (2 H, m), 3.24 (2 H, t), 2.92 (2 H,m), 2.77 (2 H, t), 2.68 (2 H, t), 2.60 (2 H, m), 1.85(2 H, m), 1.63 (3 H, t), 1.03 (3 H, t).
21
1-methyl-5-{2-ethoxy-5-{[1-methyl-1-[2-[1-methyl-1-(2-hydroxyethyl)]amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.83 (1 H, s), 8.84 (1 H, d) , 7.89 (1 H, dd), 7.14(1 H, d), 4.37 (2 H, m), 4.27 (3 H, s), 3.56 (4 H, m),2.91 (2 H, t), 2.83 (3 H, s), 2.66 (2 H, t), 2.58 (2 H, t),2.33 (3 H, s), 1.84 (2 H, m), 1.64 (3 H, t), 1.03 (3 H,t).
22
1-methyl-5-{2-ethoxy-5-{[1-methyl-1-[2-[1-methyl-1-(2-benzyloxyethoxyethoxyethyl)]amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one8.81 (1 H, d) , 7.86 (1 H, dd), 7.30 (5 H, m), 7.12(1 H, d), 4.53 (2 H, s), 4.33 (2 H, m), 4.27(3 H, s), 3.62 (8 H, m), 3.54 (2 H, t), 3.18 (2 H,t), 2.92 (2 H, t), 2.83 (3 H, s), 2.62 (4 H, m), 2.28(3 H, s), 1.85 (2 H, m), 1.61 (3 H, t), 1.013 H, t).
23
1-methyl-5-{2-propoxy-5-{[1-methyl-1-[2-[1-methyl-1-(2-hydroxyethyl)]amino]ethyl]amidosulfonyl}phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.85 (1 H, d), 7.89 (1 H, dd), 7.161 H, d), 4.28 (3 H, s), 4.27 (2 H, q), 3.58 (2 H, t),3.24 (2 H, t), 2.93 (2 H, t), 2.83 (3 H, s), 2.67 (2 H, t),2.59 (2 H, t), 2.34 (3 H, s), 2.04 (2 H, m), 1.86 (2 H,m), 1.19 (3 H, t), 1.02 (3 H, t)
24
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one7.98 (2 H, m), 7.35 (6 H, m), 4.37 (2 H, s), 4.16 (3 H,s), 4.11 (2 H, t), 3.86 (2 H, t), 3.68 (2 H, t), 3.57 (2 H,t), 3.25 (2 H, t), 3.10 (2 H, t), 2.95 (2 H, t), 2.77 (2 H,t), 1.68-1.76 (4 H, m), 0.89-0.96 (6 H, 2 × t).(DMSO)
25
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolol[4,3-d]pyrimidin-7-one8.01 (1 H, dd), 7.96 (1 H, d), 7.34 (6 H, m), 4.38(2 H, s), 4.12 (3 H, s), 3.88 (2 H, t), 3.67 (2 H, t), 3.55(2 H, t), 3.26 (2 H, t), 3.11 (2 H, t), 2.97 (2 H, t), 2.78(2 H, t), 1.71 (2 H, m), 0.92 (3 H, t). (DMSO)
26
1-methyl-5-{2-methoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one8.03 (1 H, dd), 7.95 (1 H, d), 7.32 (6 H, m), 4.37(2 H, s), 4.15 (3 H, s), 3.92 (3 H, s), 3.86 (2 H, t),3.65 (2 H, t), 3.53 (2 H, t), 3.26 (2 H, t), 3.09 (2 H, t),2.98 (2 H, t), 2.77 (2 H, t), 1.72 (2 H, m), 0.92 (3 H,t). (DMSO)
27
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-diydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.94 (1 H, d), 7.95 (1 H, dd), 7.29(5 H, m), 7.14 (1 H, d), 4.44 (2 H, s), 4.28 (3 H, s),3.55 (2 H, t), 3.28 (2 H, t), 2.97 (2 H, q), 2.36 (2 H, t),2.25 (4 H, t), 1.65 (3 H, t), 1.25 (3 H, t)
28
1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one8.84 (1 H, d), 7.90 (1 H, dd), 7.13 (1 H, d), 4.37(2 H, m), 4.27 (3 H, s), 3.65 (8 H, m), 3.49 (4 H,m), 3.43 (2 H, t), 2.94 (2 H, t), 2.64 (4 H,d), 2.46 (2 H, t), 1.85 (2 H, m), 1.64 (3 H, t), 1.01(3 H, t) (DMSO).
29
1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.15 (1 H,d), 4.37 (2 H, q), 4.27 (3 H, s), 3.68 (2 H, t), 3.39 (2 H,t), 2.93 (2 H, t), 2.69 (2 H, t), 2.49 (2 H, t), 2.41 (4 H,br s), 1.85 (2 H, m), 1.64 (3 H, t), 1.62 (4 H, m), 1.44(2 H, m), 1.02 (3 H, t)
30
1-methyl-5-{2-ethoxy-5-[bis(2-methylsulfonylethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.22 (1 H, d), 7.92 (1 H, dd), 7.21(1 H, d), 4.43 (4 H, t), 4.27 (3 H, s), 4.27 (2 H, t), 3.59(4 H, t), 3.07 (6 H, s), 2.94 (2 H, t), 2.04 (2 H, m),1.87 (2 H, m), 1.19 (3 H, t), 1.04 (3 H, t).
31
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.83 (1 H, s), 8.84 (1 H, d), 7.90 (1 H, dd), 7.16 (1 H,d), 4.27 (3 H, s), 4.26 (2 H, t), 3.81 (2 H, t), 3.25 (2 H,t), 2.93 (2 H, t), 2.90 (3 H, t), 2.11 (1 H, t), 2.05 (2 H,m), 1.85 (2 H, m), 1.18 (3 H, t), 1.03 (3 H, t)
32
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-nicotinoyloxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.93 (1 H, s), 9.05 (1 H, dd), 8.83 (1 H, d), 8.78(1 H, dd), 8.28 (1 H, dt), 7.89 (1 H, dd), 7.38 (1 H, m),7.12 (1 H, d), 4.53 (2 H, t), 4.27 (3 H, s), 4.21 (2 H,t), 3.55 (2 H, t), 2.98 (3 H, s), 2.92 (2 H, t), 2.02 (2 H,t), 1.86 (2 H, m), 1.17 (3 H, t), 1.01 (3 H, t)
33
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.86 (1 H, d), 7.88 (1 H, dd), 7.16 (1 H,d), 4.27 (3 H, s), 4.24 (4 H, m), 3.35 (2 H, t), 2.92(2 H, t), 2.90 (3 H, t), 2.07 (3 H, s), 2.03 (2 H, t), 1.86(2 H, m), 1.18 (3 H, t), 1.02 (3 H, t)
34
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-(pyrrolidin-2-yl)formoxylethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one8.75 (1 H, d), 7.88 (1 H, dd), 7.14 (1 H, d), 4.30 (2 H,t), 4.27 (3 H, s), 4.23 (2 H, t), 3.68 (1 H, m),3.37 (2 H, t), 3.08 (1 H, m), 2.92 (2 H, m), 2.90 (3 H,t), 2.12 (2 H, m), 2.01 (2 H, q), 1.88 (2 H, m), 1.80(2 H, m), 1.75 (2 H, m), 1.16 (3 H, t), 1.10 (3 H, t)
35
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.15 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.67 (4 H, t), 3.21(2 H, t), 2.91 (2 H, m), 2.87 (3 H, s), 2.58 (2 H, t),2.47 (4 H, t), 2.03 (2 H, m), 1.84 (2 H, m), 1.18 (3 H,t), 1.02 (3 H, t)
