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Non-volatile memory and non-volatile memory data rewriting method |
A nonvolatile memory and a data rewriting method of the nonvolatile memory that can readily detect a state of operation at a time of a system failure due to a power failure or the like and quickly and reliably restore the nonvolatile memory to a normal storage state by a simple method. In the nonvolatile memory including a physical block as a storage unit, the physical block having a data area (1) and a redundant area (2), the redundant area (2) includes: a logical block address storing area (3) for storing an address of a corresponding logical block; a previously used physical block address storing area (4) for storing an address of a physical block to be erased; and a status information storing area (6) for storing status information for distinguishing a state of operation in each stage occurring in performing data rewriting operation on the physical block. |
1. A nonvolatile memory comprising a physical block as a storage unit, said physical block having a data area for storing data and a redundant area for storing various management information, wherein each said redundant area includes: a logical block information storing area for storing information for identifying a logical block corresponding to a physical block including said redundant area; a previously used physical block information storing area for storing information for identifying a previously used physical block, which is an immediately preceding physical block with which the corresponding logical block was associated; and a status information storing area for storing status information for distinguishing a state of operation in each stage occurring in performing data rewriting operation using the physical block including said redundant area for data writing. 2. The nonvolatile memory as claimed in claim 1, wherein said status information storing area stores at least first status information indicating that the physical block including said status information storing area is in an erased state, second status information indicating that while data writing to the physical block including said status information storing area is completed, data of the corresponding previously used physical block is not erased, and third status information indicating that data writing to the physical block including said status information storing area is completed and that the data of the corresponding previously used physical block is erased. 3. The nonvolatile memory as claimed in claim 2, wherein the first status information, the second status information, and the third status information are represented by an identical number of bits; and the second status information is formed by changing binary data of one or a plurality of bits in a bit string representing the first status information from “1” to “0”. and the third status information is formed by changing binary data of one or a plurality of bits in a bit string representing the second status information from “1” to “0”. 4. A nonvolatile memory data rewriting method for rewriting data in a nonvolatile memory, said nonvolatile memory including a physical block as a storage unit, said physical block having a data area for storing data and a redundant area for storing various management information, said data rewriting method comprising: a first step for determining a logical block for data rewriting; a second step for determining a physical block for data writing from among empty blocks, which are erased physical blocks allowing writing; a third step for identifying a previously used physical block, which is a physical block associated with the logical block for rewriting, by referring to an address conversion table for associating the logical block with the physical block; a fourth step for writing data to the physical block for writing; a fifth step for erasing data from the previously used physical block; and a sixth step for updating the address conversion table such that the physical block for writing is associated with the logical block for rewriting; wherein in the physical block for writing, first status information indicating that the physical block for writing is in an erased state is set initially, second status information indicating that the writing of the data is completed is set after completion of processing at the fourth step, and third status information indicating that the erasure of the data from the previously used physical block is completed is set after completion of processing at the fifth step. 5. The nonvolatile memory data rewriting method as claimed in claim 4, wherein the first status information, the second status information, and the third status information are represented by an identical number of bits; and the second status information is formed by changing binary data of one or a plurality of bits in a bit string representing the first status information from “1” to “0,” and the third status information is formed by changing binary data of one or a plurality of bits in a bit string representing the second status information from “1” to “0.” 6. The nonvolatile memory data rewriting method as claimed in claim 4, wherein the second step includes: a seventh step for determining a number of empty blocks, and an eighth step for generating a random number, selecting one empty block from among a plurality of the empty blocks, and determining the empty block as a physical block to be written. 7. The nonvolatile memory data rewriting method as claimed in claim 6, wherein an empty block registration table including a plurality of storage units sequentially arranged so as to correspond in number with the empty blocks is provided, each of the storage units storing information for identifying an empty block; and the empty block to be written is determined by selecting one of the storage units in the empty block registration table according to the generated random number. 8. A nonvolatile memory data rewriting method for rewriting data in a nonvolatile memory, said nonvolatile memory including a physical block as a storage unit, said physical block having a data area for storing data and a redundant area for storing various management information, each said redundant area having a status information storing area for storing status information for distinguishing a state of operation in each stage occurring in a physical block for writing in performing data rewriting operation, said data rewriting method comprising: a first step for determining a logical block for data rewriting; a second step for determining a physical block for data writing from among empty blocks, which are erased physical blocks allowing writing; a third step for identifying a previously used physical block, which is a physical block associated with the logical block for rewriting, by referring to an address conversion table for associating the logical block with the physical block; a fourth step for writing data to the physical block for writing; a fifth step for erasing data from the previously used physical block; and a sixth step for updating the address conversion table such that the physical block for writing is associated with the logical block for rewriting; wherein the second step includes: a seventh step for determining a number of empty blocks; and an eighth step for generating a random number, selecting one empty block from among a plurality of the empty blocks, and determining the empty block as a physical block to be written. |
<SOH> BACKGROUND ART <EOH>Low-cost nonvolatile memories such for example as NAND-type flash memories suitable for storing a large amount of data have recently been widely used in household electrical appliances, portable electronic devices, and electronic devices such as memory cards and the like. When a system failure caused by a power failure, a malfunction or the like occurs in an electronic device having a flash memory, for example, part of data stored in the flash memory can be destroyed. As one method for protecting data from such a system failure, redundancy is provided to data written to the flash memory using a check sum or CRC (Cyclic Redundancy Check) code, for example, and a check sum is calculated from the data stored in the flash memory at a time of system restoration by turning on power to determine whether or not there is abnormality in the data. As another method for data protection, an auxiliary nonvolatile memory capable of writing at higher speed than the flash memory is provided in addition to the flash memory, and the auxiliary nonvolatile memory stores bus information on a predetermined number of latest states of operation (statuses). FIG. 1 is a block diagram schematically showing a configuration of an electronic device having such a conventional flash memory. In FIG. 1 , reference numeral 101 denotes the electronic device; reference numeral 102 denotes a CPU; reference numeral 103 denotes the flash memory provided as a main memory; reference numeral 104 denotes an auxiliary nonvolatile memory capable of writing at higher speed than the flash memory; reference numeral 105 denotes a bus for connecting the CPU 102 with the flash memory 103 ; reference numeral 106 denotes a bus branched off from the bus 105 and connected to the auxiliary nonvolatile memory 104 ; and reference numeral 107 denotes a signal line for supplying a control signal to the auxiliary nonvolatile memory 104 . Operation of the electronic device shown in FIG. 1 will next be described. For example, the CPU 102 supplies a control signal to the auxiliary nonvolatile memory 104 in a first half of each operation period of the flash memory 103 , and the auxiliary nonvolatile memory 104 records information on the bus 105 via the bus 106 in response to the control signal. The auxiliary nonvolatile memory 104 records the bus information on only a plurality of latest statuses of statuses occurring in data writing, reading, erasing and other processing. The auxiliary nonvolatile memory 104 therefore does not need a very high storage capacity. Thus, even when a system failure due to a power failure or the like occurs during operation in the flash memory requiring a long time for writing operation and erasure operation, the bus information on a predetermined number of statuses immediately before the system failure is recorded in the auxiliary nonvolatile memory. Hence, the bus information recorded in the auxiliary nonvolatile memory is analyzed after system restoration to thereby determine a state of operation at the time of occurrence of the system failure, detect abnormality in data in the flash memory, and restore the flash memory to a normal storage state. The conventional electronic device including a flash memory has the data protection function as described above. In the former method of using a check sum or CRC code, a state of operation at the time of a system failure cannot be detected, and therefore a complex system needs to be constructed to perform processing for system restoration or processing for restoring the data in the flash memory. In the latter method of storing bus information in the auxiliary nonvolatile memory, it is necessary to analyze the stored bus information, determine a state of operation at the time of a system failure, and restore the data in the flash memory according to the determined state of operation, and a complex system needs to be constructed to perform the data restoration processing. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram schematically showing a configuration of a conventional electronic device having a flash memory; FIG. 2 is a diagram showing a relation between a logical block and a physical block in a storage area of a nonvolatile memory; FIG. 3 is a diagram showing a data structure of management information stored in a physical block; FIG. 4 is a flowchart of data rewriting operation in the nonvolatile memory; FIG. 5 is a diagram showing changes of data within physical blocks in data rewriting; FIG. 6 is a flowchart of a storage state normalizing method according to a first embodiment of the present invention; FIG. 7 is a flowchart of processing for searching an erased physical block among abnormal blocks; FIG. 8 is a flowchart of normalization processing for an abnormal block; FIG. 9 is a diagram showing an empty block registration table and the like used in a second embodiment of the present invention; and FIG. 10 is a flowchart of a method of detecting an appropriate empty block according to the second embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Penetration master cylinder with reduced backlash and application thereof |
This invention relates to a master cylinder of the so-called “penetration” type, in which a cup (3), which is fitted inside a groove (11) of the master cylinder, bears on the wall (20) of a piston (2) in a sealing manner, and in which such wall (20) is provided with main resupply ports (51). According to the invention, the wall (20) of the piston (2) also comprises secondary resupply ports (52) having a smaller size than that of the main resupply ports (51) and disposed farther from the bottom part (33) of the cup (3), and achieving an outstanding static resupply of the master cylinder with brake fluid, with a reduced dynamic dead stroke. |
1. Penetration master cylinder, comprising at least a body (1) in which a cylindrical bore (10) is provided along an axis of symmetry (X), a piston (2) fitted for a sliding axial travel inside the bore (10), at least between a rest position and a pressure-rise position, and a sealing cup (3) having a long bent portion (31), stationarily housed inside a groove (11) provided in the bore (10), a lip (32) applied against a cylindrical wall (20) of the piston (2), in a sealing manner, so as to define a pressure chamber (4) inside the bore (10), and a bottom portion (33) joining the long bent portion (31) to the lip (32), wherein the cylindrical wall (20) of the piston provides a cavity (40), intended for the pressure chamber (4), and exhibits at least a first resupply port (51) having a determined first cross-sectional area and disposed adjacent to the bottom portion (33) of the cup (3) in the rest position of the piston (2), a position in which said first port (51) causes the pressure chamber (4) to communicate with a resupply passage (6), which is located inside the body (1) and outside the chamber (4), characterised in that it comprises at least a second port (52) having a smaller cross-sectional area than that of the first port, and in that the first and second ports (51, 52) are comparatively nearer and farther from the lip (32) of the cup (3), respectively, in the rest position of the piston (2), in which the second port (52) causes the pressure chamber (4) to communicate with the resupply passage (6). 2. Master cylinder according to claim 1, characterised in that the first and second cross-sectional areas have an area ratio at least equal to 6 and for example equal to 10. 3. Master cylinder according to claim 1 or claim 2, characterised in that the first and second ports (51, 52) are separated from each other. 4. Master cylinder according to claim 1 or claim 2, characterised in that the first and second ports (51, 52) are mutually angularly offset through a rotation about the axis of symmetry (X). 5. Master cylinder according to claim 1 or claim 2, characterised in that the first and second ports (51, 52) are interconnected. 6. Master cylinder according to claim 5, characterised in that the second ports (52) has an elongated shape extended in a direction parallel to the symmetry axle (X). 7. Master cylinder according to any one of the preceding claims, characterised in that the first and second ports (51, 52) belong to a first and a second group (510, 520) of ports, respectively, each group of ports comprising evenly distributed ports (51, 52) about the axis of symmetry. 8. Application of the master cylinder, according to any one of the preceding claims, to a braking system, comprising a hydraulic pump too. |
Self-cleaning enclosed belt conveyor for loose materials |
The self-cleaning enclosed belt conveyor for loose materials comprises a mobile belt (10) operatively connected to proper containment walls (2), where mechanical means (1, 15) are provided for, connected to said conveyor belt (10), wherein said mechanical means perform together with a bottom (8) of said containment walls (2) a recovery operation of the loose materials present in the area between the belt (10), the bottom (8) and said containment walls (2), bringing the materials back either to belt's upper stretch or to adequate containment systems. |
1. A self-cleaning enclosed belt conveyor for loose materials comprising a steel conveyor belt (10) operatively connected to proper containment walls (2), characterized by providing mechanical means (1) and (15) operatively connected to said conveyor belt (10), wherein said mechanical means perform together with a bottom (8) of said containment walls (2) a recovery operation of the loose materials present in the area between the belt (10) and the bottom (8) of said containment walls (2), in order to bring the materials back to said belt (10) or towards collection means (9) of said materials. 2-7. (canceled). 8. A self-cleaning enclosed belt conveyor for loose materials comprising a steel conveyor belt (10) operatively connected to containment walls (2), characterized by mechanical means comprising one or more scraping elements (1, 15) operatively connected to said conveyor belt (10), said scraping elements (1, 15), when located on the lower side of the belt (10) and because of the relative position where they are found, perform together with a bottom (8) of said containment walls (2) a recovery operation of the loose materials present between the belt (10) and the bottom (8) of said containment walls (2) to bring the loose materials back to said belt (10) or towards a collection means (9) for said materials. 9. The self-cleaning enclosed belt conveyor for loose materials according to claim 8, characterized in that said scraping element (1) is hinged upon said belt (10) and comprises a plate shaped into a contour fit to push and/or collect the loose materials present on the bottom. 10. The self-cleaning enclosed belt conveyor for loose materials according to claim 9, characterized in that said scraping element (15) is fixed to said belt (10) and comprises a metal net (11), or another equivalent flexible element, connected at one end to the belt (10) and at the other end to a hanging mass (12), said hanging mass (12) keeping in tension said flexible element (11) when it is near the bottom (8) in order to push the loose material present at the bottom (8). 11. The self-cleaning enclosed belt conveyor for loose materials according to claim 9, characterized in that said walls (2) comprise near a back section of said belt (10) a tilted portion (4) which together with said scraping elements (1, 15) allows the said scraping elements to hold back all the materials collected up to that point, thus allowing disposition of the collected materials on the bearing side of said belt (10) or in said collection means (9). 12. The self-cleaning enclosed belt conveyor for loose materials according to claim 9, characterized in that said walls (2) define a collecting device (9) for the material transported by the scraping elements (1, 15) near a back section of said belt (10). |
Respirator module with speech transmission and exhalation valve |
A respirator speech transmitter and exhalation valve module comprising a resilient exhalation valve having a low airflow resistance for exhalation but providing a secure seal against inadvertent inhalation through the exhalation valve module. An exhalation airflow channel is formed between a module body on the outside of the channel and a conical airflow guide and the exhalation valve on the inside of the channel. The exhalation airflow channel is in the form of an amplification horn. The airflow channel produces a smooth airflow for unrestricted exhalation and high intelligibility of a user's speech. The module includes a drinking conduit for selectively fluidly connecting a mouthpiece in the respirator to a beverage container and further includes an electrical communication block with internal and external fittings for connecting a microphone in the mask to a radio or amplifier carried by the mask user. |
1. A respirator comprising a facepiece defining an interior chamber for filtered air and including at least one inhalation opening for passage of filtered air from the atmosphere to the interior chamber; at least one exhalation opening for passage of air from the interior chamber to the atmosphere; and a filtration canister removably mounted to the facepiece and in fluid communication with the at least one inhalation opening for passage of purified atmospheric air to the facepiece interior chamber; a self-sealing valve mounted in the at least one inhalation opening and adapted to seal the at least one inhalation opening to prevent inhalation of air therethrough when the filtration canister is removed from the facepiece and to open the at least one inhalation opening to permit inhalation of air therethrough when the filter canister is mounted to the facepiece; and a speech transmitter and exhalation valve module mounted in the at least one exhalation opening and adapted to seal the at least one exhalation opening to prevent inhalation of air therethrough and to open the at least one exhalation opening to permit exhalation of air therethrough, the speech transmitter and exhalation valve module comprising: a module body having an inner face, an outer face and an outer wall; a airflow cavity defined by an inner side wall of the module body and extending between openings in the inner and outer faces of the module for fluidly connecting the inner face and the outer face; an airflow guide positioned within the central cavity; and an outlet valve, mounted to the module body and in the airflow cavity, and adapted to close and fluidly seal the airflow cavity during inhalation and to open during exhalation, characterized in that: the inner side wall of the module forms with the airflow guide and the outlet valve an airflow channel in the form of a horn expansion contour during exhalation when the outlet valve is in an open position. 2. A respirator according to claim 1 wherein the form of the horn expansion is conical, exponential, hyperbolic, tractrix or a combination thereof. 3. The respirator of claim 1 wherein the airflow channel from the interior to the exterior of the module extends radially and axially outwardly, then bends radially inwardly and axially outwardly through a smooth curve and then bends through a smooth curve axially outwardly, and does not reverse axial direction. 4. The respirator of claim 1 and further comprising a drinking tube for selectively fluidly connecting a mouthpiece projecting from the inner face of the module body to a beverage container adjacent the outer face of the module body. 5. The respirator of claim 1 wherein the outlet valve has a dome shape with a central body and a generally conical skirt. 6. The respirator according to claim 5 wherein the outlet valve conical skirt is slightly convex outwardly toward the outer face of the module body. 7. The respirator of claim 5 wherein the outlet valve further has convex shoulder hinge between the central body and the conical skirt to toggle the outlet valve between an open position and a closed position. 8. The respirator of claim 7 wherein the convex shoulder hinge forms a channel that opens toward the inner face of the module body. 9. The respirator according to claim 1 wherein the airflow guide has a generally conical surface facing the outer face of the module. 10. The respirator according to claim 9 wherein the airflow guide conical surface is concave. 11. The respirator of claim 9 wherein the airflow guide has a relatively flat bottom surface facing the inner face of the module. 12. The respirator of claim 11 wherein an outer edge of the exhalation valve abuts the bottom surface of the airflow guide when the exhalation valve is in the open position. 13. The respirator of claim 12 wherein the bottom surface of the airflow guide has relief channels to prevent sticking of the exhalation valve in the open position. 14. The respirator of claim 1 wherein the module further includes an electrical communication block with internal and external fittings for connecting a microphone in the mask to a radio or amplifier carried by the mask user. 15. A speech transmitter and exhalation valve module adapted for mounting in an exhalation opening of a respirator and adapted to seal the exhalation opening to prevent inhalation of air therethrough and to open the exhalation opening to permit exhalation of air therethrough, the speech transmitter and exhalation valve module comprising: a module body having an inner face and an outer face; a central cavity for fluidly connecting the inner face and the outer face; an airflow guide positioned within the central cavity, wherein the airflow guide forms with the module body an airflow channel in the form of a horn expansion contour during exhalation; and an outlet valve adapted to close and fluidly seal the central cavity from the inner face during inhalation and to open during exhalation, characterized in that: the airflow channel from the interior to the exterior of the module extends radially and axially outwardly, then bends radially inwardly and axially outwardly through a smooth curve and then bends through a smooth curve axially outwardly, and does not reverse axial direction. 