36
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.85 (1 H, d), 7.89 (1 H, dd), 7.14 (1 H,d), 4.37 (2 H, q), 4.27 (3 H, s), 3.68 (4 H, t), 3.22(2 H, t), 2.92 (2 H, t), 2.87 (3 H, s), 2.58 (2 H, t), 2.48(4 H, t), 1.84 (2 H, m), 1.64 (3 H, t), 1.02 (3 H, t)
37
1-methyl-5-{2-propoxy-5-[bis(3-hydroxypropyl)amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.75 (1 H, s), 8.80 (1 H, d), 7.92 (1 H, dd), 7.14(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.71 (4 H,t), 3.37 (4 H, t), 2.93 (2 H, t), 2.55 (2 H, s),2.04 (2 H, m), 1.82 (6 H, m), 1.17 (3 H, t), 1.02(3 H, t)
38
1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.78 (1 H, s), 8.84 (1 H, d), 7.95 (1 H, dd), 7.15(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.81 (4 H, t),3.37 (4 H, m), 2.93 (3 H, t), 2.73 (1 H, s), 2.03 (2 H,m), 1.85 (4 H, m), 1.18 (3 H, t), 1.02 (3 H, t)
39
1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethoxyethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.82 (1 H, d), 7.92 (1 H, dd), 7.14(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.75 (2 H, t),3.68 (4 H, t), 3.53 (2 H, t), 3.42 (2 H, t), 3.37 (2 H, t),2.92 (2 H, t), 2.69 (2 H, s), 2.02 (2 H, m), 1.87 (4 H,m), 1.17 (3 H, t), 1.02 (3 H, t)
40
1-methyl-5-{2-propoxy-5-[[1-(4-hydroxybutyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.78 (1 H, s), 8.78 (1 H, d), 7.89 (1 H, dd), 7.13(1 H, d), 4.27 (3 H, s), 4.24 (2 H, t), 3.74 (2 H, t),3.66 (2 H, t), 3.34 (2 H, t), 3.25 (2 H, t), 3.01 (1 H, s),2.92 (2 H, t), 2.58 (1 H, s), 2.02 (2 H, m), 1.82 (4 H,m), 1.60 (4 H, m), 1.16 (3 H, t), 1.02 (3 H, t))
41
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.89 (1 H, d), 7.92 (1 H, dd), 7.12 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.65 (4 H, t), 3.33(4 H, m), 2.92 (2 H, t), 2.58 (2 H, t), 2.47 (4 H, t),2.03 (2 H, m), 1.85 (2 H, m), 1.19 (3 H, t), 1.18 (3 H,t), 1.02 (3 H, t)
42
1-methyl-5-{2-propoxy-5-[bis(2-hydroxypropyl)amidosulfonyl]phenyl}-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.89 (1 H, d), 7.92 (1 H, dd), 7.16(1 H, d), 4.27 (3 H, s), 4.26 (2 H, t), 4.18 (2 H,m), 3.12~3.49 (m, 4 H), 2.05 (2 H, m), 1.85 (2 H,m), 1.19 (9 H, m), 1.02 (3 H, t)
43
1-methyl-5-{2-ethoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.88 (1 H, d), 7.92 (1 H, dd), 7.12 (1 H,d), 4.36 (2 H, q), 4.27 (3 H, s), 3.65 (4 H, t), 3.33(4 H, m), 2.92 (2 H, t), 2.58 (2 H, t), 2.46 (4 H, t),1.85 (2 H, m), 1.63 (3 H, t), 1.18 (3 H, t), 1.02 (3 H, t)
44
1-methyl-5-{2-ethoxy-5-[bis(3-hydroxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.71 (1 H, s), 8.79 (1 H, d), 7.92 (1 H, dd), 7.13(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 3.70 (4 H,t), 3.38 (4 H, t), 2.93 (2 H, t), 2.55 (2 H, t), 1.80(6 H, m), 1.62 (3 H, t), 1.02 (3 H, t)
45
1-methyl-5-{2-ethoxy-5-[bis(2-hydroxypropyl)amidosulfonyl]phenyl}-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.86 (1 H, d), 7.91 (1 H, dd), 7.15 (1 H,d), 4.28 (3 H, s), 4.27 (2 H, t), 4.19 (2 H, m),3.09~3.48 (in, 4 H), 2.92 (2 H, t), 1.84 (2 H, m),1.63 (3 H, t), 1.21 (3 H, d), 1.16 (3 H, d), 1.00 (3 H, t)
46
1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.76 (1 H, s), 8.81 (1 H, d), 7.93 (1 H, dd), 7.14(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 3.81 (4 H, t),3.36 (4 H, m), 3.04 (1 H, s), 2.93 (2 H, t), 2.80 (1 H,s), 1.84 (4 H, m), 1.63 (3 H, t), 1.02 (3 H, t)
47
1-methyl-5-{2-ethoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(3-hydroxypropyl)]amidosuifonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.76 (1 H, s), 8.81 (1 H, d), 7.92 (1 H, dd), 7.14(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 3.75 (2 H, t),3.68 (4 H, t), 3.53 (2 H, t), 3.43 (2 H, t), 3.38 (2 H, t),2.93 (2 H, t), 2.68 (2 H, s), 1.86 (4 H, m), 1.63 (3 H,t), 1.02 (3 H, t)
48
1-methyl-5-{2-methoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.63 (1 H, s), 8.84 (1 H, d), 7.91 (1 H, dd), 7.17 (1 H,d), 4.27 (3 H, s), 4.13 (3 H, s), 3.67 (4 H, t), 3.22(2 H, t), 2.92 (2 H, t), 2.87 (3 H, s), 2.58 (2 H, t), 2.484 H, t), 1.85 (2 H, m), 1.01 (3 H, t)
49
1-methyl-5-{2-methoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-dlpyrimidin-7-one10.65 (1 H, s), 8.88 (1 H, d), 7.95 (1 H, dd), 7.15 (1 H,d), 4.27 (3 H, s), 4.12 (3 H, s), 3.65 (4 H, t), 3.32(4 H, m), 2.92 (2 H, t), 2.58 (2 H, t), 2.46 (4 H, t),1.85 (2 H, m), 1.19 (3 H, t), 1.01 (3 H, t)
50
1-methyl-5-{2-methoxy-5-[[1-(4-fluorobenzyl)-1-2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.65 (1 H, s), 8.91 (1 H, d), 7.96 (1 H, dd), 7.31(2 H, m), 7.16 (1 H, d), 7.01 (2 H, m), 4.41 (2 H, s),4.28 (3 H, s), 4.14 (3 H, s), 3.56 (4 H, t), 3.27 (2 H, t),2.91 (2 H, t), 2.33 (2 H, t), 2.26 (4 H, t), 1.84 (2 H,m), 0.99 (3 H, t).