16. The module of claim 15 wherein the form of the horn expansion is conical, exponential, hyperbolic, tractrix or a combination thereof. 17. The module of claim 15 wherein the outlet valve has a dome shape with a central body and a generally conical skirt. 18. The module according to claim 17 wherein the outlet valve conical skirt is slightly convex outwardly toward the outer face of the module body. 19. The module of claim 17 wherein the outlet valve further has convex shoulder hinge between the central body and the conical skirt to toggle the outlet valve between an open position and a closed position. 20. The module of claim 19 wherein the convex shoulder hinge forms a channel that opens toward the inner face of the module body. 21. The module of claim 15 wherein the outlet valve forms a part of the airflow passage when it is in the open position. 22. The module of claim 15 and further including an electrical communication port with internal and external fittings for connecting a microphone in the mask to a powered transmitter carried by the mask user. 23. The module according to claim 15 wherein the airflow guide has a generally conical surface facing the outer face of the module. 24. The module of claim 23 wherein the airflow guide has a relatively flat bottom surface facing the inner face of the module. 25. The module of claim 24 wherein an outer edge of the exhalation valve abuts the bottom surface of the airflow guide when the exhalation valve is in the open position. 26. The module of claim 25 wherein the bottom surface of the airflow guide has relief channels to prevent sticking of the exhalation valve in the open position. 27. A respirator comprising a facepiece defining an interior chamber for filtered air and including at least one inhalation opening for passage of filtered air from the atmosphere to the interior chamber; at least one exhalation opening for passage of air from the interior chamber to the atmosphere; and a filtration canister removably mounted to the facepiece and in fluid communication with the at least one inhalation opening for passage of purified atmospheric air to the facepiece interior chamber; a self-sealing valve mounted in the at least one inhalation opening and adapted to seal the at least one inhalation opening to prevent inhalation of air therethrough when the filtration canister is removed from the facepiece and to open the at least one inhalation opening to permit inhalation of air therethrough when the filter canister is mounted to the facepiece; and a speech transmitter and exhalation valve module mounted in the at least one exhalation opening and adapted to seal the at least one exhalation opening to prevent inhalation of air therethrough and to open the at least one exhalation opening to permit exhalation of air therethrough, the speech transmitter and exhalation valve module comprising: a module body having an inner face, an outer face and an outer wall; a airflow cavity defined by an inner side wall of the module body and extending between openings in the inner and outer faces of the module for fluidly connecting the inner face and the outer face; an airflow guide positioned within the central cavity; an outlet valve, mounted to the module body and in the airflow cavity, and adapted to close and fluidly seal the airflow cavity during inhalation and to open during exhalation, and wherein inner side wall of the module forms with the airflow guide an airflow channel in the form of a horn expansion contour during exhalation when the outlet valve is in an open position; characterized in that: an electrical communication block with internal and external fittings for connecting a microphone in the mask to a radio or amplifier carried by the mask user. 28. A respirator comprising a facepiece defining an interior chamber for filtered air and including at least one inhalation opening for passage of filtered air from the atmosphere to the interior chamber; at least one exhalation opening for passage of air from the interior chamber to the atmosphere; and a filtration canister removably mounted to the facepiece and in fluid communication with the at least one inhalation opening for passage of purified atmospheric air to the facepiece interior chamber; a self-sealing valve mounted in the at least one inhalation opening and adapted to seal the at least one inhalation opening to prevent inhalation of air therethrough when the filtration canister is removed from the facepiece and to open the at least one inhalation opening to permit inhalation of air therethrough when the filter canister is mounted to the facepiece; and a speech transmitter and exhalation valve module mounted in the at least one exhalation opening and adapted to seal the at least one exhalation opening to prevent inhalation of air therethrough and to open the at least one exhalation opening to permit exhalation of air therethrough, the speech transmitter and exhalation valve module comprising: a module body having an inner face, an outer face and an outer wall; a airflow cavity defined by an inner side wall of the module body and extending between openings in the inner and outer faces of the module for fluidly connecting the inner face and the outer face; an airflow guide positioned within the central cavity; and an outlet valve, mounted to the module body and in the airflow cavity, and adapted to close and fluidly seal the airflow cavity during inhalation and to open during exhalation, characterized in that the outlet valve has a dome shape with a central body and a generally conical skirt. 29. The respirator according to claim 28 wherein the outlet valve conical skirt is slightly convex outwardly toward the outer face of the module body. 30. The respirator of claim 27 wherein the outlet valve further has convex shoulder hinge between the central body and the conical skirt to toggle the outlet valve between an open position and a closed position. 31. The respirator of claim 30 wherein the convex shoulder hinge forms a channel that opens toward the inner face of the module body. |
<SOH> BACKGROUND OF INVENTION <EOH>1. Field of the Invention The invention relates to a respirator with a module that includes a speech transmission and exhalation valve functions. In one of its aspects, the invention relates to a respirator module incorporating an exhalation valve, a speech transmitter and a drinking tube. In another of its aspects, the invention relates to a respirator speech transmission module with integral electrical connections for communications devices. In another of its aspects, the invention relates to a respirator with a speech transmission and an exhalation valve module. In yet another of its aspects, the invention relates to a respirator and speech transmitter module therefore with low airflow resistance through the module. 2. Description of the Related Art When a respirator such as a gas mask is used in a contaminated environment, it is critical that the wearer only inhale air from a purified source or air that has been passed through a filtration canister. In the typical gas mask having removable filtration canisters, the filtration canisters are attached to a filter mount including an inhalation valve that provides for one-way flow, opening during inhalation and closing during exhalation to prevent exhalation of hot, moisture-laden air through the filter. It is important that the inhalation valve introduce no restrictions in the airflow path that will put additional strains on the wearer. In like fashion, it is important that an exhalation valve has minimal restrictions in the exhalation airflow but has secure sealing during inhalation. As the inhalation valve must have a low-opening pressure, the exhalation valve must also have a low-opening pressure to reduce the burden on the wearer and the likelihood of breaking the seal of the respirator. Further, it is important that the wearer has the ability to communicate clearly with others in the vicinity or by radio while the respirator is in place and functioning in the contaminated environment. It is therefore advantageous for an exhalation module to have low-resistance opening during wearer exhalation, complete sealing during wearer inhalation and with high intelligibility of wearer speech. U.S. Pat. No. 4,958,633, issued Sep. 25, 1990, to Angell, discloses a respirator with a speech and exhalation module incorporating an elastomeric exhalation valve. The exhalation valve is constructed of resilient material in a generally dished form anchored at a central portion and adapted to seal on a peripheral edge onto a valve seat on the module housing. The exhalation valve has an annular channel, formed by an annular arcuate section and that faces the outside of the mask. The module forms an air path in the form of an exponential horn between the inside and outside of the mask. The air path reverses axial direction between the inlet and the outlet, creating some turbulence. The speech module and exhalation valve have a fairly low resistance to exhalation, in the range of about 15 mm at 85 l/min air flow. The respirator also has interchangeable mountings on the face piece for a secondary speech outlet, such as a microphone, and for an air-purifying canister. The speech transmitter module is disclosed more fully in the U.S. Pat. No. 4,539,983, issued Sep. 10, 1985, to Angell. These two Angell patents are incorporated herein by reference in their entirety. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention relates to a respirator and a front module therefor as set forth in the preamble to claim 1 and wherein the inner side wall of the module body forms with the airflow guide an airflow channel in the form of a horn expansion contour during exhalation when the outlet valve is in an open position. The airflow channel from the interior to the exterior of the module extends radially and axially outwardly, then bends radially inwardly and axially outwardly through a smooth curve and then bends through a smooth curve axially outwardly. The airflow pattern does not reverse direction and thus has a very low resistance. In one embodiment, the outlet valve forms a part of the airflow channel with the inner side wall of the module body. In one embodiment, the form of the horn expansion is conical, exponential, hyperbolic, tractrix or a combination thereof. In a preferred embodiment, the airflow guide has a generally conical surface facing the outer face of the module. In addition, the airflow guide conical surface is concave and the airflow guide has a relatively flat bottom surface facing the inner face of the module. An outer edge of the exhalation valve abuts the bottom surface of the airflow guide when the exhalation valve is in the open position. In one embodiment of the invention, the bottom surface of the airflow guide has relief channels to prevent sticking of the exhalation valve in the open position. The invention also relates to a respirator and a front module therefor as set forth in the preamble to claim 1 and wherein the outlet valve has a dome shape with a central body and a generally conical skirt. In one embodiment, the outlet valve conical skirt is slightly convex outwardly toward the outer face of the module body. Further, the outlet valve further has convex shoulder hinge between the central body and the conical skirt to toggle the outlet valve between an open position and a closed position. Still further, the convex shoulder hinge forms a channel that opens toward the inner face of the module body. The invention further relates to a respirator and a front module therefor as set forth in the preamble to claim 1 and wherein the module further includes an electrical communication block with internal and external fittings for connecting a microphone in the mask to a radio or amplifier carried by the mask user. |
Output driver equipped with a sensing resistor for measuring the current in the ouput driver |
An electronic circuit has an output driver (DRV) for providing a driving signal (U0). The output driver has a transistor (T) with a first main terminal, a second main terminal and a control terminal coupled to receive a control signal (Vcntrl), a power supply terminal (VSS), an output terminal (OUT) for providing the driving signal (U0) that is coupled to the second main terminal, and a sensing resistor (Rm) coupled between the power supply terminal (VSS) and the first main terminal. The output driver (DRV) further has means for temporarily disabling the coupling between the control terminal and the control signal (Vcntrl) during a peak voltage across the sensing resistor (Rm). The means may have a circuit that has a unidirectional current behavior, such as a diode (D), in series with the control terminal of the transistor (T). |
1. An electronic circuit comprising an output driver for providing a driving signal, which output driver comprises a transistor with a first main electrode, a second main electrode and a control electrode coupled to receive a control signal, a supply terminal, an output terminal to provide the driving signal, which output terminal is coupled to the second electrode, and a sensing resistor which is coupled between the supply terminal and the first main electrode, the output driver (DRV) further comprising means for rendering ineffective said coupling between the control electrode and the control signal (VCNTRL) during a peak voltage across the sensing resistor (RM). 2. An electronic circuit as claimed in claim 1, wherein said means comprises a unipolar circuit that is arranged in series with the control electrode of the transistor (T). 3. An electronic circuit as claimed in claim 2, wherein the unipolar circuit comprises a diode (D). 4. An electronic circuit as claimed in claim 1, wherein the output driver (DRV) further comprises current means (J) which are coupled between a further supply terminal (VDD) and the control electrode of the transistor (T). 5. An electronic circuit as claimed in claim 1, wherein the output driver (DRV) additionally comprises limiting means for limiting the voltage on the control electrode of the transistor (T). 6. An electronic circuit as claimed in claim 1, wherein the output driver (DRV) additionally comprises limiting means for limiting the voltage between the control electrode and the first main electrode of the transistor (T). 7. An electronic circuit as claimed in claim 5, wherein the limiting means comprise a zener diode (Z). |
FOLD FLAT STOW IN FLOOR SEAT ASSEMBLY WITH COLLAPSIBLE BOLSTERS |
A seat assembly for use in an automotive vehicle comprising a seat cushion and a eat back pivotally coupled to the seat cushion for movement between a generally upright seating position and a fold flat position resting against the seat cushion. A side bolster panel is pivotally coupled to lateral opposing sides of each of the seat cushion and seat back and operable between a flexed position facing the toward the center of the seat cushion and the seat back and a relaxed position generally flush with the seat cushion and the seat back. A cam mechanism is operatively coupled to the each side bolster panel for automatically releasing the side bolster panels from the flexed position to the relaxed position in response to pivotal movement of the seat back from the seating position to the fold flat position to provide a low profile folded seat assembly. |
1. A seat assembly for use in an automotive vehicle comprising: a seat cushion; a seat back pivotally coupled to the seat cushion for movement between a generally upright seating position and a fold flat position resting against the seat cushion; a side bolster panel pivotally coupled to lateral opposing sides of at least one of said seat cushion and seat back and operable between a flexed position facing toward the center of the seat cushion and seat back and a relaxed position generally flush with the seat cushion and seat back; and a cam mechanism operatively coupled to the side bolster panel for automatically releasing the side bolster panel from the flexed position to the relaxed position in response to pivotal movement of the seat back from the seating position to the fold flat position to provide a low profile folded seat assembly. 2. The seat assembly of claim 1 wherein the side bolster panel is pivotally coupled to lateral opposing sides of the seat back. 3. The seat assembly of claim 2 wherein the seat back includes a rigid seat back frame. 4. The seat assembly of claim 3 wherein the side bolster panel is hingedly connected to each opposite lateral side of the rigid seat back frame. 5. The seat assembly of claim 4 wherein the cam mechanism is pivotally coupled to each lateral side of the rigid seat back frame behind each side bolster panel midway between opposite ends of the side bolster panel. 6. The seat assembly of claim 5 wherein the cam mechanism comprises a post pivotally connected to and laterally projecting from the rigid seat back frame, and a cam lobe extending from the post for engagement with the side bolster panel. 7. The seat assembly of claim 6 including an arm rest pivotally connected to each lateral side of the seat back for pivotal movement between an extended use position and a retrace position. 8. The seat assembly of claim 7 wherein the armrest is fixedly secured to the post for pivoting the cam lobe between an actuated position pressing the side bolster panel to the flexed position with the armrest in the extended use position and a released position disengaged from the side bolster panel when the arm rest is in the retracted position. 9. The seat assembly of claim 1 including a recliner mechanism pivotally coupling the seat back and seat cushion. 10. The seat assembly of claim 9 wherein the side bolster panel is pivotally coupled to lateral opposing sides of the seat cushion. 11. The seat assembly of claim 10 wherein the seat back includes a rigid seat cushion frame. 12. The seat assembly of claim 11 wherein the side bolster panel is hingedly connected to each opposite lateral side of the rigid seat cushion frame. 13. The seat assembly of claim 12 wherein the cam mechanism is pivotally coupled to each lateral side of the rigid seat cushion frame behind each side bolster panel midway between opposite end of the side bolster panel. 14. The seat assembly of claim 13 wherein the cam mechanism comprises a post pivotally connected to and laterally projecting from the rigid seat cushion frame, and a cam lobe extending from the post for engagement with the side bolster panel. 15. The seat assembly of claim 14 including a push-pull cable connected between the post and the recliner mechanism. 16. The seat assembly of claim 15 including an arcuate cable guide associated with the recliner mechanism for winding the cable about the recliner mechanism. 17. The seat assembly of claim 16 wherein the cam lobe is pressed against the side bolster panel for maintaining the side bolster panel in the flexed position when the seat assembly is in the seated position, and wherein the cable winds about the cable guide to rotate the cam lobe away from the side bolster panel for maintaining the side bolster panel in the relaxed position when the seat assembly is in the fold flat position. 18. The seat assembly of claim 1 further including a headrest assembly operatively coupled to an upper distal end of the seat back and pivotal between a generally upright use position and a stowed position. 19. The seat assembly of claim 18 wherein the headrest assembly comprises a pair of guide posts pivotally coupled to a tube rotatably journaled to a top portion of a seat back frame by a bearing sleeve. 20. The seat assembly of claim 19 including a spring connected to the seat back frame and the tube for biasing the headrest assembly to the stowed position. 21. The seat assembly of claim 20 including a disk recliner clutch connected to the tube for releasing the headrest assembly for pivotal movement from the upright use position to the stowed position. 22. The seat assembly of claim 21 including a cable connected between the disk recliner clutch and a recliner mechanism pivotally coupling the seat back and seat cushions. 23. The seat assembly of claim 22 wherein the cable pulls and releases the disk recliner clutch such that the spring automatically pivots the headrest assembly to the stowed position when the seat back is pivoted from the seating position to the fold flat position. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The subject invention relates to a seat assembly which is folded and stowed within the floor of a vehicle, and more particularly, to a seat assembly having automatically collapsible bolsters and a stowable headrest. 2. Description of the Related Art Seat assemblies within an automotive vehicle include a seat cushion and a seat back, often pivotally coupled to the seat cushion. It is commonly known to provide a seat assembly wherein the seat back is pivotal from an upright seating position for supporting an occupant in the seat to a folded flat position against the seat cushion for stowage. It is also known to provide a tumble seat assembly wherein the seat cushion pivots about the floor of the vehicle with the seat back in the folded flat position to provide addition cargo storage within the compartment of the vehicle. The seat cushion and seat back of an automotive seat assembly typically comprise a frame assembly for supporting a contoured cellular foam pad encased by a trim cover. The seat cushion and seat back often include side bolsters provided by thick side areas of the foam pad or mechanical mechanisms such as inflatable air bladders for providing the occupant with side or lateral support when seated in the seat assembly. However, these side bolsters create a thick seat profile and complicate the ability of the seat back to be pivoted to the fold flat position relative to the seat cushion. Therefore, it is desirable to provide a seat assembly having side bolsters in either or both of the seat back and seat cushion which maintain a thin seat profile in both the folded flat position and the tumbled position for stowage within a bin in the floor of the vehicle. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to one aspect of the invention there is provided a seat assembly for use in an automotive vehicle comprising a seat cushion and a seat back pivotally coupled to the seat cushion for movement between a generally upright seating position and a fold flat position resting against the seat cushion. A side bolster panel is pivotally coupled to lateral opposing sides of at least one of the seat cushion and seat back and operable between a flexed position facing toward the center of the seat cushion and the seat back and a relaxed position generally flush with the seat cushion and the seat back. A cam mechanism is operatively coupled to the side bolster panel for automatically releasing the side bolster panel from the flexed position to the relaxed position in response to pivotal movement of the seat back from the seating position to the fold flat position to provide a low profile folded seat assembly. |
Substituted isoindoles and the use thereof |
The invention relates to the field of blood clotting, to novel compounds of formula (I), to a method for their production and to the use of these compounds as active ingredients in medicaments for preventing and/or treating diseases. The compounds are factor Xa inhibitors. |