51
1-methyl-5-{2-ethoxy-5-[[1-ethyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.87 (1 H, d), 7.92 (1 H, dd), 7.13 (1 H,d), 4.36 (2 H, q), 4.27 (3 H, s), 3.80 (2 H, q),3.35 (4 H, m), 2.92 (2 H, t), 2.38 (1 H, t), 1.85 (2 H,m), 1.63 (3 H, t), 1.20 (3 H, t), 1.02 (3 H, t)
52
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.88 (1 H, d), 7.93 (1 H, dd), 7.14 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.81 (2 H, t), 3.36(4 H, m), 2.94 (2 H, t), 2.02 (3 H, m), 1.86 (2 H, m),1.21 (3 H, t), 1.18 (3 H, t), 1.02 (3 H, t)
53
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.63 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.15 (1 H,d), 4.27 (3 H, s), 4.26 (2 H, t), 3.70 (4 H, t), 3.26(2 H, t), 2.97 (2 H, q), 2.87 (3 H, s), 2.63 (2 H, t),2.54 (4 H, t), 2.04 (2 H, m), 1.41 (3 H, t), 1.18 (3 H, t)
54
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.90 (1 H, d), 7.92 (1 H, dd), 7.13 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.69 (4 H, t), 3.34(4 H, m), 2.97 (2 H, q), 2.63 (2 H, t), 2.52 (4 H, t),2.04 (2 H, m), 1.41 (3 H, t), 1.19 (3 H, t), 1.18 (3 H, t)
55
1-methyl-5-{2-ethoxy-5-[[1-(4-fluorobenzyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.83 (1 H, s), 8.92 (1 H, d), 7.94 (1 H, dd), 7.31(2 H, m), 7.14 (1 H, d), 7.01 (2 H, m), 4.42 (2 H, s),4.37 (2 H, q), 4.28 (3 H, s), 3.56 (4 H, t), 3.27 (2 H,t), 2.92 (2 H, t), 2.33 (2 H, t), 2.26 (4 H, t), 1.85 (2 H,m), 1.65 (3 H, t), 1.00 (3 H, t).
56
1-methyl-5-{2-propoxy-5-[[1-(4-fluorobenzyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.92 (1 H, d), 7.92 (1 H, dd), 7.33(2 H, m), 7.16 (1 H, d), 7.02 (2 H, m), 4.41 (2 H, s),4.28 (3 H, s), 4.27 (2 H, t), 3.61 (4 H, t), 3.31 (2 H, t),2.92 (2 H, t), 2.39 (2 H, t), 2.31 (4 H, t), 2.05 (2 H,m), 1.85 (2 H, m), 1.19 (3 H, t), 1.00 (3 H, t).
57
1-methyl-5-{2-ethoxy-5-[bis(3-hydroxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolol[4,3-d]pyrimidin-7-one10.56 (1 H, s), 8.77 (1 H, d), 7.94 (1 H, dd), 7.15(1 H, d), 4.27 (3 H, s), 4.12 (3 H, s), 3.70 (4 H, t),3.37 (4 H, t), 2.93 (2 H, t), 2.15 (2 H, s), 1.80 (6 H,m), 1.01 (3 H, t)
58
1-methyl-5-{2-methoxy-5-[[1-(2-hydroxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.52 (1 H, s), 8.84 (1 H, d), 7.95 (1 H, dd), 7.17(1 H, d), 4.27 (3 H, s), 4.13 (3 H, s), 3.82 (4 H, t),3.38 (4 H, m), 2.93 (2 H, t), 2.88 (1 H, s), 2.73 (1 H,s), 1.85 (4 H, m), 1.02 (3 H, t)
59
1-methyl-5-{2-methoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.57 (1 H, s), 8.81 (1 H, d), 7.95 (1 H, dd), 7.16(1 H, d), 4.27 (3 H, s), 4.12 (3 H, s), 3.75 (2 H, t),3.68 (4 H, t), 3.52 (2 H, t), 3.43 (2 H, t), 3.38 (2 H, t),2.92 (2 H, t), 2.63 (2 H, s), 1.86 (4 H, m), 1.02 (3 H,t)
60
1-methyl-5-{2-propoxy-5-[[1-(2-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.91 (1 H, d), 7.92 (1 H, dd), 8.45(1 H, d), 7.94 (1 H, d), 7.68 (1 H, t), 7.60 (1 H, d),7.18 (1 H, t), 7.16 (1 H, d), 4.56 (2 H, s), 4.28 (3 H,s), 4.26 (2 H, t), 3.58 (4 H, t), 3.42 (2 H, t), 2.92 (2 H,t), 2.45 (2 H, t), 2.34 (4 H, t), 2.04 (2 H, m), 1.85(2 H, m), 1.19 (3 H, t), 1.01 (3 H, t).
61
1-methyl-5-{2-ethoxy-5-[[1-(3-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.91 (1 H, d), 8.54 (1 H, dd), 8.48(1 H, d), 7.95 (1 H, dd), 7.84 (1 H, d), 7.31 (1 H, dd),7.15 (1 H, d), 4.48 (2 H, s), 4.38 (2 H, q), 4.28 (3 H,s), 3.56 (4 H, t), 3.32 (2 H, t), 2.92 (2 H, t), 2.38 (2 H,t), 2.28 (4 H, t), 1.85 (2 H, m), 1.65 (3 H, t), 1.00(3 H, t).
62
1-methyl-5-{2-propoxy-5-[[1-(3-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.92 (1 H, d), 8.54 (1 H, d), 8.49 (1 H,s), 7.94 (1 H, dd), 7.82 (1 H, d), 7.30 (1 H, dd),7.16 (1 H, d), 4.47 (2 H, s), 4.28 (3 H, s), 4.27 (2 H, t),3.60 (4 H, t), 3.34 (2 H, t), 2.92 (2 H, t), 2.41 (2 H, t),2.32 (4 H, t), 2.05 (2 H, m), 1.85 (2 H, m), 1.19 (3 H,t), 1.00 (3 H, t).
63
1-methyl-5-{2-propoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.91 (1 H, d), 8.S6 (2 H, d), 7.93 (1 H,dd), 7.29 (2 H, d), 7.15 (1 H, d), 4.48 (2 H, s), 4.27(3 H, s), 4.26 (2 H, t), 3.55 (4 H, t), 3.33 (2 H, t), 2.92(2 H, t), 2.38 (2 H, t), 2.26 (4 H, t), 2.04 (2 H, m),1.86 (2 H, m), 1.19 (3 H, t), 1.01 (3 H, t)
64
1-methyl-5-{2-ethoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.83 (1 H, s), 8.92 (1 H, d), 8.56 (2 H, dd), 7.93 (1 H,dd), 7.29 (2 H, d), 7.14 (1 H, d), 4.49 (2 H, s), 4.38(2 H, q), 4.28 (3 H, s), 3.55 (4 H, t), 3.34 (2 H, t),2.92 (2 H, t), 2.39 (2 H, t), 2.26 (4 H, t), 1.82 (2 H,m), 1.65 (3 H, t), 1.01 (3 H, t)
65
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.89 (1 H, d), 7.91 (1 H, dd),7.27-7.32 (5 H, m), 7.14 (1 H, d), 4.38 (2 H, s), 4.27(s, 3 H), 4.26 (2 H, t), 3.55 (2 H, t), 3.33 (2 H, t), 2.92(2 H, t), 2.03 (2 H, m), 1.83 (2 H, m), 1.50 (2 H, m),1.18 (3 H, t), 1.03 (3 H, t)
66
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(3-hydroxypropyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.87 (1 H, d), 7.92 (1 H, dd),7.28-7.33 (5 H, m), 7.14 (1 H, d), 4.39 (2 H, s), 4.36(2 H, t), 4.28 (s, 3 H), 3.55 (2 H, t), 3.33 (2 H, t), 2.92(2 H, t), 1.83 (2 H, m), 1.64 (3 H, t), 1.50 (2 H, m),0.99 (3 H, t)
67
1-methyl-5-{2-ethoxy-5[[1-benzyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.92 (1 H, d), 7.94 (1 H, dd),7.28-7.34 (5 H, m), 7.14 (1 H, d), 4.45 (2 H, s), 4.36(2 H, t), 4.27 (s, 3 H), 3.56 (2 H, t), 3.32 (2 H, t), 2.92(2 H, t), 1.85 (2 H, m), 1.64 (3 H, t), 0.99 (3 H, t)
68
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihyro-7H-pyrazolol[4,3-d]pyrimidin-7-one10.81 (1 H, s), 8.94 (1 H, d), 7.95 (1 H, dd),7.28-7.34 (5 H, m), 7.15 (1 H, d), 4.45 (2 H, s),4.27 (s, 3 H), 4.26 (2 H, t), 3.57 (2 H, t), 3.33 (2 H, t),2.92 (2 H, t), 2.03 (2 H, m), 1.83 (2 H, m), 1.18 (3 H,t), 0.99 (3 H, t)
69
1-methyl-5-{2-ethoxy-5-[[1-ethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.78 (1 H, s), 8.85 (1 H, d), 7.91 (1 H, dd), 7.12(1 H, d), 4.36 (2 H, q), 4.26 (s, 3 H), 3.74 (2 H, t),3.34 (2 H, t), 3.32 (2 H, q), 2.92 (2 H, t), 1.85 (2 H,m), 1.78 (2 H, m), 1.62 (3 H, t), 1.18 (3 H, t), 1.01(3 H, t)
70
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.84 (1 H, d), 7.90 (1 H, dd), 7.13(1 H, d), 4.27 (s, 3 H), 4.24 (2 H, t), 3.74 (2 H, t), 3.35(2 H, t), 3.32 (2 H, q), 2.93 (2 H, t), 2.02 (2 H, m),1.85 (2 H, m), 1.78 (2 H, m), 1.18 (3 H, t), 1.17 (3 H, t), 1.02 (3 H, t)
71
1-methyl-5-{2-ethoxy-5-[[1-(2-furanylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.86 (1 H, d), 7.86 (1 H, dd), 7.25(1 H, m), 7.22 (1 H, m), 7.07 (1 H, d), 6.22 (2 H, m),4.55 (2 H, s), 4.35 (2 H, q), 4.27 (3 H, s), 3.62 (4 H,t), 3.34 (2 H, t), 2.92 (2 H, t), 2.53 (2 H, t), 2.44 (4 H,t), 1.85 (2 H, m), 1.63 (3 H, t), 1.00 (3 H, t)
72
1-methyl-5-{2-propoxy-5-[[1-(2-furanylmethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.87 (1 H, d), 7.86 (1 H, dd), 7.25(1 H, m), 7.22 (1 H, m), 7.08 (1 H, d), 6.22 (2 H, m),4.55 (2 H, s), 4.27 (3 H, s), 4.24 (2 H, t), 3.66 (4 H, t),3.33 (2 H, t), 2.92 (2 H, t), 2.53 (2 H, t), 2.44 (4 H, t),2.02 (2 H, m), 1.85 (2 H, m), 1.17 (3 H, t), 1.00 (3 H,t)
73
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-dimethylaminoethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.94 (1 H, d), 7.95 (1 H, dd),7.29-7.33 (5 H, m), 7.14 (1 H, d), 4.42 (2 H, s), 4.38(2 H, q), 4.27 (s, 3 H), 3.25 (2 H, m), 2.92 (2 H, t),2.32 (2 H, m), 2.08 (6 H, s), 1.85 (2 H, m), 1.65 (3 H,t), 1.00 (3 H, t)
74
1-methyl-5-{2-ethoxy-5-[[1-phenyl-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-ethyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.71 (1 H, d), 7.67 (1 H, dd), 7.32(3 H, m), 7.15 (2 H, m), 7.06 (1 H, d), 4.36 (2 H, q),4.27 (3 H, s), 3.76 (2 H, t), 3.64 (4 H, t), 2.88 (2 H, t),2.53 (2 H, t), 2.44 (4 H, t), 1.82 (2 H, m), 1.64 (3 H,t), 1.01 (3 H, t)
75
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-dimethylamino)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.86 (1 H, d), 7.88 (1 H, dd), 7.16(1 H, d), 4.27 (s, 3 H), 4.26 (2 H, t), 3.29 (2 H, t),2.92 (2 H, t), 2.87 (3 H, s), 2.72 (2 H, t), 2.40 (6 H, s),2.04 (2 H, m), 1.85 (2 H, m), 1.18 (3 H, t), 1.01 (3 H, t)
76
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-dimethylamino)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.86 (1 H, d), 7.88 (1 H, dd), 7.16(1 H, d), 4.37 (2 H, q), 4.27 (s, 3 H), 3.22 (2 H, t),2.92 (2 H, t), 2.86 (3 H, s), 2.60 (2 H, t), 2.32 (6 H, s),1.85 (2 H, m), 1.64 (3 H, t), 1.01 (3 H, t)
77
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-[2-(4-ethylpiperazin-1-yl)]ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.85 (1 H, d), 7.88 (1 H, dd), 7.14(1 H, d), 4.37 (2 H, q), 4.27 (s, 3 H), 3.22 (2 H, t),2.92 (2 H, t), 2.87 (3 H, s), 2.58 (2 H, t), 2.52 (4 H, t),2.44 (4 H, t), 2.38 (2 H, q), 1.85 (2 H, m), 1.65 (3 H,t), 1.06 (2 H, t), 1.02 (3 H, t)
78
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.14(1 H, d), 4.27 (3 H, s), 4.26 (2 H, t), 3.22 (2 H, t),2.93 (2 H, t), 2.86 (3 H, s), 2.54 (2 H, t), 2.40 (4 H, t),2.04 (2 H, m), 1.85 (2 H, m), 1.54 (4 H, t), 1.41 (2 H,m), 1.18 (3 H, t), 1.02 (3 H, t)
79
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.83 (1 H, s), 8.85 (1 H, d), 7.89 (1 H, dd), 7.13 (1 H,d), 4.37 (2 H, q), 4.27 (3 H, s), 3.21 (2 H, t), 2.93(2 H, t), 2.86 (3 H, s), 2.54 (2 H, t), 2.40 (4 H, t), 1.86(2 H, m), 1.64 (3 H, t), 1.53 (4 H, t), 1.40 (2 H, m),1.02 (3 H, t)
80
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.87 (1 H, d), 7.89 (1 H, dd), 7.15(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.22 (2 H, t),2.92 (2 H, t), 2.86 (3 H, s), 2.70 (2 H, t), 2.54 (4 H,m), 2.04 (2 H, m), 1.86 (2 H, m), 1.75 (4 H, m), 1.18(3 H, t), 1.02 (3 H, t)
81
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.85 (1 H, d), 7.88 (1 H, dd), 7.13(1 H, d), 4.37 (2 H, q), 4.27 (3 H, s), 3.22 (2 H, t),2.92 (2 H, t), 2.86 (3 H, s), 2.70 (2 H, t), 2.53 (4 H,m), 1.86 (2 H, m), 1.75 (4 H, m), 1.64 (3 H, t), 1.02(3 H, t)
82
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.93 (1 H, d), 7.95 (1 H, dd),7.29-7.32 (5 H, m), 7.13 (1 H, d), 4.46 (2 H, s), 4.38(2 H, q), 4.28 (3 H, s), 3.30 (2 H, t), 2.92 (2 H, t),2.33 (2 H, t), 2.24 (4 H, t), 1.85 (2 H, m), 1.65 (3 H, t),1.46 (4 H, t), 1.35 (2 H, m), 1.00 (3 H, t)