1. A compound of the formula (I) in which R1 and R2 together represent O and R3 and R4 together represent O, or R1 represents hydrogen, hydroxy or (C1-C4)-alkoxy, R2 represents hydrogen and R3 and R4 together represent O, or R1 and R2 together represent O, R3 represents hydrogen, hydroxy or (C1-C4)-alkoxy and R4 represents hydrogen, R5 and R6 represent hydrogen and R7 and R8 together represent in which R9 represents halogen, trifluoromethyl or methyl, or R5, R6, R7 and R8 together represent in which R9 is as defined above, A represents (C1-C4)-alkanediyl or (C2-C4)-alkenediyl, B represents phenylene or cyclohexanediyl, which radicals may be substituted by amino, urea, sulfamoyl, —C(═N—NH—C(═NH)—NH2)—H, or —C(═NR10)—R11, in which R10 represents hydrogen or —NH—C(═NH)—NH2, R11 represents —NR12R13 or 5- to 10-membered heterocyclyl, in which R12 and R13, independently of one another, represent hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl, (C1-C4)-alkyl, which for its part may be substituted by cyano, (C1-C4)-alkoxycarbonyl, optionally (C1-C4)-alkyl-substituted 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, tri-(C1-C4)-alkylammonium, —NR14R15, —C(═NR16)—R17, —N—C(═O)—R18 or —N—C(═O)—NH—R19, in which R14 represents hydrogen, mono- or di-(C1-C4)-alkylamino, (C1-C4)-alkyl which is optionally substituted by 5- to 10-membered heteroaryl, represents 5- to 10-membered heterocyclyl, (C6-C10)-aryl or 5- to 10-membered heteroaryl, where the rings for their part may be substituted by halogen, R15 represents hydrogen or optionally cyano-substituted (C1-C4)-alkyl, R16 represents hydrogen or hydroxy, R17 represents amino, 5- to 10-membered heterocyclyl, optionally amino- or trifluoromethyl-substituted mono- or di-(C1-C4)-alkylamino, optionally trifluoromethyl-substituted (C3-C7)-cycloalkylamino, R18 represents trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or 5- to 10-membered heterocyclyl which is optionally substituted by (C1-C4)-alkyl, R19 represents hydrogen, amino, dimethylamino, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or represents (C1-C4)-alkyl which is optionally substituted by (C1-C4)-alkoxycarbonyl, dimethylamino, carbamoyl or 5- to 10-membered heteroaryl, (C1-C4)-alkoxy, which for its part may be mono- or disubstituted, independently of one another, by cyano, thiocarbamoyl, optionally (C1-C4)-alkyl-substituted 5- to 10-membered heterocyclyl, optionally halogen-substituted 5- to 10-membered heteroaryl, optionally —C(═NR20)—R21-substituted (C6-C10)-aryl or —C(═NR20)—R21, in which R20 represents hydrogen, hydroxy, (C3-C7)-cycloalkyl or optionally hydroxy-substituted (C1-C4)-alkyl, R21 represents amino, (C1-C4)-alkylthio, (C3-C7)-cycloalkylamino, benzylamino or 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl which for its part may be substituted by (C1-C4)-alkyl, (C6-C10)-aryl which for its part may be mono- or disubstituted, independently of one another, by halogen, cyano, carbamoyl or optionally amino-substituted (C1-C4)-alkyl, 5- to 10-membered heteroaryloxy which for its part may be substituted by amino or N—(C1-C4)-alkylaminocarbonyl, or 5- to 10-membered heteroaryl which for its part may be substituted by amino, or a salt hydrate, hydrate of the salt, or solvate thereof. 2. The compound as claimed in claim 1 in which R1 and R2 together represent O and R3 and R4 together represent O, or R1 represents hydrogen, hydroxy, methoxy or ethoxy, R2 represents hydrogen and R3 and R4 together represent O, or R1 and R2 together represent O, R3 represents hydrogen, hydroxy, methoxy or ethoxy and R4 represents hydrogen, R5 and R6 represent hydrogen and R7 and R8 together represent in which R9 represents halogen or trifluoromethyl, or R5, R6, R7 and R8 together represent in which R9 is as defined above, A represents (C1-C3)-alkanediyl or (C2-C3)-alkenediyl, B represents phenylene or cyclohexanediyl, which radicals may be substituted by —C(═NR10)—R11 in which R10 represents hydrogen, R11 represents —NR12R13 or 5- to 10-membered heterocyclyl, in which R12 and R13, independently of one another, represent hydrogen, (C1-C4)-alkyl or (C3-C7)-cycloalkyl, methyl or ethyl which for their part may be substitued by cyano, methoxycarbonyl, optionally methyl- or ethyl-substituted 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, tri-(C1-C2)-alkylammonium, —NR14R15, —C(═NR16)—R17, —N—C(═O)—R18 or —N—C(═O)—NH—R19, in which R14 represents hydrogen, dimethylamino, methyl or ethyl, which radicals are optionally substituted by 5- or 6-membered heteroaryl, represents 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl, which may be substituted by halogen, R15 represents hydrogen, methyl or ethyl, R16 represents hydrogen, R17 represents amino, 5- or 6-membered heterocyclyl, optionally amino- or trifluoromethyl-substituted mono- or di-(C1-C4)-alkylamino, optionally trifluoromethyl-substituted (C3-C7)-cycloalkylamino, R18 represents trifluoromethyl or (C1-C4)-alkyl, R19 represents hydrogen, amino or optionally methoxy- or ethoxycarbonyl-substituted (C1-C4)-alkyl, methoxy or ethoxy which for their part may be mono- or disubstituted, independently of one another, by optionally methyl-substituted 5- or 6-membered heterocyclyl or —C(═NR20)—R21, in which R20 represents hydrogen, R21 represents amino, (C3-C6)-cycloalkylamino, benzylamino or 5- or 6-membered heterocyclyl, or pyridyl, or a salt, hydrate, hydrate of the salt, or solvate thereof. 3. The compound as claimed in claim 1 in which R1 and R2 together represent O and R3 and R4 together represent O, or R1 represents hydrogen, hydroxy or methoxy, R2 represents hydrogen and R3 and R4 together represent O, or R1 and R2 together represent O, R3 represents hydrogen, hydroxy or methoxy and R4 represents hydrogen, R5 and R6 represent hydrogen and R7 and R8 together represent in which R9 represents chlorine or bromine, or R5, R6, R7 and R8 together represent in which R9 is as defined above, A represents methanediyl or ethanediyl, B represents phenylene which may be substituted by —C(═NR10)—R11 in which R10 represents hydrogen, R11 represents amino, methyl which for its part may be substituted by cyano, optionally methyl-substituted imidazolinyl or tetrahydropyrimidinyl, —NR14R15 or —C(═NR16)—R17, in which R14 represents optionally pyridyl-substituted methyl or pyridyl, R15 represents hydrogen, R16 represents hydrogen, R17 represents amino, piperidinyl, morpholinyl, pyrrolidinyl, optionally amino- or trifluoromethyl-substituted mono- or di-(C1-C3)-alkylamino or optionally trifluoromethyl-substituted cyclopropyl-, cyclopentyl- or cyclohexylaamino, or methoxy or ethoxy which for their part may be substituted by —C(═NH)—NH2, or a salt, hydrate, hydrate of the salt, or solvate thereof. 4. A process for preparing compounds of the formula (1) as defined in claim 1, characterized in that either (A) a compound of the formula (IV) in which R5, R6, R7 and R8 are as defined in claim 1 is reacted with a compound of the formula (V) Y-A-B in which A and B are as defined in claim 1 and Y represents a suitable leaving group to give a compound of the formula (I) in which both R1 and R2 and R3 and R4, in each case together, represent O and R5, R6, R7, R8, A and B are as defined in claim 1, or (B1) a compound of the formula (VIII) or (VIIIa) in which A and B are as defined in claim 1 is reacted with a compound of the formula (III) in which R9 is as defined in claim 1 and X represents a leaving group to give a compound of the formula (I) in which both R1 and R2 and R3 and R4, in each case together, represent O and R5, R6, R7, R8, A and B are as defined in claim 1, or (B2) a compound of the formula (IX) in which A and B are as defined in claim 1 or a compound of the formula (X) in which A and B are as defined in claim 1 is reacted with a compounds a compound of the formula (III) to give a compound of the formula (I) in which R1 and R2 together represent O, R3 represents hydrogen or hydroxy, R4 represents hydrogen or R3and R4 together represent O, R1 represents hydrogen or hydroxy, R2 represents hydrogen and R5, R6, R7, R8, A and B are as defined in claim 1, or (C) a compound of the formula (XIV) in which A and B are as defined in claim 1 is reacted with a compound of the formula (III) to give a compound of the formula (I) in which R1 and R2 represent hydrogen, R3 and R4 together represent O and R5, R6, R7, R8, A and B are as defined in claim 1, where the resulting compound of the formula (I) may, if appropriate, subsequently be subjected to further derivatization which can be carried out by customary methods. 5. (Canceled) 6. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in claim l and at least one further auxiliary. 7. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in claim 1 and at least one further active compound. 8. A method for the treatment of thromboembolic disorders, comprising administering an effective amount of a compound of claim 1. 9. A method for treatment of disseminated intravascular coagulation (DIC) comprising administering an effective amount of a compound of claim 1. 10. A method for treatment of atherosclerosis, arthritis, Alzheimer's disease or cancer comprising administering an effective amount of a compound of claim 1. 11. A method for preventing the coagulation of blood in vitro, characterized in that a compound of the formula (I) as defined in claim 1 is added. 12. The method of claim 8 wherein said thromboembolic disorder is myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, stroke, transitory ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis. 13. The method of claim 12 wherein said angina pectoris is unstable angina. 14. The method of claim 11, wherein said blood is banked blood or a biological sample containing factor Xa. |
Semiconductor device and method for fabricating the same and semiconductor device application system |
A semiconductor surface treatment and a film deposition method capable of realizing surface protection and surface inactivation using a boron nitride film is provided. A high-performance semiconductor device can be manufactured by using the same surface protection technology and surface inactivation technology. Additionally, a electronic device for a communication system or a high-performance information processing device may incorporate such a semiconductor device. |
1. A semiconductor device, comprising a first film including at least boron and nitrogen atoms. 2. The semiconductor device according to claim 1, wherein said film includes at least one of Al, Ga, In, P, C, and Si. 3. The semiconductor device according to claim 1, comprising a composed film structure of said first film and a silicon nitride film. 4. The semiconductor device according to claim 1, comprising a compound film structure of said first film and a silicon oxide film. 5. The semiconductor device according to claim 1, wherein said first film is configured for use as at least one of a surface protection film, a surface inactivated film, and a wiring interlayer isolation film of semiconductor. 6. The semiconductor device according to claim 1, further comprising a group-III nitride compound semiconductor heterojunction. 7. The semiconductor device according to claim 1, further comprising a group-Ill to group-V nitride compound semiconductor heterojunction. 8. The semiconductor device according to claim 1, wherein the semiconductor device is an FET. 9. The semiconductor device according to claim 1, wherein the semiconductor device is an HBT. 10. A manufacturing method of a semiconductor device, comprising the steps of: arranging a substrate in a plasma atmosphere, the plasma atmosphere including nitrogen; supplying boron atoms onto the substrate, and forming a boron nitride film on the substrate. 11. A manufacturing method of a semiconductor device, comprising the steps of: providing a substrate; and forming a boron nitride film onto the substrate by laser abrasion or spatter of boron nitride thereupon. 12. The manufacturing method of the semiconductor device according to claim 10, further comprising the step of supplying at least one of Al, Ga, In, P, C and Si as an additional atom when forming the film. 13. The manufacturing method of a semiconductor device according to claim 10 or 11, further comprising the step of making the exposing a surface of the substrate to be upon which the film is formed to a plasma including at least one element of H, N, Ar and P before forming the film. 14. The semiconductor device according to claim 10, wherein the semiconductor device is an FET. 15. The semiconductor device according to claim 10, wherein the semiconductor device is an HBT. 16. A communication system device having the semiconductor device according claim 1. 17. An information processing system device having the semiconductor device according to claim 1. 18. The manufacturing method of the semiconductor device according to claim 11, further comprising the step of supplying at least one of Al, Ga, In, P, C and Si as an additional atom when forming the film. 19. The manufacturing method of a semiconductor device according to claim 11, further comprising the step of exposing a surface of the substrate to be upon which the film is formed to a plasma including at least one element of H, N, Ar and P before forming the film. 20. The semiconductor device according to claim 11, wherein the semiconductor device is an FET. 21. The semiconductor device according to claim 11, wherein the semiconductor device is an HBT. 22. A semiconductor device, comprising: a substrate, said substrate being composed of one of sapphire, M-type SiC, and an SiC high-resistance material; and a first film formed on said substrate, said first film include at least boron and nitrogen, said first film being configured for use as at least one of a surface protection film and a surface inactivated film. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention concerns performance improvement of a semiconductor device through the protection and the inactivation of a semiconductor surface. 2. Description of the Related Art A field effect transistor (FET) and a Hetero Bipolar Transistor (HBT) are developed for use in a high frequency electric device. A surface level generation occurs due to a dangling bond and/or oxidation of the semiconductor surface. Such generation is provoked on the semiconductor surface exposed between the FET gate and drain and between the FET source and gate or on the edges of an HBT base area. The deterioration of transistor performance thus results. Increased leak of current between the gate and the drain may be observed for the FET, while few carriers decrease in the base as the surface recombination occurs for the HBT. Electronic devices composed of group-III nitrogen compounds are expected to form the next generation of high frequency power devices. However, it is difficult to easily apply a manufacturing process technology of the electronic device when using a chemical compound semiconductor such as conventional GaAs—AlGaAs type material. It is impossible to sufficiently bring out the characteristics of new group-III nitrogen compound materials using only silicon oxide film or silicon nitride film, i.e., the types of films that have typically been used for the semiconductor surface protection or the inactivation film. Thus, it is necessary to introduce a novel semiconductor surface protection technology and a surface inactivation technology. |
<SOH> SUMMARY OF THE INVENTION <EOH>The development of the surface protection technology and the surface inactivation technology for group-Ill nitride semiconductors and the accompanying performance improvement of the high frequency electronic devices are in demand. The present invention has been devised in view of the aforementioned situation, and an objective of the present invention is to provide a semiconductor surface treatment and a film deposition method capable of realizing surface protection and surface inactivation, using boron nitride film, a high performance semiconductor device manufactured by using the same surface protection technology and surface inactivation technology and an electronic device for communication systems including a semiconductor device. The semiconductor device of the present invention provides a film comprising at least boron and nitrogen atoms. Moreover, the semiconductor device of the present invention can further include one or more of aluminum, gallium, indium, phosphorus, carbon and silicon in the film. Moreover, the semiconductor device of the present invention advantageously has a composite film structure of the film and a silicon nitride film. Moreover, the semiconductor device of the present invention uses the film as any one of a semiconductor surface protection film, a surface inactivation film, and a wiring interlayer insulation film. Moreover, the semiconductor device of the present invention can employ group-III nitride semiconductor heterojunctions. Moreover, the semiconductor device of the present invention can include group-V nitride semiconductor heterojunctions. Moreover, a manufacturing method of the semiconductor device of the present invention may involve arranging a substrate for deposition in a plasma atmosphere including nitrogen, supplying the substrate with boron atoms, and forming a boron nitride film. Moreover, the manufacturing method of the semiconductor device of the present invention can advantageously include forming a boron nitride film on the substrate by laser abrasion or spattering of boron nitride. Moreover, the manufacturing method of the semiconductor device of the present invention can advantageously employ a step of supplying as an additional atom any one among aluminum, gallium, indium, phosphorus, carbon and silicon thereto during the manufacturing of the film. Moreover, the manufacturing method of the semiconductor device of the present invention may include exposing the surface of the substrate in a plasma including at least one element of hydrogen, nitrogen, argon and phosphorus before the manufacturing of the film. Moreover, a communication system device of the present invention can advantageously employ the semiconductor device manufactured by the present invention. Moreover, an information-processing device of the present invention can usefully employ the semiconductor device manufactured by the present invention. |
Mannose binding lectin and uses thereof |
The present inventors have shown that MASP-depleted MBL is able to recruit MASPs from plasma and successfully activate complement cascade. Furthermore, it has been discovered that MBL purified as a complex has limited ability to activate the complement cascade when compared to MASP-depleted MBL. Accordingly, the present invention provides a pharmaceutical composition comprising an isolated non-recombinant mannose binding lectin (MBL) substantially free from activated MBL associated serine proteases (MASPs) together with a pharmaceutically acceptable carrier or diluent. Also provided is a method of treating a subject in need of MBL comprising administering to the subject an effective amount of a pharmaceutical composition of the invention. |
1. A pharmaceutical composition comprising isolated non-recombinant mannose binding lectin (MBL) substantially free from activated MBL associated serine proteases (MASPs) together with a pharmaceutically acceptable carrier or diluent. 2. A composition according to claim 1, wherein the MBL is substantially free from MASPs. 3. A composition according to claim 1 or claims 2, wherein the MBL is human MBL. 4. A composition according to any one of claims 1 to 3, wherein the MBL is obtained by a method comprising: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) incubating the complex in a suitable buffer to dissociate the MBL from the one or more MASPs; and (iii) separating the MBL from the one or more MASPs. 5. A composition according to claim 4, wherein the buffer in step (ii) is an EDTA/acetate buffer at a pH of from 4.0 to 5.0. 6. A composition according to claim 4 or claim 5, wherein the buffer in step (ii) comprises NaCl. 7. A composition according to any one of claims 4 to 6, wherein step (iii) includes a chromatographic method and/or filtration. 8. A composition of claim 7, wherein the chromatographic method is selected from the group consisting of: size exclusion chromatography and ion exchange chromatography. 9. A method of producing a pharmaceutical composition, the method comprising: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) dissociating the MBL from at least some of the one or more MASPs; (iii) separating the MBL from at least some of the one or more MASPs; and (iv) admixing the resulting MBL from step (iii) with a pharmaceutically acceptable carrier or diluent. 10. A method of claim 9, wherein step (ii) involves incubating the complex in a suitable buffer. 11. A method according to claim 10, wherein the buffer is an EDTA/acetate buffer at a pH of from 4.0 to 5.0. 12. A method according to claim 10 or claim 11, wherein the buffer comprises NaCl. 13. A method according to any one of claims 9 to 12, wherein step (iii) includes a chromatographic method and/or filtration. 14. A method of claim 13, wherein the chromatographic method is selected from the group consisting of: size exclusion chromatography and ion exchange chromatography. 15. A method according to any one of claims 9 to 14, wherein step (i) comprises providing a side fraction from plasma fraction processes. 16. A method according to claim 15, wherein step (i) further comprises separating complexes of non-recombinant MBL and one or more MASPS from other plasma proteins present in the side fraction from plasma fraction processes by mannan affinity chromatography. 17. A pharmaceutical composition obtained by the method of any one of claims 9 to 16. 18. The pharmaceutical composition of claim 17, wherein the composition is substantially free of activated MASPs. 19. A method of treating or preventing a disease in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of claims 1 to 8, 17 or 18. 20. A method according to claim 19, wherein the subject is a bone marrow allograft recipient. 21. A method according to claim 19, wherein the subject is immunodeficient. 22. A method according to claim 19, wherein the subject has community acquired or nosocomial septicaemia. 23. A method according to claim 19, wherein the subject is a low birthweight and/or premature infant. 24. A method according to claim 19, wherein the subject is infected with a pathogen. 25. A method according to any one of claims 19 to 24, wherein the subject has an MBL deficiency. 26. A method according to claim 25, wherein the subject is an infant at risk from developing acute lymphoblastic leukaemia. 27. A composition comprising isolated non-recombinant MBL, said composition being substantially free of activated MASPs, for use prophylactically or in therapy. 28. A composition comprising isolated non-recombinant MBL, said composition being substantially free of MASPs, for use prophylactically or in therapy. 29. Use of a composition comprising isolated non-recombinant MBL, said composition being substantially free of MASPs, in the manufacture of a medicament for use in administering to a subject in need of said composition. 30. Use according to claim 29, wherein the subject is a bone marrow allograft recipient. 31. Use according to claim 29, wherein the subject is immunodeficient. 32. Use according to claim 29, wherein the subject has community acquired or nosocomial septicaemia. 33. Use according to claim 29, wherein the subject is an infant at risk from developing has acute lymphoblastic leukaemia. 34. Use according to claim 29, wherein the subject is a low birthweight and/or premature infant. 35. Use according to claim 29, wherein the subject is infected with a pathogen 36. Use according to any one of claims 29 to 35, wherein the composition is substantially free of MASPs. 37. A peptide of formula X-R1-Arg-R2-Y, wherein R1-Arg-R2 is a peptide consisting of 6 or more contiguous amino acids derived from the MASP cleavage site of a complement protein; X is NH2, a blocking group or a detectable label; and Y is COOH or a detectable label, provided that when X is NH2 or a blocking group, Y is not COOH and when Y is COOH, X is not NH2 or a blocking group. 38. A peptide according to claim 37, wherein the complement protein is C4. 39. A peptide according to claim 38, wherein the C4 protein is human C4 and the cleavage site comprises Arg756. 40. A peptide according to any one of claims 37 to 39, wherein X is a quencher molecule and Y is a fluorescent label, or vice-versa, such that a fluorescent signal is obtained when the substrate is cleaved. 41. Use of a peptide according to any one of claims 37 to 40, in a method of determining the presence of MASP activity in a sample. 42. Use according to claim 41, wherein the sample is a composition according to any one of claims 1 to 8, 17 or 18. 43. A method of determining the presence of MASP activity in a sample which method comprises contacting the sample with a peptide according to any one of claims 37 to 40 and determining whether said peptide has been cleaved. 44. A method according to claim 43, wherein the sample is a composition according to any one of claims 1 to 8, 17 or 18. 45. A method of producing a pharmaceutical composition according to any one of claims 1 to 3 which method comprises: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) incubating the complex in a suitable buffer to dissociate the MBL from the one or more MASPs; (iii) separating the MBL from the one or more MASPs; (iv) screening the MBL obtained from (iii) for MASP activity using a method according to claim 43; and (v) admixing the resulting purified MBL with a pharmaceutically acceptable carrier or diluent. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Mannose binding lectin (MBL), sometimes referred to as mannan binding lectin or mannose binding protein, is a liver derived C-type serum lectin with structural homology to complement component C1q. MBL can activate complement via the lectin and classical pathways, and can interact with specific C1q-like receptors on the surface of phagocytes, thus playing an important role in first-line host defence. MBL is a member of the collectin family of proteins that are characterised by the presence of both a collagenous region and a globular lectin domain. The structural unit of MBL is a 96 kDa collagen triple helix of three 32 kDa subunits, each with a carbohydrate-recognition domain. The helix is stabilised by disulphide bonds between N-terminal cysteines. MBL oligomerizes as multiples of this 96 kDa unit and the native protein is commonly found as trimers to hexamers ranging from 270 kDa to approximately 650 kDa. MBL full functionality is only obtained when it is in its higher oligomeric forms. There is evidence that MBL must at least be tetrameric to enable effective complement activation. This oligomeric structure allows MBL multiple ligand binding sites and mimics the multiple binding characteristics of IgM. MBL binds many different sugars, but binds most avidly to mannose and N-acetylglucosamine. These sugars are prevalent on the cell walls of many pathogens such as yeast, gram negative enteric bacteria, gram positive bacteria, mycobacteria, some viruses, and certain parasites. As most of the MBL sugar targets are not expressed at high densities on the surface of mammalian cells, MBL has the ability to distinguish self from non-self. MBL thus serves as a pattern recognition molecule in the first-line of host defence, a central part of the so-called innate immune system (Turner, 1996). Central in the efficient and effective complement activation function of MBL is its close association in vivo with at least two pro-enzymes called MBL associated serine proteases 1, 2 and 3 (MASP1, MASP2 and MASP-3). These single polypeptides of 93 kDa, 76 kDa and 105 kDa, respectively become activated when MBL binds its ligand and promote efficient complement activation via the lectin pathway (Turner, 1996). It has been demonstrated that MASP2 is essential for complement activation and this enzyme alone is capable of initiating the complement cascade without the presence of either MASP1, or the recently described MASP3. MASP2 is thus the critical enzyme associating with MBL to promote activation of the complement cascade. The MBL gene (MBL2) is located on chromosome 10 at 10q11.2-q21 and contains four exons. A number of mutations in MBL2 that have an impact on the expression of functional protein have been described. Single nucleotide substitutions in codons 52, 54 and 57 of exon 1 of the MBL2 gene are believed to disrupt the assembly of MBL subunits into the basic trimeric structural unit. In addition, at least two polymorphisms have been described in the promoter region (at positions −550 and −221 respectively) that alter the level of expression of individual MBL sub-units. The frequency of mutations in the MBL gene varies among ethnic groups. For example the codon 54 variant occurs with a frequency of 15% in Caucasians while the codon 57 variant is seen exclusively in Africans. The practical significance of the common occurrence of both the gene mutations and the promoter polymorphisms is that MBL deficiency is relatively common in the general population. The serum level of MBL in individuals homozygous for the wild-type gene ranges from 1 to 5 μg/mL while those individuals homozygous for MBL2 mutations have levels of 5 to 25 ng/mL and heterozygous individuals have levels approximately ⅛ th normal, but there is considerable observed variation in levels. A number of lines of evidence suggest that MBL deficiency has clinically important consequences. A childhood syndrome of recurrent infections, failure to thrive and chronic diarrhoea was first linked to an in vitro opsonic defect of plasma in 1968. It was subsequently confirmed that this syndrome was associated with low MBL levels in 10 children aged from 15 mths to 9 yrs. The importance of MBL2 deficiency as a risk factor for childhood infection was confirmed in a consecutive series of 345 children admitted to hospital with infection. The prevalence of MBL2 gene mutations in children with infection was twice that in those without infection and the increased susceptibility was seen in both heterozygote and homozygote individuals. Infections seen ranged from chest infections and otitis media through to life threatening meningococcaemia. The association of MBL deficiency with meningococcal disease in children has been confirmed in a large study of 266 cases. 7.7% of the hospital based cases were homozygous for MBL polymorphisms in comparison to 1.5% of the control group giving an odds ratio of 6.5. It was concluded that the genetic variants of MBL may account for a third of all cases. These data in the paediatric population have led to the hypothesis that the major role of MBL is to provide protection during the so called “window of vulnerability” that occurs after maternal antibodies are lost and before the maturation of an infants own antibody repertoire (6 mths to 18 mths). The recent findings that MBL genotypic variants are associated with an early age of onset of presentation of common variable immunodeficiency and acute lymphoblastic leukaemia adds weight to the hypothesis that MBL mediated host defence takes on greater importance when other components of the immune system are immature or impaired. Common genetic variations in the MBL gene have recently been associated with increased disease severity and risk of infection with Burkholderia cepacia in 149 cystic fibrosis (CF) patients. MBL variant alleles were also associated with poor prognosis and early death—predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes in the CF population. There is increasing evidence of the clinical importance of MBL deficiency in adults. Four adult patients with “severe and unusual” infections (including recurrent skin infections, Cryptosporidiosis, Meningococal meningitis with recurrent herpes simplex and oesophageal candidiasis, and Klebsiella pneumonia ) were shown to have MBL2 mutations involving either codons 52 or 54. In 228 adult patients suspected of having non-HIV-related immunodeficiency, the frequency of heterozygosity for MBL2 mutations was the same as a control population. However, there was a significant increase in homozygous MBL2 mutations amongst those with presumed immunodeficiency (8.3% vs 0.8%). Data have also been presented showing that the risk of HIV infection is greater and the rate of progression of AIDS is faster in men homozygous for MBL polymorphisms. In patients in whom the adaptive immune response has been compromised by chemotherapeutic regimens, the effect of MBL structural gene mutations and low levels of circulating MBL has been clearly associated with increased incidence of infection and severity of infection. Adults receiving chemotherapy for haematological malignancies with MBL levels below 0.5 μg/ml had significantly increased incidence and severity of infection. Donor and recipient MBL genotype were found to be important in influencing the risk of infection in adults following allogeneic stem cell transplantation. Amongst 100 children undergoing chemotherapy, those with structural MBL gene mutations had twice as many days of febrile neutropenia as those with wild type MBL genes and four of these were admitted to ICU with infection. MBL levels less than 1 μg/ml were thought to be critical in this study. In one of the few prospective, community based studies yet performed 252 children were examined (Koch et al., 2001). It was discovered that MBL deficiency as strongly linked (twice the risk) to acute respiratory infection in children aged 6 to 17 months. MBL deficiency had less impact in those aged 0 to 5 months and had no impact on acute respiratory infection in those aged 18 to 23 months. MBL-MASP complex has been purified routinely on a laboratory scale since 1980. MBL-MASP complex purification has been performed by affinity chromatography in various forms. The ligand is usually yeast mannan (Anderson et al., 1992; Holmskov et al., 1993). One or two cycles through the column are performed with the first elution with high salt or EDTA (Koppel et al., 1994; Anderson et al., 1992; Holmskov et al., 1993) and the final elution with mannose (Koppel et al., 1994; Anderson et al., 1992; Matsushita et al., 1992; Holmskov et al., 1993). Human MBL-MASP complex has also been purified from a waste fraction produced during the fractionation of plasma proteins, on a laboratory scale (Kilpatrick, 2000), and under GMP conditions at the Statens Serum Institut (Valdimarsson et al., 1998). Scottish Cohn fraction m is a waste product of IgG production by plasma fractionation. Cryosupernatant produced from plasma is precipitated with 21% ethanol. The precipitate from this step is called fraction I+II+III. A further precipitation with 8% ethanol produces fraction I+m from which MBL-MASP complex can be affinity captured using an Emphaze-mannan column. Elution of MBL-MASP complex was achieved with first EDTA, then mannose solutions. The yield of MBL-MASP complex from this procedure is quoted as 10 mg/kg of fraction I+III paste; a specific activity seven fold greater than pooled plasma (Kilpatrick, 2000). In this way, highly pure MBL-MASP complex (300-600 μg/litre plasma) can be recovered with simple mannose elution. An alternative purification technique is discussed in WO99/64453 which discloses a chromatographic purification step using a non-conjugated polysaccharide matrix. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present inventors have discovered that MASP-depleted MBL compositions are superior at activating the complement cascade when compared to MBL purified in complex with its associated MASPs. Consequently, the present inventors have found that for the purpose of formulating a safe, effective therapeutic product for administration to subjects, MASPs, or at least activated MASPs should be removed from the MBL during, or prior to, or after purification of the MBL-MASP complex Accordingly, in a first aspect, the present invention provides a pharmaceutical composition comprising isolated non-recombinant mannose binding lectin (MBL) substantially free from activated MBL associated serine proteases (MASPs) together with a pharmaceutically acceptable carrier or diluent. Preferably the composition is substantially free of MASPs, whether activated or not. Typically, the MBL is human MBL. The present inventors have found that MASP-depleted MBL is able to recruit MASPs from plasma to produce a functional complex that can successfully activate the complement cascade. In contrast, it appears that purified MBL-MASP complex has a limited capacity to recruit proenzyme (or fresh) MASP. This is probably due to the presence in the purified complex of activated MASP attached to the binding sites on MBL as a result of activation during the purification process (e.g. being activated upon binding to mannan columns), the activated MASP being difficult to displace. By contrast, proenzyme MASPs can be freshly recruited to available binding sites on purified MASP-depleted MBL. This also restores the regulation component of the MBL-MASP complex, making it a safer, more effective therapeutic product. In a preferred embodiment, the MBL is obtained by a method comprising: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) incubating the complex in a suitable buffer to dissociate the MBL from the one or more MASPs; and (iii) separating the MBL from the one or more MASPs. Preferably, the buffer in step (ii) is an EDTA/acetate buffer at a pH of from 4.0 to 5.0. Furthermore, it is preferred that the buffer comprises NaCl. Preferably, the buffer has an NaCl concentration of at least 0.5 M. More preferably, the buffer has an NaCl concentration of about 1 M. Preferably step (iii) includes a chromatographic method and/or filtration. In a further preferred embodiment, the chromatographic method is selected from the group consisting of: size exclusion chromatography and ion exchange chromatography. In a second aspect, the present invention also provides a method of producing a pharmaceutical composition, the method comprising: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) dissociating the MBL from at least some of the one or more MASPs; (iii) separating the MBL from at least some of the one or more MASPs; and (iv) admixing the resulting MBL from step (iii) with a pharmaceutically acceptable carrier or diluent. Preferably, step (ii) involves incubating the complex in a suitable buffer. Preferably, the buffer is an EDTA/acetate buffer at a pH of from 4.0 to 5.0. Furthermore, it is preferred that the buffer comprises NaCl. Preferably, the buffer has an NaCl concentration of at least 0.5 M. More preferably, the buffer has an NaCl concentration of about 1 M. Preferably step (iii) includes a chromatographic method and/or filtration. In a further preferred embodiment, the chromatographic method is selected from the group consisting of: size exclusion chromatography and ion exchange chromatography. In a preferred embodiment step (i) comprises providing a side fraction from plasma fraction processes. Preferably step (i) further comprises separating complexes of non-recombinant MBL and one or more MASPs from other plasma proteins present in the side fraction from plasma fraction processes by mannan affinity chromatography. The present invention also provides a pharmaceutical composition obtained by the method of the second aspect of the invention. Preferably, the composition is substantially free of activated MASPs In another aspect, the present invention provides a method of treating or preventing a disease in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition of the invention. The disease can be any condition, the treatment or prevention of which would be aided by the subject being administered with purified MASP-depleted MBL. Examples of suitable recipients of the method include, but are not limited to, bone marrow allograft recipients, subjects with cystic fibrosis, subjects with an immunodeficiency, subjects with acute lymphoblastic leukaemia, subjects with community acquired or nosocomial septicaemia, subjects with or susceptible to an infection by a pathogen, low birthweight and/or premature infants. Typically, the subject has an MBL deficiency. The present invention also provides a composition comprising isolated non-recombinant MBL, said composition being substantially free of MASPs, for use prophylactically or in therapy. The present invention further provides the use of a composition comprising isolated non-recombinant MBL, said composition being substantially free of MASPs, in the manufacture of a medicament for use in administering to a subject in need of said composition. Examples of suitable recipients include, but are not limited to, bone marrow allograft recipients, subjects with cystic fibrosis, subjects with an immunodeficiency, subjects with acute lymphoblastic leukaemia, subjects with community acquired or nosocomial septicaemia, subjects with or susceptible to an infection by a pathogen, low birthweight and/or premature infants. Typically, the subject has an MBL deficiency. The present inventors have also devised cleavage substrates, and assays for the use thereof, for determining the levels of MASP activity in a sample. Such assays can be used for monitoring MBL purification procedures described herein, or for any other purpose where it is desirable to analyse MASP activity. Thus, in a further aspect the present invention provides a peptide of formula X-R1-Arg-R2-Y wherein R1-Arg-R2 is a peptide consisting of 6 or more contiguous amino acids derived from the MASP cleavage site of a complement protein; X is NH 2 , a blocking group or a detectable label; and Y is COOH or a detectable label, provided that when X is NH 2 or a blocking group, Y is not COOH and when Y is COOH, X is not NH 2 or a blocking group. Preferably, the complement protein is C4. Preferably, the C4 protein is human C4 and the cleavage site comprises Arg756. In a further preferred embodiment, X is a quencher molecule and Y is a fluorescent label, or vice-versa, such that a fluorescent signal is obtained when the substrate is cleaved. In a further aspect, the present invention provides for the use of a peptide of the invention in a method of determining the presence of MASP activity in a sample. In yet another aspect, the present invention provides a method of determining the presence of MASP activity in a sample which method comprises contacting the sample with a peptide according to the invention and determining whether said peptide has been cleaved. In a further aspect, the present invention provides a method of producing a pharmaceutical composition of the invention which method comprises: (i) providing a complex of non-recombinant MBL and one or more MASPs; (ii) incubating the complex in a suitable buffer to dissociate the MBL from the one or more MASPs; (iii) separating the MBL from the one or more MASPs; (iv) screening the MBL obtained from (iii) for MASP activity using a method of the invention; and (v) admixing the resulting purified MBL with a pharmaceutically acceptable carrier or diluent. |
Heteropolymer complexes and methods for their use |
The present invention relates to an improved heteropolymer complex. The improved heteropolymer complex comprises a first monoclonal antibody specific for a C3b-like receptor (known as complement receptor (CR1) or CD35 in primates and Factor H in other mammals, e.g., dog, mouse, rat, pig, rabbit) site chemically crosslinked (covalently linked) to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest affinity for the Fc receptor, e.g., in humans, IgG1 or IgG3. The present invention also relates to methods for immune clearance of an antigen in a mammal via the C3b-like receptor comprising administering to said mammal an improved heteropolymer complex of the invention. The present invention also relates to methods for treating or preventing viral infection or microbial infection in a mammal comprising administering to said mammal an improved heteropolymer complex of the invention. The present invention also relates to methods for treating or preventing septic shock in a mammal comprising administering to said mammal an improved heteropolymer complex of the invention. The present invention also relates to methods for treating cancer in a mammal comprising administering to said mammal an improved heteropolymer complex of the invention. The present invention further relates to pharmaceutical compositions for the treatment or prevention of viral infection, microbial infection, septic shock, and cancer comprising an improved heteropolymer complex of the invention. |
1. A heteropolymer complex comprising a first monoclonal antibody specific for a C3b-like receptor of a mammal chemically crosslinked (covalently linked) to a second monoclonal antibody, in which the isotype of at least the second monoclonal is the isotype having the highest known affinity for the Fc receptor in said mammal. 2. The complex of claim 1 in which the first monoclonal antibody is specific for the complement receptor on a primate erythrocyte. 3. The complex of claim 2 in which the primate erythrocyte is a human erythrocyte. 4. A heteropolymer complex, which complex comprises a first monoclonal antibody specific complement receptor CR1 expressed on a human erythrocyte chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is human IgG1 or human IgG3. 5. The complex of claim 4, in which the second monoclonal antibody is a human, humanized or chimeric antibody. 6. The complex of claim 4 in which the first monoclonal antibody is a human, humanized or chimeric antibody. 7. The complex of claim 4 in which the isotype of the first monoclonal antibody is human IgG1 or human IgG3. 8. The complex of claim 4 in which the first monoclonal antibody is selected from the group consisting of 7G9, 1B4, 3D9, E-11, 57F, YZ1, and HB8592. 9. A heteropolymer cocktail composition comprising at least two heteropolymer complexes, in which at least one complex comprises a first monoclonal antibody specific for a C3b-like receptor of a mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. 10. The complex of claim 4 in which the second monoclonal antibody specifically binds a viral antigen. 11. The complex of claim 10 in which the viral antigen is an antigen of a retrovirus, a herpes virus, an arenavirus, a paramyxovirus, an adenovirus, a bunyavirus, a cornavirus, a filovirus, a flavivirus, a hepadnavirus, an orthomyovirus, a papovavirus, a picornavirus, a poxvirus, a reovirus, a togavirus, or a rhabdovirus. 12. The complex of claim 10 in which the viral antigen is selected from the group consisting of HIV gp120, influenza neuramimidase, influenza hemagglutinin, and RSV F glycoprotein. 13. The complex of claim 4 in which the second monoclonal antibody specifically binds a microbial antigen. 14. The complex of claim 13 in which the microbial antigen is lipopolysaccharide. 15. The complex of claim 13 in which the microbial antigen is an antigen of Streptococcus sp., Streptococcus sp., Neisseria sp., Corynebacterium sp., Clostridium sp., Haemophilus sp., Klebsiella sp., Staphylococcus sp., Vibrio sp., Escherichia sp., Pseudomonas sp., Campylobacter (Vibrio) sp., Aeromonas sp., Bacillus sp., Edwardsiella sp., Yersinia sp., Shigella sp., Salmonella sp., Treponema sp., Borrelia sp., Leptospira sp., Mycobacterium sp., Toxoplasma sp., Pneumocystis sp., Francisella sp., Brucella sp., Mycoplasma sp., Rickettsia sp., Chlamydia sp., or Helicobacter sp. 16. The complex of claim 4 in which the second monoclonal antibody specifically binds a cancer cell-specific antigen. 17. The complex of claim 16 in which the cancer cell-specific antigen is selected from the group comprising CD20, Her-2, and PSMA. 18. A method for immune clearance of an antigen comprising administering to a mammal an effective amount of a heteropolymer complex according to any of claims 1-17. 19. A method for immune clearance of an antigen comprising administering to a mammal an effective amount of a heteropolymer complex cocktail according to claim 9. 20. A method for immune clearance of an antigen comprising administering to a mammal an effective amount of franked cells expressing a C3b-like receptor bound to a heteropolymer complex, said complex comprising a first monoclonal antibody specific for the C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. 21. A method of detecting the presence of an antigen in a mammal, said method comprising contacting a sample obtained from the mammal containing cells expressing a C3b-like receptor with a heteropolymer complex according to any of claims 1-17; and detecting binding of the antigen in the sample. 22. A method for treating or preventing viral infection or microbial infection in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex according to any of claim 1-17. 23. The method of claim 22 in which the viral infection is caused by a retrovirus, a herpes virus, an arenavirus, a paramyxovirus, an adenovirus, a bunyavirus, a cornavirus, a filovirus, a flavivirus, a hepadnavirus, an orthomyovirus, a papovavirus, a picornavirus, a poxvirus, a reovirus, a togavirus, or a rhabdovirus. 24. The method of claim 22 in which the microbial infection is a yeast infection, fungal infection, protozoan infection or bacterial infection. 25. The method of claim 24 in which the bacterial infection is caused by Streptococcus sp., Streptococcus sp., Neisseria sp., Corynebacterium sp., Clostridium sp., Haemophilus sp., Klebsiella sp., Staphylococcus sp., Vibrio sp., Escherichia sp., Pseudomonas sp., Campylobacter (Vibrio) sp., Aeromonas sp., Bacillus sp., Edwardsiella sp., Yersinia sp., Shigella sp., Salmonella sp., Treponema sp., Borrelia sp., Leptospira sp., Mycobacterium sp., Toxoplasma sp., Pneumocystis sp., Francisella sp., Brucella sp., Mycoplasma sp., Rickettsia sp., Chlamydia sp., or Helicobacter sp. 26. The method of claim 22 in which the complex is administered intravenously. 27. The method of claim 22, in which the complex is administered intravenously to a human in an amount of 1-10 mg. 28. The method of claim 22 in which the microbial antigen is lipopolysaccharide. 29. A method for treating or preventing septic shock in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex according to any of claims 1-17. 30. The method of claim 29 in which the complex is administered intravenously. 31. The method of claim 29, in which the complex is administered intravenously to a human in an amount of 1-10 mg. 32. The method of claim 31 in which the human is immunocompromised, immunodeficient, elderly, suffering from burns, or an infant. 33. A method for treating cancer in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex according to any of claims 1-17. 34. The method of claim 33 in which the complex is administered intravenously. 35. The method of claim 33, in which the complex is administered intravenously to a human in an amount of 1-10 mg. |