83
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.89 (1 H, s), 8.94 (1 H, d), 7.95 (1 H, dd),7.28-7.33 (5 H, m), 7.14 (1 H, d), 4.45 (2 H, s), 4.28(3 H, s), 4.26 (2 H, t), 3.33 (2 H, t), 2.92 (2 H, t), 2.38(2 H, t), 2.27 (4 H, t), 2.05 (2 H, m), 1.85 (2 H, m),1.50 (4 H, t), 1.36 (2 H, m), 1.19 (3 H, t), 1.00 (3 H, t)
84
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.89 (1 H, s), 8.94 (1 H, d), 7.95 (1 H, dd),7.30-7.34 (5 H, m), 7.14 (1 H, d), 4.42 (2 H, s), 4.28(3 H, s), 4.27 (2 H, t), 3.32 (2 H, t), 2.92 (2 H, t), 2.54(2 H, t), 2.45 (4 H, s), 2.05 (2 H, m), 1.85 (2 H, m),1.72 (4 H, m), 1.19 (3 H, t), 1.00 (3 H, t)
85
1-methyl-5-{2-ethoxy-5-[[1-benzyl-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.93 (1 H, d), 7.95 (1 H, dd),7.29-7.34 (5 H, m), 7.14 (1 H, d), 4.43 (2 H, s), 4.38(2 H, q), 4.28 (3 H, s), 3.32 (2 H, t), 2.92 (2 H, t),2.55 (2 H, t), 2.46 (4 H, m), 1.85 (2 H, m), 1.72 (4 H,m), 1.65 (3 H, t), 1.00 (3 H, t)
86
1-methyl-5-{2-propoxy-5-[1-(2-pyridyl)-1-(2-hydroxyethyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.85 (1 H, d), 7.92 (1 H, dd), 7.33(2 H, m), 7.12 (1 H, d), 6.54 (1 H, dd), 6.18 (1 H,ddd), 4.36 (2 H, q), 4.27 (s, 3 H), 4.10 (2 H, t), 3.39(2 H, t), 2.92 (2 H, t), 1.85 (2 H, m), 1.65 (3 H, t),1.02 (3 H, t)
87
1-methyl-5-{2-propoxy-5-[[1-(2-pyridylmethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.91 (1 H, d), 7.92 (1 H, dd), 8.45(1 H, d), 7.95 (1 H, d), 7.68 (1 H, ddd), 7.57 (1 H, d),7.17 (1 H, t), 7.13 (1 H, d), 4.55 (2 H, s), 4.28 (3 H,s), 4.26 (2 H, t), 3.45 (2 H, t), 2.93 (2 H, t), 2.47 (2 H,t), 2.33 (4 H, t), 2.05 (2 H, m), 1.86 (2 H, m), 1.50(4 H, t), 1.38 (2 H, m), 1.19 (3 H, t), 1.01 (3 H, t)
88
1-methyl-5-{2-ethoxy-5-[[1-(2-pyridylmethyl)-1-(2-piperidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-dlpyrimidin-7-one10.83 (1 H, s), 8.90 (1 H, d), 8.45 (1 H, d), 7.95 (1 H,d), 7.68 (1 H, ddd), 7.56 (1 H, d), 7.18 (1 H, m), 7.13(1 H, dd), 4.56 (2 H, s), 4.38 (2 H, q), 4.28 (3 H, s),3.46 (2 H, t), 2.92 (2 H, t), 2.48 (2 H, t), 2.34 (4 H, t),1.85 (2 H, m), 1.65 (3 H, t), 1.52 (4 H, t), 1.38 (2 H,m), 1.02 (3 H, t)
89
1-methyl-5-{2-propoxy-5-[[1-(3-pyridylmethyl)-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.93 (1 H, d), 8.54 (1 H, dd), 8.50(1 H, s), 7.94 (1 H, dd), 7.81 (1 H, d), 7.30 (1 H, dd),7.15 (1 H, d), 4.46 (2 H, s), 4.28 (3 H, s), 4.27 (2 H,t), 3.36 (2 H, t), 2.92 (2 H, t), 2.58 (2 H, t), 2.48 (4 H,t), 2.05 (2 H, m), 1.85 (2 H, m), 1.73 (4 H, t), 1.19(3 H, t), 1.00 (3 H, t)
90
1-methyl-5-{2-ethoxy-5-[[1-(3-pyridylmethyl)-1-(2-pyrrolidin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.91 (1 H, d), 8.54 (1 H, dd), 8.50(1 H, d), 7.94 (1 H, dd), 7.81 (1 H, d), 7.30 (1 H, dd),7.15 (1 H, d), 4.46 (2 H, s), 4.38 (2 H, q), 4.28 (3 H,s), 3.37 (2 H, t), 2.92 (2 H, t), 2.60 (2 H, t), 2.50 (4 H,t), 1.85 (2 H, m), 1.74 (4 H, t), 1.65 (3 H, t), 1.00(3 H, t)
91
1-methyl-5-{2-propoxy-5-[[1-(2-acetoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.87 (1 H, d), 7.92 (1 H, dd), 7.15(1 H, d), 4.30 (2 H, t), 4.27 (3 H, s), 4.25 (2 H, t),3.82 (2 H, t), 3.48 (2 H, t), 3.38 (2 H, t), 2.93 (2 H, t),2.06 (3 H, s), 2.04 (2 H, m), 1.85 (2 H, m), 1.17 (3 H,t), 1.02 (3 H, t)
92
1-methyl-5-{2-propoxy-5-[[1-(3-acetoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolol[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.82 (1 H, d), 7.90 (1 H, dd), 7.14(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 4.08 (2 H, t),3.72 (2 H, t), 3.35 (2 H, t), 3.27 (2 H, t), 2.92 (2 H, t),2.05 (3 H, s), 2.04 (2 H, m), 1.95 (2 H, m), 1.85 (2 H,m), 1.78 (2 H, m), 1.17 (3 H, t), 1.02 (3 H, t)
93
1-methyl-5-{2-propoxy-5-[bis(3-acetoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.86 (1 H, d), 7.88 (1 H, dd), 7.14(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 4.08 (4 H, t),3.26 (4 H, t), 2.92 (2 H, t), 2.03 (6 H, s), 2.02 (2 H,m), 1.94 (4 H, m), 1.85 (2 H, m), 1.17 (3 H, t), 1.02(3 H, t)
94
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.88 (1 H, d), 7.90 (1 H, dd), 7.12 (1 H,d), 4.27 (3 H, s), 4.24 (4 H, m), 3.42 (2 H, t),3.34 (2 H, q), 2.92 (2 H, t), 2.04 (3 H, s), 2.02 (2 H,m), 1.85 (2 H, m), 1.20 (3 H, t), 1.17 (3 H, t), 1.02(3 H, t)
95
1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.81 (1 H, s), 8.85 (1 H, d), 7.88 (1 H, dd), 7.15 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.83 (2 H, t), 3.74(4 H, t), 3.28 (2 H, t), 3.22 (2 H, t), 2.92 (2 H, t), 2.72(2 H, t), 2.58 (4 H, t), 2.03 (2 H, m), 1.85 (2 H, m),1.18 (3 H, t), 1.02 (3 H, t)
96
1-methyl-5-{2-propoxy-5-[[1-(2-acetoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.88 (1 H, d), 7.91 (1 H, dd), 7.13 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 4.23 (2 H, t), 3.63(4 H, t), 3.48 (2 H, t), 3.35 (2 H, t), 2.92 (2 H, t), 2.58(2 H, t), 2.44 (4 H, t), 2.04 (2 H, m), 2.02 (3 H, s),1.85 (2 H, m), 1.17 (3 H, t), 1.02 (3 H, t)
97