<SOH> 2. BACKGROUND OF THE INVENTION <EOH>The immune adherence reaction was first described in 1953 by Nelson, 1953, Science 118:733-737 and provided strong support for a biological role for primate erythrocytes (E) in defense against infectious agents. Nelson reported that opsonization of bacteria with specific antibodies followed by complement activation promoted binding and immobilization of the bacteria on primate E. Once adhered to the E, the immune-complexed bacteria were efficiently transferred to acceptor phagocytic cells in a reaction in which the bacteria were stripped from the E without any discernable damage to the E. Twenty-seven years later Fearon, 1980, J. Exp. Med. 152:20-30 identified and characterized the first complement receptor, CR1, most specific for the complement activation product C3b, which is now known to facilitate the E immune adherence reaction. The putative role of primate E CR1 in providing a defense against microorganisms, involves the rapid immobilization and capture of bacteria and/or viruses present in the bloodstream on E before the bacteria and/or viruses can invade susceptible organs and tissues and/or adhere to and colonize sites in the vasculature. Moreover, Nelson reported that transfer of the E-bound bacteria to phagocytes occurred efficiently and rapidly in vitro and this reaction was followed by the phagocytosis and degradation of the internalized bacteria. This observation implies that similar reaction would occur in vivo, where the E-bound pathogen would be transferred to acceptor cells such as fixed tissue macrophages in the liver and spleen. 2.1 The Transfer Reaction and CR1 CR1 was first identified based on its ability to down-regulate amplification of the complement cascade and in particular to serve as a cofactor in the Factor I-mediated degradation of activated C3b. Cornacoff et al., 1983, J Clin Invest 71:236-247 reported that primate E CR1 can bind soluble, as well as particulate, complement opsonized immune complexes (IC) in the circulation. In fact, in vitro models of the transfer reaction with soluble IC have often focused on the potential role of Factor I in catalyzing the breakdown of CR1-bound and IC-associated C3b to C3bi and then C3dg, ligands that do not bind to CR1. The degradation of C3b thus releases complement-opsonized IC from E CR1 back into the plasma. This release, which has been shown to be quite rapid in vitro (half-life of ˜5 min) for IC prepared with small soluble proteins, might be expected to play a role in IC clearance and the transfer reaction in vivo. However, extensive kinetic analyses of E-bound IgG antibody/dsDNA IC in plasma demonstrated the marked stability of these complexes in vitro, which is in contrast to their rapid clearance from the circulation of non-human primates. In addition, the work of Emlen et al. demonstrated that in vitro transfer of E-bound IC to human monocytes was independent of Factor I (see Emlen et al., 1989, J Immunol 142:4366-4371 and Emlen et al., 1992, Clin Exp Immunol 89:8-17). 2.2 Immune Complexes (IC) IC prepared with systemic lupus erythematosus (SLE) IgG anti-dsDNA antibodies and dsDNA of varying lengths provide a particularly useful model for examining the immune adherence reaction. The multivalent nature of dsDNA allows for high avidity IgG binding. This leads to the generation of stable and soluble complexes which activate complement, capture C3b, and then rapidly bind to primate E. There is little crosslinking between dsDNA molecules in these complexes; therefore their properties and ability to interact with the complement system are essentially defined by the relative number and density of IgG bound per dsDNA molecule. It has been reported that in vitro binding of IgG antibody/dsDNA IC to chimpanzee E is stable in the presence of a source of Factor I, as manifested by less than 10% release after 1 h for a variety of IC prepared with different sizes of dsDNA (Kimberly et al., 1989, J Clin Invest 84:962-970 and Edberg et al., 1992, Eur J Immunol 22:1333-1339). However, when these complexes are labeled with 125 I, opsonized with complement and bound in vitro to 51 Cr-labeled chimpanzee E and then re-infused into the animal, the E-bound IC are cleared from the circulation with a half-life of only 5 min, less than 2% of the infused material is released into the plasma, and there is virtually no loss of the 51 Cr-labeled E during this process. Thus, the specific properties of E-bound complement-opsonized IgG antibody/dsDNA IC reveal a contradiction: although the complexes are very stable in vitro in plasma containing Factor I, they are rapidly stripped from the E surface and cleared from the circulation in vivo. This kinetic contradiction provides an important clue that, at least for the IgG antibody/dsDNA IC, and presumably for other IC if the results can be generalized, the in vivo transfer reaction is facilitated by a process which is unlikely to depend upon Factor I-mediated release. 2.3 Heteropolymers Based on the analyses of the dynamics of the in vitro and in vivo binding and in vivo clearance of IgG antibody/dsDNA IC mediated by primate E in the presence of complement, the immune adherence function of primate E was used to develop therapeutic modalities for targeting and clearing pathogens in the bloodstream (see U.S. Pat. Nos. 5,487,890 and 5,879,679, the disclosures of which are incorporated herein). In particular, bispecific monoclonal antibody (mAb) complexes (heteropolymers, HP), comprising a mAb specific for CR1 chemically crosslinked with a mAb specific for a target pathogen, were used to bind and immobilize a pathogen onto CR1 of the primate E. Several mouse mAbs specific for E CR1 with affinities in excess of 10 9 M −1 have been generated, and thus through the use of high affinity pathogen specific mAbs, it is possible to bind virtually any target pathogen to E in the absence of complement, including bacteria and viruses. HP-mediated binding can also be enhanced by the simultaneous ligation of several HP to a single pathogen and to a clustered CR1 region on the E. See, Kuhn et al., 1998, J. Immunol. 160:5088; Hahn et al., 2001, J. Immunol. 166:1057; Taylor et al., 1991, Proc. Natl. Acad. Sci. USA 88:3305; Taylor et al., 1997, J. Immunol. 159:4035; Reist et al., 1994, Eur. J. Immunol. 24:2018; Taylor et al., 1997, J. Immunol. 158:842; Nardin et al., 1999, Mol. Immunol. 36:827; and Cornacoff et al., 1983, J. Clin. Invest. 71:236. 2.4 Concerted Loss of CR1 and IC Clearance Although not intending to be limited to any specific mechanism, FIG. 1 shows a schematic of the proposed mechanism for the transfer reaction. The first step in the transfer reaction involves recognition and engagement of the E-bound IC by Fc receptors on the phagocytic cell. This step should occur for both C3b-opsonized IC as well as for IC bound to E via HP. This binding is followed by a concerted reaction in which CR1 is cleaved by membrane-associated proteases on the acceptor cell (Step 2), and then the entire IC, including CR1, is internalized via Fc receptors of acceptor cells such as Kupffer cells in the liver (Step 3). A simple in vivo model for the study of complement independent binding of IC to E CR1 in nonhuman primates can be established by intravenous infusion of a mouse anti-CR1 mAb, followed by polyclonal monkey anti-mouse IgG. Infusion of 125 I-labeled anti-CR1 mouse mAb 7G9 into the circulation of a rhesus monkey resulted in rapid binding of the mAb to E; however, there was little clearance from the circulation over 1 h ( FIG. 2A , filled circles). When polyclonal monkey anti-mouse IgG preparation was infused, the infused monkey IgG bound directly to the mouse mAb 7G9 already liganded to CR1 ( FIG. 2B , open squares, mouse anti-human IgG; filled diamonds, capture of mouse IgG), and was rapidly removed from the E and cleared from the circulation without loss of the E (i.e., no change in hematocrit). In fact, more than 90% of the E-bound IC (both 125 I-labeled anti-CR1 as well as the monkey anti-mouse IgG) were removed from the E. Western blot analysis and a RIA with a second non-crossreacting anti-CR1 mAb HB8592, demonstrated that CR1 was also removed from the E at the same rate at which the IC were cleared ( FIG. 2A , open circles). A plausible mechanism to explain this concerted reaction would be loss of CR1 by proteolytic cleavage followed by uptake of the released IC by acceptor macrophages. In fact, when anti-CR1 mAb was labeled with 131 I, and imaged, the cleared counts were localized principally to the liver, and to a lesser extent to the spleen. Citation of a reference in this section or any section of this application shall not be construed as an admission that such reference is prior art to the present invention. |
<SOH> 3. SUMMARY OF THE INVENTION <EOH>The present inventors have surprisingly discovered that the selection of the isotype used for the monoclonal antibody component of a heteropolymer complex can dramatically affect the efficiency of the complex to clear pathogens or immunogens or antigens that are bound to the complement receptor CR1 (CD35) expressed on erythrocytes in primates or a functionally analogous molecule. More particularly, the present inventors have concluded that immune clearance efficiency is dramatically and advantageously enhanced by use of heteropolymer complexes in which at least the second monoclonal antibody is of the isotype having the highest known affinity for the Fc receptor in a particular species, e.g. in humans, IgG1 or IgG3. The present invention is directed to a heteropolymer complex, comprising a first monoclonal antibody specific for a C3b-like receptor of a mammal chemically crosslinked (covalently linked) to a second monoclonal antibody, in which the isotype of at least the second monoclonal is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In a preferred aspect of this embodiment, the first monoclonal antibody is a human or humanized monoclonal antibody, preferably having the human IgG1 or human IgG3 isotype. In certain embodiments where the second monoclonal antibody is a human, humanized or chimeric antibody, the antibody has at least equal affinity for the human Fc receptor as a human IgG1 or human IgG3 antibody. Where the first monoclonal antibody is a mouse monoclonal antibody specific for primate CR1, the second monoclonal antibody is not a mouse monoclonal antibody having the isotype IgG2a. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. The antigen to which the second monoclonal antibody specifically binds can be a viral, microbial or cancer cell-specific antigen. In another embodiment, the present invention is directed to a heteropolymer cocktail composition comprising at least two heteropolymer complexes, in which at least one complex comprises a first monoclonal antibody specific for a C3b-like receptor of a mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In a preferred aspect of this embodiment, the isotype of the second monoclonal antibody in each complex is human IgG1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. In another embodiment, the present invention is directed to a method for immune clearance of an antigen comprising administering to a mammal an effective amount of a heteropolymer complex, said complex comprising a first monoclonal antibody specific for a C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. The method may further comprise allowing said complex to bind to at least one C3b-like receptor site and to said antigen. The method may yet further comprise permitting said bound complex to be cleared from circulation of said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG 1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. In yet another embodiment, the present invention is directed to a method for immune clearance of an antigen comprising administering to a mammal an effective amount of a heteropolymer complex cocktail comprising at least two complexes, in which at least one complex comprises a first monoclonal antibody specific for a C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In a preferred aspect of this embodiment, the isotype of the second monoclonal antibody in each complex is human IgG1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. The method may further comprise allowing said cocktail to bind to at least one C3b-like receptor site and to said antigen. The method may yet further comprise permitting said bound cocktail to be cleared from circulation of said mammal. The present invention is also directed to a method for immune clearance of an antigen comprising administering to a mammal an effective amount of franked cells expressing a C3b-like receptor bound to a heteropolymer complex, said complex comprising a first monoclonal antibody specific for the C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. The method may further comprise permitting the antigen to be cleared from circulation of said mammal. In yet another embodiment, the present invention is directed to a method of detecting the presence of an antigen in a mammal, said method comprising contacting a sample obtained from the mammal containing cells expressing a C3b-like receptor with a heteropolymer complex, which complex comprises a first monoclonal antibody specific for the C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal, and detecting binding of the antigen in the sample. In one aspect of this embodiment, the detecting step comprises separating the cells from soluble components; and contacting the cells with a labeled secondary antibody specific for the antigen. In a preferred embodiment, the method comprises contacting a human whole blood sample containing erythrocytes with a heteropolymer-complex, which complex comprises a first monoclonal antibody specific for erythrocyte complement receptor CR1 site on a human erythrocyte chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is human IgG1 or human IgG3, and detecting binding of the antigen. In yet another embodiment, the present invention is directed to a method for treating or preventing viral infection or microbial infection in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex, said complex comprising a first monoclonal antibody specific for a C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. In yet another embodiment, the present invention provides a method for treating or preventing septic shock in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex, said complex comprising a first monoclonal antibody specific for a C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody specific for lipopolysaccharide, endotoxin or a constituent of the outer wall of a Gram-negative bacterium, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. In yet another embodiment, the present invention is directed to a method for treating cancer in a mammal comprising administering to said mammal an effective amount of a heteropolymer complex, said complex comprising a first monoclonal antibody specific for a C3b-like receptor of said mammal chemically crosslinked to a second monoclonal antibody specific for a cancer cell-specific antigen, in which the isotype of at least the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said mammal. In a preferred embodiment, the first monoclonal antibody is specific for complement receptor (CR1 or CD35) on a human erythrocyte and the isotype of the second monoclonal antibody is human IgG1 or human IgG3. In another embodiment, the first monoclonal antibody is specific for Factor H on a non-primate mammalian platelet and the isotype of the second monoclonal antibody is the isotype having the highest known affinity for the Fc receptor in said non-primate mammal. In an alternative embodiment to any of the above methods, two or more heteropolymer complexes are administered, in which each first monoclonal antibody in the complex can be specific for the same, or a different epitope on the C3b-like receptor; and ach second monoclonal antibody can be specific for the same or a different epitope on the same antigen, or specific for a different antigen. 3.1 Definitions and Abbreviations The term “antibody specific for a viral antigen, microbial antigen, or cancer cell-specific antigen” and the like as used herein refer to an antibody that immunospecifically binds to a viral antigen, a microbial antigen or a cancer cell-specific antigen and does not specifically bind to other polypeptides. Antibodies that immunospecifically bind to viral antigens, microbial antigens or cancer cell-specific antigens may have cross-reactivity with other antigens. Preferably, an antibody that immunospecifically binds to a viral antigen, a microbial antigen or a cancer cell-specific antigen does not cross-react with other antigens. Antibodies that immunospecifically bind to viral antigens, microbial antigens or cancer cell-specific antigens can be identified, for example, by immunoassays or other techniques known to those of skill in the art. As used herein, the term “C3b-like receptor” is understood to mean any mammalian circulatory molecule which has an analogous function to the C3b receptor, for example, CR1 (CD35) in human or non-human primates, or Factor H in non-primate mammals (Alexander et al, 2001, J. Biol. Chem. 276:32129). Illustrative examples of C3b-like receptors include, but are not limited to, CR1 (CD35) of human or non-human primates, and Factor H of non-primate mammals. The term “fragment” as used herein refers to a peptide or polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least contiguous 80 amino acid residues, at least contiguous 90 amino acid residues, at least contiguous 100 amino acid residues, at least contiguous 125 amino acid residues, at least 150 contiguous amino acid residues, at least contiguous 175 amino acid residues, at least contiguous 200 amino acid residues, or at least contiguous 250 amino acid residues of the amino acid sequence of a viral peptide or polypeptide, a microbial peptide or polypeptide or an antibody that specifically binds to a viral, microbial or cancer cell-specific antigen. The term “franking” as used herein refers to the ex vivo binding of a heteropolymer complex to a cell expressing a C3b-like receptor, e.g., a primate erythrocyte. The cell-bound heteropolymer complex can then be administered to the mammal. The cells can be obtained from the individual to which the franked complex is to be administered or can be obtained from another suitable donor. The term “fusion protein” as used herein refers to a polypeptide that comprises an amino acid sequence of an antibody or fragment thereof and an amino acid sequence of a heterologous polypeptide (i.e., an unrelated polypeptide). The term “host cell” as used herein refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome. The term “immune clearance” as used herein refers to the removal of an antigen from the blood of a mammal by the binding of the antigen to a cell-bound heteropolymer complex and results in the reduction of the antigen in the blood, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99%, of a mammal administered a heteropolymer or heteropolymer cocktail composition of the invention relative to a mammal having a similar concentration of antigen in the blood but not administered the composition. As used herein, an “isolated” or “purified” material is material that is substantially free of other contaminating material. The language “substantially free” includes preparations which are at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% pure (by dry weight). When the material is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the material. In a preferred embodiment, the heteropolymer complexes of the invention are isolated or purified. In certain embodiments of the invention, an “effective amount” is the amount of a heteropolymer or heteropolymer cocktail composition of the invention that reduces the incidence, the severity, the duration and/or the symptoms associated with viral infection or microbial infection or septic shock in a mammal, e.g., a human or non-human primate. In certain other embodiments of the invention, an “effective amount” is the amount of a composition of the invention that results in a reduction in viral titer or microbial titer by at least 2.5%, at least 5%, at least 10%, at least 15%, at least 25%, at least 35%, at least 45%, at least 50%, at least 75%, at least 85%, by at least 90%, at least 95%, or at least 99% in a mammal administered a composition of the invention relative to the viral titer or microbial titer in a mammal or group of mammals (e.g., two, three, five, ten or more mammals) not administered a composition of the invention. In certain embodiments of the invention, an “effective amount” is the amount of a heteropolymer or heteropolymer cocktail composition of the invention that reduces the incidence, the severity, the duration and/or the symptoms associated with a cancer in a mammal, e.g., a human or non-human primate. In certain other embodiments, an “effective amount” is the amount of a composition of the invention that results in a reduction of the growth or spread of cancer or number of circulating cancer cells by at least 2.5%, at least 5%, at least 10%, at least 15%, at least 25%, at least 35%, at least 45%, at least 50%, at least 75%, at least 85%, by at least 90%, at least 95%, or at least 99% in a mammal administered a composition of the invention relative to the growth or spread of cancer or number of circulating cancer cells in a mammal or group of mammals (e.g., two, three, five, ten or more mammls) not administered a composition of the invention. Abbreviations used herein include: IC, immune complex(es); HCT, hematocrit; NHS, normal human serum; CR1, primate E complement receptor; CH50, hemolytic complement activity; HP, heteropolymer; CVF, cobra venom factor; CCS, cell culture supernatant; GFP, green fluorescent protein; C3b, and C3bi, C3dg, the major cleavage fragment and further degradation products of C3, respectively; RT, room temperature; SATA, N-succinimidyl S-acetylthioacetate; sSMCC, sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate. |
Communication application server for converged communication services |
A communication application server for supporting converged communications in a communication system. The communication application server is responsive to communication service requests from external endpoints, applications or other c requesting entities, and in one embodiment comprises at least first and second components. The first component is operative: (i) to process a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server, (ii) to determine one or more executable communication tasks associated with the identified communication service; and (iii) to establish communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication taks associated with the communication service. The second component is coupled between the first component and the one or more external servers, and provides, for each of the external servers, a corresponding interface for connecting the communication application server to the external server. |
1. A communication application server responsive to communication service requests in a communication system, the server comprising: a first component operative: (i) to process a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; (ii) to determine one or more executable communication tasks associated with the identified communication service; and (iii) to establish communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service; and a second component coupled between the first component and the one or more external servers, the second component providing for each of the external servers a corresponding interface for connecting the communication application server to the corresponding external server, wherein the first component comprises a session manager operative to manage session information associated with the communication services request; wherein the session information comprises a session hierarchy; wherein the session hierarchy comprises a user session associated with a plurality of communication services, a service session associated with a given one of the plurality of communication services, and a communication session associated with a communication task corresponding to the given one of the plurality of communication services; and wherein the communication session comprises at least a presence session. 2. The communication application server of claim 1 wherein the first component comprises a communication service and session management component, the communication service and session management component comprising the session manager, and the second component comprises a connectors component. 3. The communication application server of claim 2 wherein the communication service and session management component further comprises: a service event manager for processing the given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; a communication services manager adapted for interaction with the service event manager and operative to determine the one or more executable tasks associated with the communication service identified by the service event manager; and a routing element operative to establish communication with the one or more external servers for execution of at least a subset of the one or more executable tasks associated with the communication service. 4. The communication application server of claim 1 further comprising an access manager for controlling access of a requesting entity to the communication application server. 5. The communication application server of claim l wherein the given one of the communication service requests originates from an endpoint external to the communication application server. 6. The communication application server of claim 5 wherein the given one of the communication service requests originates from an application running on an endpoint external to the communication application server. 7. The communication application server of claim 1 wherein the set of one or more external servers comprises at least one of an enterprise server and a communications server. 8. The communication application server of claim 7 wherein the communications server comprises a communication system telephony switch. 9. The communication application server of claim 1 wherein the communication service comprises at least one federated communication service. 10. The communication application server of claim 1 wherein the communication service comprises at least one federated core service. 11. The communication application server of claim 10 wherein the federated core service comprises one or more communication service scripts. 12. The communication application server of claim 10 wherein the federated core service comprises a user profile database service. 13. The communication application server of claim 10 wherein the federated core service comprises at least one of a directory service, a registry service, a persistent store service, a QoS service and a security service. 14. The communication application server of claim 1 wherein the communication application server receives the communication service requests from a plurality of external applications, and provides communication services in response to the requests, utilizing the one or more external servers. 15. The communication application server of claim 1 wherein the given communication service request is received via a portal associated with the communication application server. 16. (canceled) 17. (canceled) 18. (canceled) 19. The communication application server of claim 1 wherein the communication session further comprises one or more of a telephony session, a messaging session, and an instant messaging session. 