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-acetoxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.87 (1 H, d), 7.90 (1 H, dd), 7.12(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 4.10 (2 H, t),3.30 (2 H, q), 3.26 (2 H, t), 2.92 (2 H, t), 2.05 (2 H,m), 2.04 (3 H, s), 1.95 (2 H, m), 1.85 (2 H, m), 1.18(6 H, t), 1.02 (3 H, t)
98
1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.89 (1 H, d), 7.92 (1 H, dd), 7.12 (1 H,d), 4.27 (3 H, s), 4.24 (2 H, t), 3.64 (4 H, t), 3.56(2 H, t), 3.43 (2 H, t), 3.37 (2 H, t), 3.29 (3 H, s), 2.92(2 H, t), 2.60 (2 H, t), 2.45 (4 H, t), 2.03 (2 H, m),1.85 (2 H, m), 1.18 (3 H, t), 1.02 (3 H, t)
99
1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.86 (1 H, d), 7.91 (1 H, dd), 7.13 (1 H,d), 4.27 (3 H, s), 4.25 (2 H, t), 3.74 (2 H, t), 3.56(2 H, t), 3.38 (4 H, m), 3.29 (3 H, s), 2.92 (2 H, t),2.02 (2 H, m), 1.85 (4 H, m), 1.17 (3 H, t), 1.02 (3 H,t)
100
1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.88 (1 H, d), 7.92 (1 H, dd), 7.11(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 3.64 (4 H, t),3.55 (2 H, t), 3.43 (2 H, t), 3.37 (2 H, t), 3.29 (3 H, s),2.92 (2 H, t), 2.60 (2 H, t), 2.45 (4 H, t), 1.86 (2 H,m), 1.63 (3 H, t), 1.02 (3 H, t)
101
1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.89 (1 H, d), 7.93 (1 H, dd), 7.16(1 H, d), 4.39 (2 H, q), 4.30 (3 H, s), 3.81 (2 H, t),3.72 (2 H, t), 3.44 (2 H, t), 3.41 (3 H, s), 3.36 (2 H, t),2.96 (2 H, t), 1.88 (2 H, m), 1.66 (3 H, t), 1.05 (3 H, t)
102
1-methyl-5-{2-ethoxy-5-[[1-(2-methoxyethyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.88 (1 H, d), 7.94 (1 H, dd), 7.15(1 H, d), 4.39 (2 H, q), 4.29 (3 H, s), 3.76 (2 H, t),3.59 (2 H, t), 3.41 (4 H, m), 3.32 (3 H, s), 2.95 (2 H,t), 1.87 (2 H, m), 1.84 (2 H, m), 1.66 (3 H, t), 1.05(3 H, t)
103
1-methyl-5-{2-propoxy-5-[bis(3-methoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.90 (1 H, d), 7.92 (1 H, dd), 7.15(1 H, d), 4.29 (3 H, s), 4.27 (2 H, t), 3.43 (4 H, t),3.32 (6 H, s), 3.29 (4 H, t), 2.96 (2 H, t), 2.05 (2 H,m), 1.89 (6 H, m), 1.20 (3 H, t), 1.05 (3 H, t)
104
1-methyl-5-{2-propoxy-5-[[1-(2-hydroxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.84 (1 H, d), 7.90 (m, dd), 7.13(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.65 (8 H, m),3.49 (4 H, t), 3.42 (2 H, t), 2.94 (2 H, t), 2.64 (2 H,t), 2.44 (4 H, t), 2.03 (2 H, m), 1.85 (2 H, m), 1.17(3 H, t), 1.01 (3 H, t)
105
1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.88 (1 H, d), 7.93 (1 H, dd), 7.12(1 H, d), 4.27 (3 H, s), 4.25 (2 H, t), 3.67 (2 H, t),3.65 (4 H, t), 3.57 (2 H, t), 3.48 (2 H, t), 3.43 (2 H, t),3.38 (2 H, t), 3.33 (3 H, s), 2.92 (2 H, t), 2.62 (2 H, t),2.46 (4 H, t), 2.03 (2 H, m), 1.85 (2 H, m), 1.18 (3 H,t), 1.02 (3 H, t)
106
1-methyl-5-{2-propoxy-5-[[1-(2-methoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.87 (1 H, d), 7.89 (1 H, dd), 7.13(1 H, d), 4.26 (3 H, s), 4.24 (2 H, q), 3.78 (2 H, t),3.69 (2 H, t), 3.40 (2 H, t), 3.38 (3 H, s), 3.32 (2 H, t),2.92 (2 H, t), 2.03 (2 H, m), 1.88 (2 H, m), 1.17 (3 H,t), 1.02 (3 H, t)
107
1-methyl-5-{2-ethoxy-5-[[1-methyl-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.82 (1 H, s), 8.83 (1 H, d), 7.88 (1 H, dd), 7.14(1 H, d), 4.36 (4 H, q), 4.26 (3 H, s), 3.79 (2 H, t),3.24 (2 H, t), 2.92 (2 H, t), 2.89 (3 H, s), 1.85 (2 H,m), 1.62 (3 H, s), 1.01 (3 H, t)
108
1-methyl-5-{2-ethoxy-5-[bis(3-acetoxypropyl)amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.80 (1 H, s), 8.84 (1 H, d), 7.88 (1 H, dd), 7.13(1 H, d), 4.36 (2 H, q), 4.27 (3 H, s), 4.08 (4 H,t), 3.26 (4 H, t), 2.92 (2 H, t), 2.03 (6 H, s),1.94 (4 H, m), 1.85 (2 H, m), 1.64 (3 H, s), 1.01(3 H, t)
109
1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.87 (1 H, d), 7.90 (1 H, dd), 7.14(1 H, d), 4.26 (3 H, s), 4.24 (2 H, t), 3.80 (2 H,t), 3.48 (2 H, t), 3.32 (3 H, s), 3.30 (4 H, m),2.92 (2 H, t), 2.03 (2 H, m), 1.92 (2 H, m), 1.85(2 H, m), 1.17 (3 H, t), 1.02 (3 H, t)
110
1-methyl-5-{2-propoxy-5-[[1-methyl-1-(3-dimethylaminopropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.88 (1 H, d), 7.90 (1 H, dd), 7.15(1 H, d), 4.30 (s, 3 H), 4.27 (2 H, t), 3.15 (2 H,t), 2.95 (2 H, t), 2.83 (3 H, s), 2.43 (2 H, t),2.30 (6 H, s), 2.06 (2 H, m), 1.89 (2 H, m), 1.80(2 H, m), 1.20 (3 H, t), 1.05 (3 H, t)
111
1-methyl-5-{2-propoxy-5-[[1-(2-ethoxyethyl)-1-(2-morpholin-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.85 (1 H, s), 8.88 (1 H, d), 7.92 (1 H, dd), 7.12(1 H, d), 4.27 (3 H, s), 4.24 (2 H, t), 3.64 (4 H,t), 3.59 (2 H, t), 3.44 (2 H, q), 3.42 (2 H, t), 3.39(2 H, t), 2.92 (2 H, t), 2.62 (2 H, t), 2.46 (4 H,t), 2.03 (2 H, t), 1.85 (2 H, m), 1.18 (3 H, t),1.12 (3 H, t), 1.02 (3 H, t)
112
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-(3-morpholin-1-yl)propyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.12(1 H, d), 4.26 (3 H, s), 4.24 (2 H, t), 3.70 (4 H,t), 3.30 (2 H, q), 3.23 (2 H, t), 2.92 (2 H, t),2.45 (4 H, t), 2.42 (2 H, t), 2.03 (2 H, m), 1.85(4 H, m), 1.17 (3 H, t), 1.15 (3 H, t), 1.02 (3 H,t)
113