20. The communication application server of claim 1 wherein the communication session corresponds to a given one of the executable communication tasks associated with the given communication service, and involves execution of at least a portion of the communication task by one of the external servers. 21. The communication application server of claim 1 wherein the communication service comprises a plurality of executable communication tasks, each of at least a subset of the plurality of executable communication tasks comprising one or more specified processing steps. 22. The communication application server of claim 1 wherein the communication service comprises one or more additional communication services, each of the one or more additional communication services having one or more executable communication tasks associated therewith. 23. The communication application server of claim 1 wherein the communication service is implemented in accordance with a communication workflow specified in a service creation environment associated with the communication application server. 24. The communication application server of claim 1 wherein the first and second components are implemented at least in part in the form of one or more software programs stored in a memory of the communication application server and executed by a processor of the communication application server. 25. The communication application server of claim 1 wherein at least one of the executable communication tasks associated with the identified communication service is executed substantially entirely within the communication application server. 26. The communication application server of claim 1 wherein the one or more external servers which carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service comprise at least one server implemented on a common processing platform with the communication application server. 27. A communication application server responsive to communication service requests in a communication system, the server comprising: a memory; a processor coupled to the memory; wherein the processor is operative: (i) to process a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; (ii) to determine one or more executable communication tasks associated with the identified communication service; and (iii) to establish communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service; wherein the processor is further operative to manage session information associated with the communication services request; wherein the session information comprises a session hierarchy: wherein the session hierarchy comprises a user session associated with a plurality of communication services, a service session associated with a given one of the plurality of communication services, and a communication session associated with a communication task corresponding to the given one of the plurality of communication services; and wherein the communication session comprises at least a presence session. 28. In a communication system, a communication application server method responsive to communication service requests, the method comprising the steps of: processing a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; determining one or more executable communication tasks associated with the identified communication service; and establishing communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service; wherein the method further includes the step of managing session information associated with the communication services request; wherein the session information comprises a session hierarchy; wherein the session hierarchy comprises a user session associated with a plurality of communication services, a service session associated with a given one of the plurality of communication services, and a communication session associated with a communication task corresponding to the given one of the plurality of communication services; and wherein the communication session comprises at least a presence session. 29. An article of manufacture comprising a machine-readable storage medium for storing one or more software programs for use in a communication application server responsive to communication service requests in a communication system, wherein the one or more programs when executed in the communication application server implement the steps of: processing a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; determining one or more executable communication tasks associated with the identified communication service; and establishing communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service; wherein the one or more programs when executed in the communication application server further implement the step of managing session information associated with the communication services request; wherein the session information comprises a session hierarchy; wherein the session hierarchy comprises a user session associated with a plurality of communication services, a service session associated with a given one of the plurality of communication services, and a communication session associated with a communication task corresponding to the given one of the plurality of communication services; and wherein the communication session comprises at least a presence session. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Efficient communication services are integral to the success of any enterprise. However, as enterprises “virtualize,” it is becoming increasingly difficult to provide the requisite degree of communication efficiency using conventional techniques. Moreover, efficient communication must occur not only within a given enterprise but also between multiple enterprises. Unfortunately, conventional stand-alone telephony systems or other types of communication system hardware and software are often unable to provide adequate support for the many different modes of communication that may be required as integral parts of the business process of a given enterprise, particularly a virtual enterprise. The needs of a virtual enterprise dictate that the user experience be consistent and personalized, regardless of the mechanism or location for collaboration. In addition, business performance needs dictate that the existing enterprise infrastructure be leveraged, regardless of types of applications or services. One conventional approach to converged communications involves deploying multiple applications on an Internet Protocol (IP) network. However, this approach is problematic in that it addresses only certain aspects of infrastructure convergence. Virtual enterprises need their users and applications to be interconnected regardless of the particular type of network infrastructure which is utilized. Improved communication techniques are therefore needed which address the convergence of voice, data and other communication applications across disparate communication networks, while also providing the ability to handle seamlessly both real-time and non-real-time communications as demanded by a virtual enterprise. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a communication application server, and an associated method and article of manufacture, for providing converged communications in a manner which addresses one or more of the above-noted issues. In accordance with one aspect of the invention, a communication application server is provided for supporting converged communications in a communication system. The communication application server is responsive to communication service requests from external endpoints, applications or other requesting entities, and in an illustrative embodiment comprises at least first and second components in the form of a communication service and session management component and a connectors component, respectively. The communication service and session management component in the illustrative embodiment is operative: (i) to process a given one of the communication service requests to identify at least one corresponding communication service supported by the communication application server; (ii) to determine one or more executable communication tasks associated with the identified communication service; and (iii) to establish communication with one or more external servers to carry out execution of at least a subset of the one or more executable communication tasks associated with the communication service. The connectors component is preferably coupled between the communication service and session management component and the one or more external servers, and provides, for each of the external servers, a corresponding interface for connecting the communication application server to the corresponding external server. The communication service and session management component in the illustrative embodiment may include a service event manager, a communication services manager, and an intelligent router. The communication application server in the illustrative embodiment may include one or more additional components, such as a common access framework component with an access manager, a feature services component, a federated communication services component, a federated core services component, and a service creation environment. In accordance with another aspect of the invention, the communication service and session manager component of the communication application server includes a session manager operative to manage session information associated with the communication services request. The session information may comprise a session hierarchy. More specifically, the session hierarchy may comprise a user session associated with a plurality of communication services, a service session associated with a given one of the plurality of communication services, and a communication session associated with a communication task corresponding to the given one of the plurality of communication services. By way of example, the communication session may comprise one or more of a telephony session, a messaging session, an instant messaging session and a presence session. The communication session generally corresponds to a given one of the executable communication tasks associated with the given communication service, and may involve execution of at least a portion of the communication task by one of the external servers. |
Light-directed molecular analysis for cancer prognosis and diagnosis |
The location at which tissue samples are obtained to determine whether cells exhibit characeristics associated with cell differentiation or cancer by molecular analysis is determined by illuminating a gross anotomic area of tissue with a light that 5 selectively distinguishes cancerous and precancerous tissue from normal tissue. |
1. A prognostic/diagnostic method for detecting and diagnosing cancerous and precancerous tissue, said method comprising, in combination and in sequence, the steps of: (a) illuminating a gross anatomical area of tissue with a light that selectively distinguishes cancerous and precancerous tissue from normal tissue, to locate such suspect tissue; (b) separating cells from said suspect tissue; and (c) subjecting said cells to molecular analysis to determine whether said cells exhibit characteristics associated with cell differentiation or cancer. 2. The method of claim 1, wherein step (a) is preceded by saliva test cancer screening to determine whether cancerous or precancerous tissues exist in head and neck tissues and step (a) is then performed on said head and neck tissues. 3. The method of claim 1, wherein step (a) is followed by topical application of a selective staining dye to said suspect tissue, to further confirm that it is suspected of containing cancerous or precancerous cells and to provide additional time to view the suspect tissue to aid in biopsy of the suspect tissue, before performing step (b). |
<SOH> BACKGROUND OF THE INVENTION <EOH>Patients who delay in obtaining a cancer consultation for at least two months have significantly higher relative hazards of death than do patients with a shorter delay. (See Cancer, 92[11]:2885-2891, 2001). Thus, if patients are more regularly subjected cancer screening, coupled with a definitive procedure for making an early prognosis or diagnosis, the mortality rate risks of cancer would be reduced. Accordingly, I provide prognostic and diagnostic methods for early prediction of eventual development of invasive cancer or for definitive diagnosis, which are stepwise, rapid, conclusive, and readily adaptable as a clinical protocol. Development of Pre-Cancerous & Cancerous Tissue: The development of tumors requires two separate mutational events. One of these events may occur in the germline and be inherited. The second then occurs somatically. Alternatively, the two mutational events may occur only in the somatic cell of an individual. |
Wavelength division multiplex optical wavelength converter |
A WDM optical wavelength converter for converting modulated radiation at a first WDM wavelength channel (λ1) to corresponding modulated radiation at another WDM wavelength channel (λ2) comprises: a semiconductor laser (e.g., a sampled grating distributed Bragg reflector SGDBR device) integrated with a semiconductor optical amplifier (SOA). The converter is characterized in that the laser is wavelength tuneable over at least a plurality of wavelength channels and preferably all wavelength channels. |
1-14. (Canceled) 15. A wavelength division multiplex (WDM) optical wavelength converter for converting modulated radiation at a first WDM wavelength channel to corresponding modulated radiation at another WDM wavelength channel, comprising: a semiconductor laser integrated with a semiconductor optical amplifier, the laser being wavelength tuneable over at least a plurality of wavelength channels. 16. The wavelength converter as claimed in claim 15, in which the laser is wavelength tuneable over all of wavelength channels of a WDM grid. 17. The wavelength converter as claimed in claim 15, in which the optical amplifier is operable to receive the modulated radiation for wavelength conversion. 18. The wavelength converter as claimed in claim 15, in which the laser is operable to receive the modulated radiation for wavelength conversion. 19. The wavelength converter as claimed in claim 15, and further comprising a further integrated semiconductor optical amplifier. 20. The wavelength converter as claimed in claim 15, in which the laser is a distributed feedback (DFB) laser. 21. The wavelength converter as claimed in claim 20, in which the DFB laser has an active region that is divided into a plurality of sections, the sections being tuneable independently of one another. 22. The wavelength converter as claimed in claim 15, in which the laser is a distributed Bragg reflector (DBR) laser. 23. The wavelength converter as claimed in claim 22, in which the DBR laser has a first reflector section, a phase section, a gain section, and a second reflector section. 24. The wavelength converter as claimed in claim 23, in which each reflector section comprises a sampled Bragg grating. 25. The wavelength converter as claimed in claim 15, in which the laser is a superstructure-grating distributed Bragg reflector laser. 26. The wavelength converter as claimed in claim 15, in which the laser has a tuning mechanism based on voltage biasing using a quantum confined stark effect (QCSE). 27. The wavelength converter as claimed in claim 15, in which the laser has a tuning mechanism based on voltage biasing using a Franz Keldysh effect. 28. The wavelength converter as claimed in claim 15, in which the laser has a tuning mechanism based on electrical current injection. 29. The wavelength converter as claimed in claim 15, and further comprising means for fine-tuning the laser by altering a temperature of the laser. |
Antisense modulation of acyl coenzyme a cholesterol acyltransferase-1 expression |
Antisense compounds, compositions and methods are provided for modulating the expression of acyl coenzyme A cholesterol acyltransferase-1. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding acyl coenzyme A cholesterol acyltransferase-1. Methods of using these compounds for modulation of acyl coenzyme A cholesterol acyltransferase-1 expression and for treatment of diseases associated with expression of acyl coenzyme A cholesterol acyltransferase-1 are provided. |
1. A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding acyl coenzyme A cholesterol acyltransferase-1, wherein said compound specifically hybridizes with and inhibits the expression of a nucleic acid molecule encoding acyl coenzyme A cholesterol acyltransferase-1. 2. The compound of claim 1 which is an antisense oligonucleotide. 3. (CANCELLED). 4. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage. 5. The compound of claim 4 wherein the modified internucleoside linkage is a phosphorothioate linkage. 6. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified sugar moiety. 7. The compound of claim 6 wherein the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety. 8. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified nucleobase. 9. The compound of claim 8 wherein the modified nucleobase is a 5-methylcytosine. 10. The compound of claim 2 wherein the antisense oligonucleotide is a chimeric oligonucleotide. 11. A compound 8 to 50 nucleobases in length which specifically hybridizes with at least an 8-nucleobase portion of an active site on a nucleic acid molecule encoding acyl coenzyme A cholesterol acyltransferase-1. 12. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent. 13. The composition of claim 12 further comprising a colloidal dispersion system. 14. The composition of claim 12 wherein the compound is an antisense oligonucleotide. 15. A method of inhibiting the expression of acyl coenzyme A cholesterol acyltransferase-1 in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that expression of acyl coenzyme A cholesterol acyltransferase-1 is inhibited. 16. A method of treating an animal having a disease or condition associated with acyl coenzyme A cholesterol acyltransferase-1 comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of acyl coenzyme A cholesterol acyltransferase-1 is inhibited. 17. The method of claim 16 wherein the condition involves abnormal lipid metabolism. 18. The method of claim 16 wherein the condition involves abnormal cholesterol metabolism. 19. The method of claim 16 wherein the condition is atherosclerosis. 20. The method of claim 16 wherein the disease is cardiovascular disease. 21. The compound according to claim 1, wherein said compound inhibits expression of acyl coenzyme A cholesterol acyltransferase-1 by at least 30%. 22. The compound according to claim 1, wherein said compound inhibits expression of acyl coenzyme A cholesterol acyltransferase-1 by at least 50%. 23. The compound according to claim 1, wherein said inhibition is measured in a Northern blot assay in cells that endogenously express human acyl coenzyme A cholesterol acyltransferase-1. 24. The compound according to claim 1, wherein said inhibition is measured in a real-time polymerase chain reaction (RT-PCR) assay in cells that endogenously express human acyl coenzyme A acyltransferase-1. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Most mammalian cells cannot degrade cholesterol. When cellular cholesterol is no longer required as a metabolic intermediate for membrane stabilization, it must either be released from the cell or stored in the cytosol. Addition of long chain fatty acids to cholesterol via the esterification process reduces its solubility in the phospholipid bilayer and triggers its transfer to the cytoplasm where it is stored as liquid droplets (Rudel and Shelness, Nat. Med., 2000, 6, 1313-1314). Storage of cholesterol in droplets may serve to protect the cells from the toxicity of free cholesterol (Buhman et al., Biochim. Biophys. Acta, 2000, 1529, 142-154). In macrophages, the accumulation of cytosolic droplets of cholesterol esters results in the formation of foam cells in early atherosclerotic lesions (Buhman et al., Biochim. Biophys. Acta, 2000, 1529, 142-154). Control of the risk factors involved in hypercholesterolemia and cardiovascular disease has been the focus of much research in academia and industry. Because an elevated level of circulating plasma low-density lipoprotein cholesterol has been identified as an independent risk factor in the development of hypercholesterolemia and cardiovascular disease, many strategies have been-directed at lowering the levels of cholesterol carried in this atherogenic lipoprotein. AcylCoA cholesterol acyltransferase (ACAT) enzymes catalyze the synthesis of cholesterol esters from free cholesterol and fatty acyl-CoA. These enzymes are also involved in regulation of the concentration of cellular free sterols (Buhman et al., Biochim. Biophys. Acta, 2000, 1529, 142-154; Burnett et al., Clin. Chim. Acta, 1999, 286, 231-242; Chang et al., Annu. Rev. Biochem., 1997, 66, 613-638; Rudel et al., Curr. Opin. Lipidol., 2001, 12, 121-127; Rudel and Shelness, Nat. Med., 2000, 6, 1313-1314). Chang et al. cloned the first example of a human ACAT gene in 1993 (Chang et al., J. Biol. Chem., 1993, 268, 20747-20755) and mapped it to chromosome 1q25 (Chang et al., Somat. Cell Mol. Genet., 1994, 20, 71-74). This original ACAT enzyme is now known as acyl coenzyme A cholesterol acyltransferase-1. The murine acyl coenzyme A cholesterol acyltransferase-1 was cloned and mapped to a syntenic position on mouse chromosome 1 (Uelmen et al., J. Biol. Chem., 1995, 270, 26192-26201). Subsequently, the work of Meiner et al. suggested the presence of more than one ACAT gene in mammals (Meiner et al., J. Lipid Res., 1997, 38, 1928-1933). A second human ACAT isoform, now known as acyl coenzyme A cholesterol acyltransferase-2, was cloned and expressed recently (Oelkers et al., J. Biol. Chem., 1998, 273, 26765-26771). Murine acyl coenzyme A cholesterol acyltransferase-2 has also been identified and cloned (Cases et al., J. Biol. Chem., 1998, 273, 26755-26764). In humans, acyl coenzyme A cholesterol acyltransferase-1 is the predominant ACAT isoform in the liver, while acyl coenzyme A cholesterol acyltransferase-2 is thought to be responsible for enzymatic activity in intestinal enterocytes (Cases et al., J. Biol. Chem., 1998, 273, 26755-26764; Chang et al., J. Biol. Chem., 2000, 275, 28083-28092). The active site of acyl coenzyme A cholesterol acyltransferase-1 is predicted to be cytoplasmic, whereas acyl coenzyme A cholesterol acyltransferase-2 is predicted to be on the lumenal side of the endoplasmic reticular membrane (Anderson et al., J. Biol. Chem., 1998, 273, 26747-26754). The gene expression of acyl coenzyme A cholesterol acyltransferase-1 has been investigated in human monocytes, macrophages, and foam cells. Each of the cell types exhibited four mRNA transcripts (all containing the same 1.7 kb coding sequence) with sizes estimated at 7.4-7.0 kb, 4.7-4.3 kb, 4.0-3.6 kb and 3.0-2.8 kb (Chang et al., J. Biol. Chem., 1993, 268, 20747-20755; Matsuda et al., Biochim. Biophys. Acta, 1996, 1301, 76-84; Wang et al., Arterioscler. Thromb. Vasc. Biol., 1996, 16, 809-814). A subsequent study has indicated that the 4.7-4.3 kb acyl coenzyme A cholesterol acyltransferase-1 mRNA is produced from genes on two different chromosomes (chromosomes 1 and 7) by a novel RNA recombination mechanism involving trans-splicing of the two discontinuous precursor mRNAs (Li et al., J. Biol. Chem., 1999, 274, 11060-11071). Investigations of human acyl coenzyme A cholesterol acyltransferase-1 gene transcription in SRD4 Chinese hamster ovary cells demonstrated that long chain free fatty acids increase acyl coenzyme A cholesterol acyltransferase-1 mRNA levels (Seo et al., Biochemistry, 2001, 40, 4756-4762). Acyl coenzyme A cholesterol acyltransferase-1 knockout mice have recently been produced and investigated (Accad et al., J. Clin. Invest., 2000, 105, 711-719; Farese, Curr. Opin. Lipidol., 1998, 9, 119-123; Fazio et al., J. Clin. Invest., 2001, 107, 163-171; Meiner et al., Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 14041-14046; Yagyu et al., J. Biol. Chem., 2000, 275, 21324-21330). Among the conclusions reached in these investigations were that acyl coenzyme A cholesterol acyltransferase-1 deficiency in mice is associated with decreased neutral lipid accumulation (Accad et al., J. Clin. Invest., 2000, 105, 711-719) and that selective and complete deficiency of acyl coenzyme A cholesterol acyltransferase-1 in hyperlipidemic mice results in xanthomatosis, a condition characterized by a morphologic change involving the accumulation of lipids in the large foam cells of tissues (Accad et al., J. Clin. Invest., 2000, 105, 711-719; Yagyu et al., J. Biol. Chem., 2000, 275, 21324-21330). In six different human cell types in vitro, Chang et al. demonstrated that anti-acyl coenzyme A cholesterol acyltransferase-1 antibodies can inhibit acyl coenzyme A cholesterol acyltransferase-1 activity (Chang et al., J. Biol. Chem., 1995, 270, 29532-29540). In hepatocytes, cholesterol esters along with triacylglycerols constitute the bulk of the neutral lipid core of very low density lipoprotein (VLDL) (Chang et al., J. Biol. Chem., 2000, 275, 28083-28092). Based on the hypothesis that inhibitors of ACAT enzymes can lower plasma cholesterol levels, considerable research efforts have focused on the discovery of small molecule inhibitors of ACAT enzymes as cholesterol-lowering and/or anti-atherosclerotic agents. This field