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(3-morpholin-1-yl)propyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.91 (1 H, d), 7.91 (1 H, dd),7.27-7.32 (5 H, m), 7.14 (1 H, d), 4.37 (2 H, s), 4.27(3 H, s), 4.26 (2 H, t), 4.24 (2 H, t), 3.57 (4 H, t), 3.20(2 H, t), 2.92 (2 H, t), 2.19 (4 H, t), 2.04 (2 H, m),1.84 (2 H, m), 1.58 (2 H, m), 1.18 (3 H, t), 0.99 (3 H,t)
114
1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(2-acetoxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.87 (1 H, d), 7.89 (1 H, dd), 7.13(1 H, d), 4.26 (3 H, s), 4.22 (2 H, t), 3.41 (4 H, m),3.31 (2 H, t), 3.29 (3 H, s), 2.92 (2 H, t), 2.04 (2 H,m), 2.02 (3 H, s), 1.92 (2 H, m), 1.86 (4 H, m), 1.17(3 H, t), 1.02 (3 H, t)
115
1-methyl-5-{2-ethoxy-5-[[1-(3-acetoxypropyl)-1-(3-hydroxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.76 (1 H, s), 8.82 (1 H, d), 7.90 (1 H, dd), 7.13(1 H, d), 4.36 (2 H, q), 4.26 (3 H, s), 4.08 (2 H, t),3.72 (2 H, t), 3.35 (2 H, t), 3.27 (2 H, t), 2.92 (2 H, t),2.43 (1 H, s), 2.02 (3 H, s), 2.04 (2 H, m), 1.94(2 H, m), 1.86 (2 H, m), 1.78 (2 H, m), 1.64 (3 H, t),1.01 (3 H, t)
116
1-methyl-5-{2-propoxy-5-[[1-(3-ethoxyethyl)-1-(2-hydroxyethyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.84 (1 H, s), 8.87 (1 H, d), 7.89 (1 H, dd), 7.14(1 H, d), 4.26 (3 H, s), 4.25 (2 H, t), 3.78 (2 H, t),3.74 (2 H, t), 3.54 (2 H, q), 3.39 (2 H, t), 3.32 (2 H, t),2.92 (2 H, t), 2.03 (2 H, m), 1.85 (2 H, m), 1.19 (3 H,t), 1.17 (3 H, t), 1.02 (3 H, t)
117
1-methyl-5-{2-propoxy-5-[[1-benzyl-1-(4-morpholin-1-yl)butyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.91 (1 H, d), 7.91 (1 H, dd),7.27-7.30 (5 H, m), 7.14 (1 H, d), 4.37 (2 H, s), 4.27(3 H, s), 4.25 (2 H, t), 3.62 (4 H, t), 3.17 (2 H, t), 2.92(2 H, t), 2.30 (4 H, t), 2.15 (2 H, t), 2.04 (2 H, m),1.84 (2 H, m), 1.35 (4 H, m), 1.18 (3 H, t), 0.99 (3 H,t)
118
1-methyl-5-{2-propoxy-5-[[1-(3-methoxypropyl)-1-(3-acetoxypropyl)]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.86 (1 H, s), 8.88 (1 H, d), 7.90 (1 H, dd), 7.14(1 H, d), 4.28 (3 H, s), 4.26 (2 H, t), 4.08 (2 H, t),3.41 (2 H, t), 3.30 (3 H, s), 3.27 (2 H, t), 3.25 (2 H, t),2.93 (2 H, t), 2.06 (2 H, m), 2.03 (3 H, s), 1.92 (2 H,m), 1.86 (4 H, m), 1.19 (3 H, t), 1.03 (3 H, t)
119
1-methyl-5-{2-propoxy-5-[[1-ethyl-1-[2-(morpholin-N-oxide)-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.87 (1 H, s), 8.86 (1 H, d), 7.89 (1 H, dd), 7.17 (1 H,d), 4.36 (2 H, m), 4.28 (3 H, s), 4.26 (2 H, t), 3.84(2 H, d), 3.77 (4 H, m), 3.45 (4 H, m), 3.35 (2 H, q),2.92 (2 H, t), 2.03 (2 H, m), 1.85 (2 H, m), 1.22 (3 H,t), 1.18 (3 H, t), 1.01 (3 H, t)
120
1-methyl-5-{2-propoxy-5-[[1-methyl-1-[2-(morpholin-N-oxide)-1-yl)ethyl]amidosulfonyl]phenyl}-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one10.88 (1 H, s), 8.88 (1 H, d), 7.87 (1 H, dd), 7.17 (1 H,d), 4.41 (2 H, t), 4.27 (3 H, s), 4.26 (2 H, t), 3.80(2 H, d), 3.70 (2 H, t), 3.60 (2 H, t), 3.43 (2 H, t), 3.23(2 H, t), 2.92 (2 H, t), 2.03 (2 H, m), 1.85 (2 H, m),1.18 (3 H, t), 1.01 (3 H, t)
Example 121 Capsules
[0162]
[0000] Quantity/1000 Formulation Capsules Active ingredient (Pyrazolopyrimidinone derivatives) 20 g Starch 80 g Lactose 60 g Microcrystalline cellulose 35 g 10% Polyvinylpyrrolidone ethanol solution q.s. Magnesium stearate 0.5 g Total 1000 Capsules
The active ingredient containing pyrazolopyrimidinone derivatives and the excipients are passed through a #80 mesh sieve, weigh out the appropriate amount of active ingredient and the excipients according the formulation. Granulate the powder mixture with 10% polyvinylpyrrolidone ethanol solution, and pass through a #16 mesh sieve to obtain suitable granules. After drying at 65° C., the granules were screened through a #14 sieve and blended with the magnesium stearate. Test the content of active ingredient in the granules, calculate the fill weight, and then fill the granules in capsules.
Example 122 Tablets
Wet Granulation
[0163]
[0000]
Quantity/1000
Formulation
Tablets
Active ingredient (Pyrazolopyrimidinone derivatives)
20 g
Lactose
120 g
Microcrystalline cellulose
40 g
8% Starch paste
q.s.
Sodium starch glycolate
10 g
Magnesium stearate
1.0 g
Total 1000 Tablets
[0164] Pass the active ingredient containing pyrazolopyrimidinone derivatives, microcrystalline cellulose, lactose, sodium starch glycolate through #80 mesh sieve, mix well. Granulate the powder mixture with 8% starch paste, and pass through a #16 mesh sieve to obtain suitable granules. After drying, the granules were screened and blended with the magnesium stearate. Test the content of active ingredient in the granules, calculate the tablet weight, and then compress the tablets.
Example 123 Tablets
Direct Compression
[0165]
[0000] Quantity/1000 Formulation Tablets Active ingredient (Pyrazolopyrimidinone derivative) 20.0 g Microcrystalline cellulose 30.0 g Lactose, anhydrous 45.0 g Polyvinyl pyrrolidone 3.0 g Aerosil 0.2 g Magnesium stearate 0.5 g Total 1000 Tablets
Charge the active ingredient containing pyrazolopyrimidinone derivatives, lactose, polyvinyl pyrrolidone, aerosol in a mixer and mix well. Blend the mixture with magnesium stearate and then compress into tablets.