has been reviewed recently (Burnett et al., Clin. Chim. Acta, 1999, 286, 231-242; Chong and Bachenheimer, Drugs, 2000, 60, 55-93; Davignon, Diabete Metab., 1995, 21, 139-146; Krause and Bocan, ACAT inhibitors: physiologic mechanisms for hypolipidemic and antiatherosclerotic activities in experimental animals. In Inflammation: Mediators and Pathways. Eds. Ruffalo, R. R Jr. and Hollinger, M. A. pp 173-197, 1995, CRC Press, Boca Raton; Matsuda, Med. Res. Rev., 1994, 14, 271-305; Roth, Drug Discovery Today, 1998, 3, 19-25). Classes of small molecule inhibitors of ACAT enzymes include: fatty acyl amides (Krause and Bocan, ACAT inhibitors: physiologic mechanisms for hypolipidemic and antiatherosclerotic activities in experimental animals. In Inflammation: Mediators and Pathways. Eds. Ruffalo, R. R Jr. and Hollinger, M. A. pp 173-197, 1995, CRC Press, Boca Raton; Roth, Drug Discovery Today, 1998, 3, 19-25), substituted ureas (Tanaka et al., J. Med. Chem., 1998, 41, 4408-4420; Tanaka et al., Bioorg. Med. Chem., 1998, 6, 15-30; Tanaka et al., J. Med. Chem., 1998, 41, 2390-2410) sulfamates (Bocan et al., Arterioscler. Thromb. Vasc. Biol., 2000, 20, 70-79; Nicolosi et al., Atherosclerosis, 1998, 137, 77-85), sulfonamides (Lee et al., Bioorg. Med. Chem. Lett., 1998, 8, 289-294), acyl phosphonamides (Lee et al., Bioorg. Med. Chem. Lett., 1998, 8, 289-294), acyl phosphoroamadites (Lee et al., Bioorg. Med. Chem. Lett., 1998, 8, 289-294), phosphonates (Sellers et al., Toxicol. Sci., 1998, 46, 151-154), phenylethylamines (Dugar et al., Bioorg. Med. Chem., 1995, 3, 1231-1236; Vaccaro et al., J. Med. Chem., 1996, 39, 1704-1719.), bioflavinoid derivatives (Lee et al., Ann. Nutr. Metab., 1999, 43, 173-180), heterocyclic amides (White et al., J. Med. Chem., 1996, 39, 3908-3919.) and tetrazole-amide derivatives (O'Brien et al., J. Med. Chem., 1996, 39, 2354-2366). There are ongoing clinical studies with small molecule ACAT inhibitors but preliminary reports suggest poor gastrointestinal tract tolerability in humans (Chong and Bachenheimer, Drugs, 2000, 60, 55-93). Disclosed and claimed in PCT publication WO 94/09126 and corresponding U.S. Pat. No. 5,484,727 is the isolated nucleic acid encoding biologically active human acyl coenzyme A cholesterol acyltransferase-1 and a method of selectively inhibiting the synthesis of the acyl coenzyme A cholesterol acyltransferase-1 by introducing into a cell a stable antisense oligonucleotide having a nucleotide sequence substantially complementary to the gene encoding acyl coenzyme A cholesterol acyltransferase-1 such that said stable antisense oligonucleotide hybridizes with said DNA to substantially block the expression of acyl coenzyme A cholesterol acyltransferase-1 (Chang and Chang, 1996; Chang and Chang Catherine, 1994). Additionally disclosed and claimed in U.S. Pat. No. 5,968,749, is a transgenic animal having cells which contain a nucleotide sequence encoding an antisense oligonucleotide which hybridizes to the transcript of the gene encoding acyl coenzyme A cholesterol acyltransferase-1 to substantially block expression of the acyl coenzyme A cholesterol acyltransferase-1 enzyme (Chang and Chang, 1999; Chang and Chang, 1996; Chang and Chang Catherine, 1994). Disclosed and claimed in Japanese patent JP 6-172186 is an inhibitor containing, as active ingredient(s), at least one pyrimidine base, purine base, and nucleoside with the above base(s) as the constituent(s) wherein said inhibitor is useful for the prevention and treatment of various diseases involving arteriosclerosis (Shohachi, 1994). Currently, non-isozyme-specific inhibitors of ACAT enzymes include several classes of small molecules, while specific ACAT protein inhibitors include only antibodies. Consequently, there remains a long felt need for additional agents capable of effectively and selectively inhibiting the function of acyl coenzyme A cholesterol acyltransferase-1. Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of expression of acyl coenzyme A cholesterol acyltransferase-1. The present invention provides compositions and methods for modulating expression of acyl coenzyme A cholesterol acyltransferase-1. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding acyl coenzyme A cholesterol acyltransferase-1, and which modulate the expression of acyl coenzyme A cholesterol acyltransferase-1. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of acyl coenzyme A cholesterol acyltransferase-1 in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of acyl coenzyme A cholesterol acyltransferase-1 by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention. detailed-description description="Detailed Description" end="lead"? |
Apparatus for and method of trapping products in exhaust gas |
A trapping apparatus traps solid substances converted from reaction products contained in exhaust gases discharged from a process apparatus by a vacuum pump. The trapping apparatus has a trap member for contacting the exhaust gases and trapping reaction products contained in exhaust gases, and a trap housing (1) accommodating the trap member (4) therein. The trap housing has an inlet port (2) for introducing exhaust gases, and an exhaust gas space (3) connected to the inlet port and having an increased cross-sectional area in the direction in which exhaust gases flow in. The trap housing has a flow passage defined therein for passing the exhaust gases in the exhaust gas space and then changing the direction of the exhaust gases so as to flow from the exhaust gas space substantially perpendicularly to the trap member so as to pass the exhaust gases through the trap member while in contact therewith. |
1. An apparatus for trapping reaction products contained in exhaust gases discharged from a process apparatus, comprising: a trap housing (1); an inlet port (2) for introducing exhaust gases into said trap housing (1); an exhaust gas space (3) connected to said inlet port (2) and having an increased cross-sectional area in a direction in which exhaust gases flow in; a trap assembly (5) disposed adjacent to said exhaust gas space (3), said trap assembly (5) comprising a laminated assembly of trap filters having respective different mesh sizes which are progressively smaller along the direction in which said exhaust gases flow through; and an outlet port (9) in which exhaust gases flow out. 2. An apparatus according to claim 1, wherein said trap assembly (5) has a trap filter (6) comprising wavy meshes lying in a plane along said exhaust gas space (3) on a surface of said trap assembly (5). 3. An apparatus according to claim 1, wherein said trap filters are cooled by cooling waters. 4. An apparatus according to claim 1, wherein said trap assembly (5) includes a perforated metal plate (7a) for developing a pressure loss and rectifying action so that said exhaust gases flow slowly. 5. An apparatus according to claim 1, wherein directions of said exhaust gases flowing into said exhaust gas space is changed perpendicularly into said trap assembly (5). 6. An apparatus according to claim 1, further comprising another trap member of a wavy mesh (6d) extending along an inner wall surface of said exhaust gas space (3) in said trap housing (1). 7. An apparatus according to claim 1, further comprising a trap member of a metal plate assembly (4) in said exhaust gas space (3) extending parallel to a direction in which said exhaust gases are introduced from said inlet port. 8. An apparatus according to claim 3, wherein said trap assembly (5) includes wire demisters (8) for developing smaller pressure loss connected to said outlet port (9). 9. An apparatus according to claim 1, wherein said trap housing has a cooling water flow passage. 10. An apparatus according to claim 1, wherein said trap filters are detachably mounted in said trap housing. 11. A method of trapping reaction products contained in exhaust gases discharged from a process apparatus, while in contact with a trap member in a trap housing, comprising: introducing the exhaust gases into an exhaust gas space (3) in said trap housing (5) to decelerate the exhaust gases in said exhaust gas space (3); and changing the direction of said exhaust gases so as to flow from said exhaust gas space substantially perpendicularly to a trap assembly (5) disposed adjacent to said exhaust gas space (3), said trap assembly (5) comprising a laminated assembly of trap filters having respective different mesh sizes which are progressively smaller along the direction in which said exhaust gases flow through, so as to further decelerate the exhaust gases to pass through said trap assembly (5). wherein a trap filter of a wavy mesh extending along the direction in which said exhaust gases flow in is disposed in the exhaust gas space in said trap housing, for contact with said exhaust gases. 12. A method according to claim 11, wherein said trap member for developing a pressure loss comprises a perforated metal plate. 13. A method according to claim 11, wherein said exhaust gases having passed through said trap assembly (5) are introduced to an outlet port. 14. A method according to claim 11, wherein said trap assembly (5) comprises a wire demister. 15. A method according to claim 11, wherein said trap filters are cooled and brought into contact with said exhaust gases so as to deposit solidified reaction products thereto. 16. A method according to claim 11, wherein said trap assembly (5) comprises a perforated metal plate perpendicular to the direction in which said exhaust gases flow. 17. A method according to claim 11, wherein a vacuum pump is connected to said trap housing. 18. An apparatus according to claim 1, wherein said trap housing is connected to an outlet port of said vacuum pump. 19. An apparatus according to claim 1, wherein said trap housing is connected to an exhaust gas treatment device. 20. An apparatus according to claim 1, wherein said wavy mesh is made of metal wires woven into a wavy mesh having ridges (6a); and a plain-weave mesh member (6b) supporting said wavy mesh (6a) fixedly thereon. 21. An apparatus according to claim 20, wherein said wavy mesh (6a) comprises a plurality layer of wavy meshes. 22. An apparatus according to claim 20, wherein said plain-weave mesh member (6b) is made of metal wires woven into a mesh. 23. An apparatus according to claim 20, wherein said wavy mesh (6a) comprises a plurality layer of wavy meshes, and said plain-weave mesh member (6h) comprises a pair of plain-weave mesh members disposed one on each side of said plurality layer of wavy meshes. |
<SOH> BACKGROUND ART <EOH>Process apparatus such as semiconductor fabrication apparatus are evacuated for film growth and etching on semiconductor substrates therein. Exhaust gases discharged from such process apparatus after film growth and etching on semiconductor substrates contain a lot of gases including unreacted gases and reaction products newly created by reactions. While these gases are flowing through an exhaust passage, they collide upon surface irregularities in the exhaust passage, and are solidified into solid substances due to changes in temperature, speed, and direction. When the solid substances are deposited in pipes and on rotor of a vacuum pump connected to the process apparatus, they lower the exhaust conductance, tending to cause a vacuum pump failure. If the vacuum pump fails during the process performed by the semiconductor fabrication apparatus, then semiconductor substrates that are being processed by the semiconductor fabrication apparatus may possibly suffer trouble. Trapping apparatus have widely been used in the art as a means for trapping reaction products contained in exhaust gases. The trapping apparatus have a trapping member such as a metal plate, mesh, or baffle plate which is cooled. Exhaust gases discharged from the process apparatus are brought into contact with the cooled trapping member, whereupon gases products contained in the exhaust gases are solidified into solid substances, which are deposited on the cooled trapping member. The products contained in the exhaust gases generally have such gas/solid temperature characteristics that they are in a gaseous state at higher temperatures and a solid phase at lower temperatures. When exhaust gases containing products contact the trapping member at a low temperature, the products are brought into contact with the surface of the cool trapping member, and are solidified into solid substances, which are deposited on the trapping member. If the mesh size of the mesh of the trapping member is reduced, then the trapping efficiency with which to trap the products in the exhaust gases increases. However, the reduced mesh size tend to cause the trapping member to be clogged frequently. Therefore, the trapping apparatus needs to be serviced often and has its service life shortened. Conversely, if the mesh size of the mesh of the trapping member is increased, then the mesh is less susceptible to clogging due to solid substances, but the trapping efficiency decreases. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a plan view of a trapping apparatus according to a first embodiment of the present invention; FIG. 2 is a front elevational view of the trapping apparatus shown in FIG. 1 ; FIG. 3 is a cross-sectional view taken along line III-III of FIG. 1 ; FIG. 4A is a fragmentary perspective view of a wavy mesh; FIG. 4B is a fragmentary perspective view of a plain-weave mesh; FIG. 4C is a cross-sectional view showing stagnant regions which are formed when exhaust gases flow perpendicular to a trap filter; FIG. 4D is a cross-sectional view showing stagnant regions which are formed when exhaust gases flow parallel to a trap filter; FIG. 5A is a fragmentary perspective view of a trap filter in the form of a wavy mesh; FIG. 5B is a fragmentary cross-sectional view of an arrangement of trap filters; FIG. 5C is a fragmentary cross-sectional view of a wire demister, FIG. 6 is a view of another perforated metal plate; FIGS. 7A through 7D are plan views showing various joint configurations between trap housings and inlet ports; FIG. 8 is a cross-sectional view taken along line VIII-VIII of FIG. 3 ; FIG. 9 is a cross-sectional view of a trapping apparatus according to a second embodiment of the present invention; and FIGS. 10A, 10B , and 10 C are block diagrams of various evacuating systems. detailed-description description="Detailed Description" end="lead"? |
Chemical reactions in compressed carbon dioxide |
A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein at least one of the reagents used in said reaction is bounded to a solid polymer support. In a second aspect, a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein said reaction is performed in the presence of a tetra-alkylammonium acetate. In a third aspect, a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein said palladium catalyst does not have any fluorinated phosphine ligands but does have at least one phosphine ligand that has at least one substituent that is selected from tert-alkyl groups, cycloalkyl groups and optionally substituted phenyl groups or 1′-diphenylphosphino-biphenyl. In a fourth aspect, there is provided a palladium-catalysed Suzuki or Heck reaction in compressed carbon dioxide wherein both of the substrates being combined in said reactions are boronic acids. |
1. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein at least one of the reagents used in said reaction is bound to a solid polymer support. 2. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 1 wherein said reaction is selected from the group consisting of Heck, Suzuki, Sonogashira and Stille reactions. 3. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 1 or claim 2 wherein said polymer-bound reagents are selected from polymer-supported bases and polymer-supported solubilising ligands. 4. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 3 wherein said polymer-supported base is a polymer-supported amine base. 5. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 4 wherein said polymer-supported amine base is a polymer having supported monoalkylaminoalkyl groups or a polymer having supported dialkylaminoalkyl groups wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms. 6. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 3 to 5 wherein said supporting solid polymer is selected from polystyrenes and macroreticular resins. 7. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 3 to 6 wherein said polymer-supported base is selected from dialkylaminoalkylpolystyrenes and dialkylamino-macroreticular resins. 8. A palladium-catalysed carbon-carbon bond forming reaction in compressed cart dioxide as a solvent according to claim 7 wherein said polymer-supported base is selected from diethylaminomethylpolystyrene, diethylaminomethyl-macroreticular resin and disopropylmethylaminopolystyrene. 9. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 7 wherein said polymer-supported base is diethylaminomethylpolystyrene. 10. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 1 to 9 wherein said polymer-supported solubilising ligand is selected from polymer-supported phosphine ligands. 11. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 10 wherein said supporting polymer is selected from polystyrenes and macroreticular resins. 12. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 1 to 11 wherein said phosphine ligands on said solid polymer supports are selected from phosphine ligands that have at least one fluoro-substituted aliphatic or aromatic substituent, and phosphine ligands that do not have any fluorinated substituents but do have at least one substituent selected from alkyl groups, cycloalkyl groups and aryl groups. 13. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 12 wherein said phosphine ligands on said solid polymer supports are selected from diarylphosphinoalkyl groups, dialkylphospinoalkyl groups and dicycloalkylphospinoalkyl groups wherein each alkyl moiety has from 1 to 6 carbon atoms, each cycloalkyl group has from 3 to 8 carbon atoms and each aryl group is a phenyl group that may optionally be substituted with at least one alkyl group having from 1 to 6 carbon atoms. 14. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 10 wherein said polymer-supported phosphine is selected from polystyrenes and macroreticular resins having supported diphenylphosphinoalkyl groups wherein said alkyl groups have from 1 to 6 carbon atoms. 15. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 14 wherein said polymer-supported phosphine is diphenylphospinomethylpolystyrene. 16. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 1 to 15 wherein at least one of the substrates of the carbon-carbon bond forming reaction is bound to a solid polymer support. 17. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 1 to 16 wherein said reaction is conducted as a continuous flow reaction. 18. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein said reaction is performed in the presence of a tetra-alkylammonium acetate wherein each alkyl group is the same or different and has from 1 to 6 carbon atoms. 19. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 18 wherein each all group of said tetra-alkylammonium acetate is the same or different and has from 1 to 4 carbon atoms. 20. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 18 wherein said tetra-alkylammonium acetate is selected from tetraethylammonium acetate and tetra(n-butyl)ammonium acetate. 21. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 18 wherein said tetra-alkylammonium acetate is tetra(n-butyl)ammonium acetate. 22. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 18 to 21 wherein said reaction is selected from the group consisting of Heck, Suzuki, Sonogashira and Stille reactions. 23. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 18 to 22 wherein said reaction is conducted using a solubilising ligand selected from phosphine ligands that have at least one fluoro-substituted aliphatic or aromatic substituent, and phosphine ligands that do not have any fluorinated substituents but, do have at least one substituent selected from alkyl groups, cycloalkyl groups and aryl groups. 24. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 23 wherein said phosphine ligands are selected from triarylphosphinoalkyl groups, trialkylphospinoalkyl groups and tricycloalkylpbospinoalkyl groups wherein each alkyl moiety has from 1 to 6 carbon atoms, each cycloalkyl group has from 3 to 8 carbon atoms and each aryl group is a phenyl group that may optionally be substituted with at least one alkyl group having from 1 to 6 carbon atoms. 25. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 23 wherein said phosphine ligands are selected from tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and 1′-diphenyl-phosphinobiphenyl. 26. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 18 to 22 wherein said reaction is conducted using a polymer-supported solubilising ligand as defined in any one of claims 10 to 15. 27. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 18 to 22 wherein at least one of the substrates of the carbon-carbon bond forming reaction is bound to a solid polymer support. 28. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 18 to 27 wherein said reaction is conducted as a continuous flow reaction. 29. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein said palladium catalyst does not have any fluorinated phosphine ligands but does have at least one phosphine ligand that has at least one substituent that is selected from the group consisting of tert-alkyl groups having from 4 to 10 carbon atoms, cycloalkyl groups having from 3 to 8 carbon atoms and phenyl groups which can be substituted with at least one alkyl group having from 1 to 6 carbon atoms or 1′-diphenyl-phosphinobiphenyl. 30. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 29 wherein said tert-alkyl substituents for said phosphine ligands are tert-butyl groups, said cycloalkyl substituents for said phosphine ligands are cyclohexyl groups and said optionally substituted phenyl groups for said phosphine ligands are o-tolyl groups. 31. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 29 wherein said phosphines are selected from tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl. 32. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 29 wherein said phosphine is tri(z-butyl)phosphine. 33. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 29 to 32 wherein said reaction is selected from the group consisting of Heck, Suzuki, Sonogashira and Stille reactions. 34. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 29 to 33 wherein said reaction is performed in the presence of a base or other reaction-promoting additive selected from diisopropylethylamine, cesium carbonate, diethylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate, triethylamine, tri-n-butylamine, perfluorinated trihexylamine, polystrenemethylammonium carbonate, tetramethylethylenediamine diamine (TMEDA), tetramethyl hexanediamine, and tetra-alkylammonium acetates wherein each alkyl group has from 1 to 6 carbon atoms. 35. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 34 wherein said reaction is performed in the presence of a base selected from tetramethyl hexanediamine and cesium carbonate. 36. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to claim 34 wherein said reaction is performed in the presence of a reaction-promoting additive selected from tetra-alkylammonium acetates wherein each alkyl group has from 1 to 6 carbon atoms. 37. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 29 to 36 wherein at least one of the substrates of the carbon-carbon bond forming reaction is bound to a solid polymer support. 38. A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent according to any one of claims 29 to 37 wherein said reactions is conducted as a continuous flow reaction. 39. A palladium-catalysed Suzuki or Heck reaction in compressed carbon dioxide as a solvent wherein both of the substrates being combined in said reactions are boronic acids. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Supercritical carbon dioxide has been used for polymer synthesis and polymer processing. This has been extensively reviewed in the past and the state of the art is summarised in an article by Cooper [A. I. Cooper, J. Mater. Chem., 2000, 10, 207]. Compressed carbon dioxide is also used as a solvent for the preparation of organic molecules and this has been summarised in a special issue of Chemical Reviews . [see Special Issue: Chem. Rev. 1999, 99, #2]. Unlike conventional liquid solvents, carbon dioxide is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying the pressure [see M. McHugh et al. “Supercritical Fluid Extraction” Boston, Butterworth-Heinemann, 1994]. Compressed carbon dioxide is an attractive alternative to conventional solvents because it is inexpensive, non-toxic and non-flammable. Compressed carbon dioxide reverts to the gaseous state upon decompression, simplifying solvent separation from solute(s) and reaction products. Metal-catalysed processes are extremely common in the synthesis of small organic molecules for the pharmaceutical industry as well as for agrochemicals, flavours, fragrances and specialist consumer products. They are assuming growing importance in the synthesis of macromolecules, particularly conjugated polymers (see for example Bernius, M. T.; Inbasekaran, M.; Brien, J.; Wu, W. Adv. Mater., 2000, 12, 1737). Metal-catalysed homogeneous reactions in supercritical carbon dioxide have been reported and the state of the art is summarised in a special edition of Chemical Reviews, 1999, 99(#2) and in a monograph “ Chemical synthesis using supercritical fluids ” P. G. Jessop and W. Leitner, Wiley-VCH, Weinheim, 1999. A comprehensive review of organic synthesis in supercritical carbon dioxide bas been written by Oakes, R. S.; Clifford, A. A.; Rayner, C. M. J. Chem. Soc., Perkin 1, 2001, 917. WO-A-98/32533 discloses the use of phosphorus ligands carrying perfluoroalkyl chains to solubilise rhodium phosphine complexes in hydroformylation and hydrogenation reactions. WO-A-99/38820 discloses the use of ligand-metal complexes in which the complex comprises a perfluorinated group for the transformation of organic molecules. In some of the reactions, the substrate was anchored to a solid polymer support. Palladium-catalysed cross coupling reactions in supercritical carbon dioxide have been disclosed (M. A. Carroll. M. A.; Holmes A. B. Chem. Commun., 1998, 1395; Morita, D. K; Pesiri, D. R; David, S. A.; Glaze, W. H.; Tumas, W.; Chem. Commun., 1998, 1397; Shezad, N., Oakes, R. S., Clifford, A. A. and Rayner, C. M., Tetrahedron Lett., 1999, 40, 2221). The first mentioned paper reported Heck, Suzuki (Suzuki, A in Metal - catalysed Cross - coupling reactions , eds. Diederich, F. and Stang, P. J., Wiley-VCH, Weinheim, 1997.) and Sonogashira reactions. The second reported, in addition, Stille reactions while the third reported the use of palladium(II) trifluoroacetate as the catalyst source. These examples teach that perfluorinated alkyl ligands (or trifluoroacetate) are needed, presumably for enhancement of solubility of the complex in supercritical carbon dioxide (sc CO 2 ). Non-fluorinated triarylphosphines have been shown to lead to lower conversions in the Heck reaction (the palladium-mediated addition of an aryl or vinyl halide to an alkene with regeneration of the double bond in the original alkene partner; see Palladium reagents in organic synthesis ”, R. F. Heck, Academic Press, Orlando, 1985; Heck, R. F., Org. React., 1982, 27, 345; Beletskaya, I.; Cheprakov, Chem. Rev., 2000, 100, 309). Exceptionally, ring closing olefin metathesis (R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413-4450) with an insoluble diphenylalkylidene ruthenium catalyst has been realised. (Fürstner, A. et al. Angew. Chem. Int. Ed., 1997, 36, 2646). |