Test 1 Pharmacodynamic Test
[0166] The test was carried out based on the methods reported (International Journal of Impotence Research 2002, 14, 251 and The Journal of Urology 1992, 147, 1124). After fasted for 12 hours, 4 male SD rats were randomized into each group. After anesthetizing the rats with sodium pentobarbital (50 mg/kg, i.p.), the penile skin was incised and the prepuce was degloved to expose completely the corpora cavernosa (CC). A needle linked to an electrophysiology instrument was inserted into the CC on the right side in order to measure the intracavernous pressure (ICP). The right carotid artery was cannulated in a similar manner to the polyethylene tube in order to monitor the mean blood pressure (MBp) continuously. After exposing the lateral surface of the prostate via an incision in the midline inferior abdomen, a bipolar platinum microelectrode was placed on the cavernous nerve. Electric stimulation was performed at 2 Hz, for 60 s with a pulse duration of 5 ms and 3V using a stimulator. The compounds were administrated orally (5 mg/kg). The change of the ICP and MBp were monitored continuously before and after the administration. The effect of the compounds on the erection induced by electric stimulation was evaluated by the ratio of ICP to MBp. The parameter (ICP/MBp) was used to estimate the influence of the compounds to the rat corpora cavernosa. We tested the effect of sildenafil and some of the example compounds on the rat corpora cavernosa according to the aforesaid method. The statistical significance of the differences between groups was calculated using Duncan's multiple comparison. The results are shown below:
[0000] Test compound ICP/BP blank 27.5 ± 2.3 sildenafil 80.1 ± 5.1*** 33 72.3 ± 28.6*** 54 86.3 ± 6.4*** 62 69.8 ± 12.2*** 75 74.2 ± 7.8*** 78 71.6 ± 8.3*** 89 70.9 ± 9.8*** 91 55.8 ± 16.8* 92 86.4 ± 4.8*** 93 77.2 ± 24.8*** 95 57.2 ± 10.1* 96 81.0 ± 9.5*** 97 72.0 ± 13.5*** 99 56.2 ± 9.3*** 111 89.1 ± 6.9*** 118 77.9 ± 2.3*** Note: Compared with the blank group, *P < 0.05, ***P < 0.001
As shown in the results, the test compounds have the same pharmacodynamic effect as sildenafil. After administration, the ICP of the rats CC, and the ICP/BP increase significantly, the penile erections of the rats are enhanced, thus, the compounds can be administrated orally for the treatment of erectile dysfunction.
Test 2 Enzyme Inhibitory Activity Test
[0167] The Enzymes used in the inhibitory activity test were isolated from different kinds of tissues after appropriate treatment by FPLC using a method similar to Thrombosis Res. 1991, 62, 31 and J. Biol. Chem. 1997, 272, 2714. The PDE5 and PDE3 were isolated form human platelets, while the PDE6 was isolated form bovine retinas. The enzyme inhibitory activity test conducted immediately after the enzymes had been isolated, using a scintillation proximity assay for the direct detection of AMP/GMP by the TRKQ7100 and TRKQ7090 kit. In summary, the effect of PDE inhibitors was investigated by assaying a fixed amount of enzyme in the presence of varying inhibitor concentrations and low substrate. The final assay volume was made up to 100 μl with 10 μl assay buffer (50 mM Tris/HCl PH 7.5, 8.3 mM MgCl2, 1.7 mM EGTA), and water. Reactions were initiated with enzyme, incubate for 30 minutes at 30° C. and terminated with 50 μl yttrium silicate SPA beads suspension containing zinc sulphate. Shook for 20 minutes and settled for 30 minutes in the dark, then counted on a BECKMAN LS6500 MULTI-PURPOSE SCINTILLATION COUNTER. The IC50 value for the compounds according the present invention was calculated according the counts.
PDE5 Inhibitory Activity Test
[0168] According to the above-mentioned method, the inhibitory activities of some compounds of formula IA and IB according to the invention against PDE5 from human platelets were determined. The result is given in the following table:
[0000]
Test compound
PDE5 IC 50 (nM)
sildenafil
15.7
1
0.080
2
0.133
3
0.056
4
3.37
5
1.08
6
0.74
7
0.50
8
2.14
9
16.9
10
22.2
11
38.1
12
6.98
13
7.37
14
0.862
15
10.6
16
13.4
17
8.55
18
6.32
19
4.29
20
0.505
21
0.928
22
0.294
23
0.072
24
0.087
25
0.335
26
24.9
27
0.456
28
0.681
29
0.310
37
4.90
41
10.47
54
9.81
78
8.72
84
11.72
87
8.77
89
7.85
92
3.85
93
3.80
94
5.41
96
4.24
97
13.08
99
4.03
103
5.61
104
13.08
108
17.44
111
6.83
112
12.08
116
11.21
118
5.41
[0169] The IC 50 values for the compounds in the previous table show that most of the compounds according to the invention have a stronger potency against PDE5 than sildenafil, therefore, the dosage for oral administration is less than sildenafil and the chance to induce side effects is relatively little.
PDE6 Inhibitory Activity Test
[0170] Considering the compounds according the invention may have inhibitory activity against PDE6 distributed in retina, and then lead to visual disorders, we tested the inhibitory activities of some of the compounds of formulae IA and IB according the invention against PDE6 from bovine retina. The result is given in the following table:
[0000] Test compound PDE6 IC 50 (nM) PDE5 IC 50 (nM) PDE6 IC 50 /PDE5 IC 50 sildenafil 195.6 15.7 12.4 1 16.8 0.080 210 2 56.5 0.133 425 3 32.9 0.056 588 4 276.4 3.37 82.1 5 130.9 1.08 131 24 5.71 0.087 65.6 25 93.6 0.335 279 54 234.7 9.81 23.9 89 215.2 7.85 27.4 92 254.3 3.85 66.0 96 244.5 4.24 57.7 118 203.2 5.41 37.6
The invention uses the value of IC 50 PDE6/IC 50 PDE5 to estimate the selectivity of PDE5 versus PDE6. The results show that most of the example compounds have a better selectivity than sildenafil, thus, the chance of visual disorder induced by the compounds according to the invention is less than sildenafil.
PDE3 Inhibitory Activity Test
[0171] PDE3 is a PDE isozyme distributed mainly in heart, so the inhibiting of PDE3 may lead to side effects associated with heart. Accordingly, the inhibitory activities of some example compounds according to the invention against PDE3 were determined. The result is given in the following table:
[0000]
Test compound
PDE3 IC 50 (μM)
sildenafil
7.31
33
30.38
54
16.27
62
2.86
92
10.52
93
6.0
96
12.41
97
5.12
111
8.73
118
20.54
[0172] As shown in the results,
[0000] As shown in the table, since the 50% inhibition concentration (IC 50 ) for PDE 3 is much higher than for PDE5 in some of the compounds of the pyrazolopyrimidinone derivatives, the probability of side effects in cardiovascular system caused by the compounds of the present invention is very little.
Test 3 Acute Oral Toxicity Test
[0173] In this test male KM mouse weighting 18-22 g were used, and 10 or 11 mouse were assigned randomly to each group. The compounds of examples 23, 33, 35, 37, 41, 54, 62, 63, 89, 92, 93, 95, 96, 97, 99, 103, 104, 110, 111, 112, 118 and sildenafil were suspended in 0.5% sodium carboxymethylcellulose respectively, and administered orally with single dose of 3 g/kg. The animals were fasted for 12 hours before the administration. After the administration, the animals were observed for clinical signs of toxicity or mortality. The results were shown in the following table:
[0000] Test compound Number of mouse Number of death mortality rate (%) sildenafil 10 6 60 23 10 0 0 33 10 0 0 35 10 0 0 37 10 3 30 41 10 0 0 54 10 0 0 62 10 6 60 63 11 1 9 89 11 5 45 92 10 0 0 93 10 0 0 95 10 1 10 96 10 0 0 97 11 5 45 99 10 1 10 103 10 0 0 111 10 0 0 112 10 2 20 118 10 0 0
There were no significant clinical symptoms, weight changes and mortalities during the test. The results of autopsy in dead animals show that no abnormal signals such as bleeding of the internal organs were found. The results show that the toxicities of most of the compounds according to the present invention to mouse are significantly lower than sildenafil.
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The invention discloses a series of pyrazolopyrimidinone derivatives, which have the following chemical structure, their preparation methods and use,
It has been proved by pharmacological experiment that the said pyrazolopyrimidinone derivatives have high inhibitory activity against PDE5, and parts of them have a much stronger potency against PDE5 than against PDE6. Most of the compounds show low toxicity. The pyrazolopyrimidinone derivatives can be used in clinics for the palliative or curative treatment of symptoms or diseases relating to cardiovascular system, urinary system, especially for the palliative or curative treatment of erectile dysfunction.
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