<SOH> SUMMARY OF THE INVENTION <EOH>An important aspect of all the above palladium-mediated carbon-carbon bond forming reactions was the need for a solubilising fluorine-containing phosphine ligand or a trifluoroacetate counterion to for a homogeneous solution of the palladium complex in compressed carbon dioxide. WO-A-99/38820 discloses the use of perfluorinated ligand-palladium complexes in which some of the reactions were performed using a substrate which was anchored to a solid polymer support. It has never been previously disclosed or suggested however, that it might be possible to perform palladium-mediated carbon-carbon bond forming reactions in compressed carbon dioxide using reagents that are anchored to a solid polymer support. We have now made the surprising discovery that it is possible to perform such palladium-mediated reactions in compressed carbon dioxide using reagents immobilised on commercially available solid supports. This gives many advantages, including increased ease of processing making it attractive as a potential means of performing these reactions on an industrial scale and the discovery that using such reagents it is possible to obtain excellent yields without the need for a fluorinated phosphine ligand. Thus, in a first aspect of the present invention there is provided a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein at least one of the reagents used in said reaction is bound to a solid polymer support. By compressed carbon dioxide, we mean carbon dioxide which has been compressed under pressure to produce liquid carbon dioxide or supercritical carbon dioxide. A supercritical fluid may be defined as a substance for which both the temperature and pressure are above the critical values for the substance and which has a density close to or higher than the critical density. Carbon dioxide is an ideal solvent because of its mild critical temperature (31.1° C.) and its relatively low critical pressure (73.8 bar). Another advantage of carbon dioxide is that it is a gas under atmospheric conditions so that the end-reaction mixture is solvent-free. By reagents we mean agents that are used to enable the palladium-catalysed reaction to be performed but which do not include the actual substrates that are being coupled in the carbon-carbon bond forming reaction. Examples of the polymer-bound reagents include polymer-supported bases and polymer-supported solubilising ligands. By solubilising ligands we mean reagents that can interact with the source of palladium in the reaction and, as a result, increase the solubility of the palladium in the compressed carbon dioxide. Typical examples of the polymer-supported bases include polymer-supported amine bases such as polymers hang supported monoalkylaminoalkyl groups and polymers having supported dialkylaminoalkyl groups wherein each alkyl group is the same or different and preferably has from 1 to 6 carbon atoms. Typical examples of the supporting polymer include polystyrenes and macroreticular resins (e.g. Amberlyst®). Preferred examples of the polymer-supported bases include dialkylaminoalkylpolystyrene and dialkylamino-macroreticular resin, of which diethylaminomethylpolystyrene, diethylaminomethyl-Amberlyst resin and a disopropylmethylaminopolystyrene are more preferred and diethylaminomethylpolystyrene is most preferred. Further examples of suitable polymer-supported bases are found in the review by S. V. Ley et all J.C.S. Perkin Trans. I, 2000, 3815. Using polymer-supported bases such as these we have found that it is even possible to perform palladium-catalysed carbon-carbon bond forming reactions without the need for the addition of a phosphine ligand to the palladium source. Typical examples of polymer-supported solubilising ligands are polymer-supported phosphine ligands. Typical examples of the supporting polymer include polystyrenes and macroreticular resins (e.g. Amberlyst®). The phosphine ligands include ones that have at least one fluoro-substituted aliphatic or aromatic substituent such as phosphines that have at least one C 1 -C 20 perfluoroalkyl substituent such as a 1H,1H,2H,2H-perfluorooctyl group but also include ones that do not have at least one fluorinated substituent but instead have substituents such as alkyl groups (e.g. alkyl groups having from 1 to 6 carbon atoms, especially t-alkyl), cycloalkyl groups such as those having from 3 to 8 carbon atoms and aryl groups such as phenyl groups which can be substituted with at least one alkyl group having from 1 to 6 carbon atoms. Preferred examples include polymers having supported diarylphosphinoalkyl groups, polymers having supported dialkylphospinoalkyl groups and polymers having supported dicycloalkylphospinoalkyl groups wherein the alkyl, cycloalkyl and aryl groups are as defined above. More preferred examples include polystyrenes and macroreticular resins having supported diphenylphosphinoalkyl groups, and the most preferred example is diphenylphosphinomethylpolystyrene. Polymer-supported phosphines are well-known in the art and are discussed, for example, in Trost et al, J. Am. Chem. Soc., 1978, 100, 7779, and Jang, Tetrahedron Lett., 1997, 38, 1793, and can be obtained commercially (e.g. from Nova Biochem). Not only is there significant potential for catalyst recyclability (as the palladium is anticipated to remain on the resin) but these reactions could potentially be monitored by on line procedures. During our work, we have found that polymer-supported reagents such as polymer supported bases and polymer-supported solubilising phosphines allow completely heterogeneous Heck and Suzuki coupling reactions to be carried out in compressed carbon dioxide. Based on this observation, all polymer-supported reagents should show significant enhancements in rates, reactivity and yields when used in these palladium-mediated carbon-carbon bond forming reactions. Examples of reactions which can all show improved yields through the use of polymer-supported reagents include Heck reactions (e.g. see “ Palladium reagents in organic synthesis ”, R. F. Heck, Academic Press, Orlando, 1985; Heck, R. F., Org. React., 1982, 27, 345; and Beletskaya, I.; Cheprakov, A. Chem. Rev., 2000, 100, 309), Suzuki reactions (e.g. see Migaura et al, Syn. Commun, 1981, 11, 513), Sonogashira reactions (e.g. see Sonogashira et al, Tetrahedron Lett, 1983, 4467) and Stille reactions and related reactions. As one example, we found that for the Heck reaction the addition of aryl iodide and bromide substrates to acrylates such as butyl acrylate was surprisingly effective using the combination of a palladium (0) source such as palladium (II) acetate and a polymer-supported base. Suitable polymer-supported bases are of the type described and exemplified above, of which we found that ones selected from diethylaminomethylpolystyrene, a diethylaminomethyl-Amberlyst resin and a disopropylmethylaminopolystyrene are preferred and diethylaminomethylpolystyrene is most preferred. Using these bases, we found that no solubilising phosphine ligand is required at all. For carbon-carbon bond forming reactions such as the Heck reaction to have useful application in the pharmaceutical industry, it is essential that the phosphine content and the fluorine-substituted solubilising groups should be kept to a minimum. Clearly, the ability to perform these reactions with no phosphine ligands or fluorine-substituted solubilising groups in some circumstances makes the process of the present invention highly promising. Furthermore, an inherent feature of this invention is that the heterogeneous reaction with palladium catalyst leaves the catalyst embedded in the polystyrene matrix. Experiments, using the recycled resin, are encouraging. This invention therefore shows the potential for a continuous flow process using recycled palladium/resin. Again using the Heck reaction as an example, although the combination of simple Pd (II) salts such as palladium acetate and aryl halides had been previously used in the phase-transfer catalysis version of the Heck reaction (Jeffery, T. Tetrahedron 1996, 30, 10113), we have surprisingly found that the Heck addition of aryl iodides or bromides to an acrylate such as butyl acrylate can be realised in the presence of a polymer-supported solubilising phosphine ligand. Suitable polymer-supported phosphine ligands are of the type described and exemplified above, of which diphenylphosphinomethylpolystyrene is particularly preferred. The Heck addition using a palladium source such as palladium (E) acetate in the presence of a polymer-supported phospine ligand is best performed in the presence of a base or another promoting additive, preferred examples of such bases and additives including: diisopropylethylamine, cesium carbonate, polymer-supported bases of the type described above such as diethylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate, triethylamine, tri-n-butylamine, perfluorinated trihexylamine, polystyrenemethylammonium carbonate, tetramethylethylamine diamine (TMEDA), tetramethylhexanediamine, and tetraalkylaminonium acetates such as tetrabutylammonium acetate. Of these, we prefer diisopropylethylamine and tetaalkylammonium acetates. Most preferably the additive is tetrabutylammonium acetate. The combination of tetrabutylammonium chloride in the palladium-mediated Stille reaction with various phosphine ligands in super critical CO 2 has been reported (Osswald, T.; Schneider, S.; Wang, S.; Bannwarth, W. Tetrahedron Lett, 2001, 42, 2965). This teaches the use of this additive, but surprisingly we have now found that tetra-alkylammonium acetates give significantly superior yields in palladium-catalysed carbon-carbon bond forming reactions. Thus, in a second aspect of the present invention, there is provided a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein said reaction is performed in the presence of a tetra-alkylammonium acetate. Each alkyl group can be the same or different and typically has from 1 to 6 carbon atoms, of which alkyl groups having from 1 to 4 carbon atoms are more preferred. Preferred are tetraethylammonium acetate and tetra(n-butyl)ammonium acetate, of which tetra(n-butyl)ammonium acetate is particularly preferred. We have surprisingly found that the yields in palladium-catalysed carbon-carbon bond forming reactions are significantly superior when a tetra-alkylammonium acetate is added to the reaction mixture in place of the known tetra-alkylammonium chlorides. While not wishing to be bound by theory, we believe that the role of the tetra-alkylammonium acetates is probably related to interfacial catalysis. Typically, the palladium-mediated carbon-carbon bond forming reaction is conducted using a solubilising ligand such as a phosphine ligand. Examples include include ones that have at least one fluoro-substituted aliphatic or aromatic substituent such as phosphines that have at least one C 1 -C 20 perfluoroalkyl substituent such as a 1H,1H,2,2H-perfluorooctyl group but also include ones that do not have at least one fluorinated substituent but instead have substituents such as alkyl groups (e.g. alkyl groups having from 1 to 6 carbon atoms, especially t-alkyl), cycloalkyl groups such as those having from 3 to 8 carbon atoms and aryl groups such as phenyl groups which can be substituted with at least one alkyl group having from 1 to 6 carbon atoms. Preferred examples include tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl. Particularly preferred, however, are polymer-supported solubilising ligands such as the polymer-supported phosphines described and exemplified above. Of these, we particularly prefer polystyrenes and macroreticular res having supported diphenylphosphinoalkyl groups, and the most preferred example is diphenylphospinomethylpolystyrene. The use of tetra-alkylammonium acetates at elevated temperatures leads to a two-phase reaction medium involving the molten ammonium salt as one component. A further aspect of this invention is that the tetra-alkyl ammonium salts (e.g tetraethyl) may be used as hydrates and the tetra-alkylammonium salts such as the acetates may be used as 1M aqueous solutions, providing a multiphase reaction medium for the actual carbon-carbon bond forming reactions. A feature of the first aspect of the invention using polymer-supported reagents is the, ease of isolation of product. This follows from a simple washing of the reaction cell with compressed carbon dioxide which selectively removes the small molecule product from the solid phase reactants. In the case of the Suzuki reaction it has been demonstrated that the biaryl product can be simply isolated by washing and extraction in compressed carbon dioxide, followed by venting the pressure. This operation shows considerable promise for continuous flow manufacturing in small bore carbon dioxide reactors where the catalyst and an amine salt remain behind in the reactor vessel and the product is enacted by carbon dioxide. It is also expected that this process should be equally possible using the tetralkylammonium additive technique. Thus, in a preferred embodiment of the present invention, there is provided a palladium-mediated carbon-carbon bond forming reaction according to the first or second aspects of the present invention defined and exemplified above wherein said reaction is conducted as a continuous flow reaction. Surprisingly the delivery of the reagents and compressed CO 2 solvent through a mixing nozzle into a reaction tube, previously charged with the catalyst, leads to an extremely rapid chemical reaction under conditions above the critical temperature and pressure. The products and unconverted starting materials emerge from the reactor through a filter. The rate of flow of the products may be controlled, for example, by the use of a back pressure regulator. This procedure can be applied to Suzuki reactions (e.g. an aryl halide coupled with a boronic acid), Heck reactions (e.g. an aryl halide coupled with an olefin), Sonogashira reactions (e.g. an aryl halide coupling with an alkyne) and Stille reactions (e.g. an aryl halide coupled with an organostannane). Most preferably the Suzuki reaction can be carried out under continuous flow conditions. Rapid formation of product is observed even when the reactants are subject to a single pass through the reactor, involving a short residence time in contact with the catalyst. A co-solvent may be employed to assist in the charging of the reactor with some reagents. Preferred co-solvents include methanol and toluene, but any selection of common solvents, including fluorinated solvents may be used. As discussed above, it has previously been believed that phospine ligands having highly fluorinated substituents or trifluroacetate counterions were needed to enable palladium-catalysed carbon-carbon bond forming reactions to be performed in compressed carbon dioxide with acceptable yields. For example, previously the electron rich tri(2-furyl)-phosphine had been employed as a non-fluorinated ligand but with low yields (Morita, D. K.; Pesiri, D. R.; David, S. A; Glaze, W. H.; Tumas, W.; Chem. Commun., 1998, 1397). Surprisingly, we have now found that a range of non-fluorinated phosphine ligands in combination with a palladium (0) source such as palladium (II) acetate catalyse carbon-carbon bond forming reactions more efficiently than the combinations employing fluorinated phosphines. Thus, in a further aspect of the present invention there is provided a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide as a solvent wherein said palladium catalyst does not have any fluorinated phosphine ligands but does have at least one phosphine ligand that has at least one substituent that is selected from the group consisting of tert-alkyl groups having from 4 to 10 carbon atoms, cycloalkyl groups having from 3 to 8 carbon atoms and phenyl groups which can be substituted with at least one alkyl group haling from 1 to 6 carbon atoms or 1′-diphenylphosphinobiphenyl. The solubility of triethylphosphine in compressed CO 2 and its use in certain hydroformylation reactions has previously been described by Cole-Hamilton (Bach, I.; Cole-Hamilton, D. J. Chem. Commun., 1998, 1463) but there has never previously been any suggestion that tert-alkylphospine solubilising groups might give superior results to perfluorinated alkylphospine solubilising groups in palladium-catalysed carbon-carbon bond forming reactions. Preferred examples of tert-alkyl substituents for the phosphine ligands include tert-butyl groups, preferred examples of the cycloalkyl substituent are cyclohexyl groups and preferred examples of the optionally substituted phenyl groups are o-tolyl groups. Preferred phosphines include tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl groups. The most preferred phosphine ligand is tri(t-butyl)-phosphine. The palladium source used as the catalyst is any suitable source of palladium (0). Preferred examples include palladium (II) acetate (by acetate we include both acetate per se and fluorinated acetates such trifluroacetate) The Suzuki cross coupling of aryl bromides and iodides is effected in carbon dioxide in the presence of a palladium (0) source such palladium (II) acetate, non-fluorinated phosphines of the type defined and exemplified above [preferably selected from tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(6-tolyl)phosphine and 1′-diphenylphosphinobiphenyl] and a base or other reaction-promoting additive. Preferred examples of bases and other reaction-promoting additives include diisopropylethylamine, cesium carbonate, diethylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate, triethylamine, tri-n-butylamine, perfluorinated trihexylamine, polystyrenemethylammonium carbonate, tetramethylethylenediamine diamine (TMEDA), tetramethyl hexanediamine, and tetraalkylammonium acetates such as tetrabutylammonium acetate. Preferred bases are tetramethyl hexanediamine and cesium carbonate, the former being surprisingly soluble in compressed carbon dioxide. As alternatives to a base, the preferred reaction-promoting additives are tetra-alkylammonium acetates, particularly tetra(n-butyl)ammonium acetate. An added feature of this invention is the use of biphasic conditions, for example the combination of water, methanol or isopropanol with compressed carbon dioxide. Water is preferred. For example, the combination phenyl boronic acid, bromobenzene, cesium carbonate, palladium (II) acetate, phosphine, and water (10 vol %) produce biphenyl in excellent yield. The second phase enhances the basicity of the base additive. The enhanced activity in the presence water is particularly surprising. Substrates are not limited to aromatic halides and boronic acids nor to acrylates. All sp 2 -substituted reagents which are potential cross coupling partners may be selected for this invention. WO-A-99/38820 discloses the Heck reaction of an acrylate REM resin (Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37, 3209). Surprisingly such substrates undergo Heck reactions in the presence of palladium (II) acetate and non-fluorinated phosphines of the type defined and exemplified above [preferred examples being selected from tri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl] and a base or other reaction-promoting additive (preferred examples being selected from diisopropylethylamine, cesium carbonate, diphylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate, triethylamine, tri-n-butylamine, perfluorinated trihexylamine, polystyrenemethylammonium carbonate, tetramethylethylenediamine diamine (TMEDA), tetramethyl hexanediamine, and tetraalkylammonium acetates such as tetrabutylammonium acetate. Most preferably the combination palladium (II) acetate, tri(z-butyl)phosphine, iodobenzene, diisopropylethylamine and the acrylate REM resin in compressed carbon dioxide afforded after, cleavage from the resin, cinnamic acid in 98% yield. Similarly, we also found that Suzuki cross coupling reactions of a selection of halo-vinyl and iodo- and bromo-aryl substituted compounds attached to a Merrifield or Wang resin through an ester linker can be effected with reagents selected from a list of aryl and vinylboronic acids and the above ligand-base-catalyst combinations. Most preferably the combination palladium (II) acetate, tri(t-butyl)phosphine, 4-iodobenzenecarboxylic (ester link to Merrifield resin), 4-methylbenzeneboronic acid and diisopropylethylamine gave 4′-methylbiphenyl-4-carboxylic acid in excess of 80% yield. Thus, based on these findings, it is a preferred feature of all three aspects of the present invention that the palladium-mediated carbon-carbon bond-forming reactions in compressed carbon dioxide as a solvent are conducted using at least one substrate of the carbon-carbon bond-forming reaction that is bound to a solid polymer support. Examples of suitable polymer supports are the same as those discussed above for the polymer-supported bases and reagents. Another surprising finding is that when Heck and Suzuki coupling procedures are conducted according to the third aspect of the present invention, they are effective on aryl bromide substrates as well as aryl iodides when the combination tri(t-butyl)phosphine and palladium (U) acetate is used. We have also found that the palladium-mediated homo-coupling of o-tolylboronic acid can be carried out in compressed carbon dioxide. This is an important and surprising advantage as halide ions are corrosive for the stainless steel vessels necessary for carbon dioxide as solvent. Therefore Heck reactions may be carried out with reactive boronic acids for the initial palladium insertion followed by coupling with an sp 2 -partner. Initiation of Suzuki reactions with a reactive boronic acid followed by cross coupling with a less reactive boronic acid should also be possible. Thus, in a further aspect of the present invention there is provided a palladium-catalysed Suzuki or Heck reaction in compressed carbon dioxide as a solvent wherein both of the substrates being combined in said reactions are boronic acids. The reagents and reaction conditions may preferably be as defined and exemplified above for the first, second and third aspects of the present invention (e.g. the bases and solubilising ligands can be the solid polymer-supported bases and solubilising ligands defined in the first aspect of the invention, the reactions can be performed in the presence of a tetra alkylammonium acetate as defined in the second aspect of the present invention and the reactions can be carried out using the non-fluorinated phosphine ligands defined in the third aspect of the present invention). |
System and method for reducing nitrogen oxides in the exhaust of an internal combustion engine |
In a system and method for the reduction of nitrogen oxides in the exhaust of an internal combustion engine, the exhaust line of the internal combustion engine contains a DeNOx catalytic converter, in which the nitrogen oxides are reduced by means of hydrogen that is produced on-board the vehicle. The DeNOx catalytic converter is incorporated into a temperature-controlled heat exchanger, allowing the DeNOx catalytic converter to be operated within a desired temperature range, thereby improving the level of conversion. |
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