The present invention provides a system and methods for coding and decoding digital data to improve the subjective quality of a voice signal. According to the invention, a sampled voice waveform is compressed by an ADPCM algorithm resulting in a sequence of samples. The sequence of samples are formed into an array and coded into parity bits. Row and column checksums are preferably performed on the parity bits to form row and column vectors. The samples and row and column vectors are transmitted to a receiving unit preferably having a diversity capability. The receiver processes each diversity block by generating row and column vectors from the received samples and comparing the generated row and column vectors to the row and column vectors received. Then based on the comparison, the samples of the best diversity block are used to reconstruct the voice waveform on a sample-by-sample basis.

In personal communication systems (PCS), such as the Personal Handy Phone (PHP) system in use in Japan, voice data is often processed by a "voice-band" process (typically 300 to 3300 Hz, as, for example, the human voice) using an Adaptive Differential Pulse Code Modulation (ADPCM) technique. ADPCM is widely utilized in telephony and is usually implemented in accordance with well known standards such as the Consultative Committee in International Telegraphy and Telephony (CCITT) Standard G.721. In general, sampled voice data is passed through an ADPCM algorithm wherein the digital voice data is compressed. The data output from the ADPCM algorithm is known as a sample, or more generally, as an ADPCM sample. According to the CCITT Standard G.721, a byte of digital voice data is compressed into a 4-bit sample. Although, the present invention will be described by way of example in which samples are defined as having 4-bits, it should be understood that the invention should not be limited by the example. More particularly, the invention should not be limited to personal communication systems in which ADPCM is employed. The invention is directed to any digital communication system in which digital data may be arranged in groups having any predetermined number of bits. These groups will be generally referred to as samples.
In existing communications systems the samples are organized in blocks of data with various overhead and control bits, which are transmitted together contiguously in time. Among the overhead bits transmitted in the block are a sequence of redundant bits which may be used for error deletion and/or correction. These bits are known as "parity" bits and are typically derived from the samples and other overhead data which form the block of data. CRC-16 is one well known standard used to generate these parity bits.
Typically, parity bits are used simply for error detection. For example, a block diagram of a typical PCS using ADPCM is shown in FIG. 1. Digitized voice data is provided as an input to the ADPCM encoder 2. The ADPCM encoder 2 compresses the digitized voice data into a block of ADPCM samples which are output to the CRC transmit processor 4 and a multiplexer 6. The CRC transmit processor 4 processes the ADPCM samples to form the parity bits. The multiplexer 6 then outputs the block of ADPCM samples and the corresponding parity bits to the modulator 8, which modulates and up converts the data for transmission via RF transmitter 10.
On the receiving end, an RF antenna 12 receives the transmitted block of data and outputs it to the demodulator 14. The demodulator 14 down converts and demodulates the received data. The down-converted data is then output to the demultiplexer 16 which outputs the down-converted data to the CRC receive processor 18 and selectively outputs the down-converted data representing the block of ADPCM samples to the ADPCM decoder 20. The ADPCM decoder 20 then processes the ADPCM sample to recover the digitized voice waveform.
With simple error detection, the presence of errors in a received block of data is determined by forming a syndrome at the receiver, i.e. generating parity bits from the received block of data and then comparing the received parity bits with those generated from the received block of data. When the syndrome is zero (i.e., the parity bits generated are the same as the parity bits received), the slot contents are assumed to be error free and the samples are processed to recover the digitized voice data. When the syndrome is non-zero (i.e., at least some of the parity bits generated by the CRC receive processor 18 differ from the parity bits received), the received block of data is discarded and the ADPCM decoder output is muted by opening switch 21 for a period of time equivalent to the duration of the transmission. This process is graphically shown in FIG. 2.
In particular, FIG. 2 shows the sampled voice waveform 22 which is processed into a block of ADPCM samples and parity bits collectively referred to as transmission blocks 24. The transmission blocks 24 are transmitted and received by a PCS receiving unit. Errors 30 may be detected in some of the received blocks such as blocks 26 and 28 shown in FIG. 2. Therefore, only block 25 in which no errors are detected is processed by the ADPCM decoder.
Due to interference and fading effects on the radio channel, a fraction of the slots experience transmission errors, so the simple error detection method results in gaps which cause break-up of the received speech as shown by the output voice waveform 32 in FIG. 2. If the parity bits were merely ignored and all of the received data was processed the reconstructed voice waveform would contain frequent "pops" and "clicks" and other objectional artifacts due to the processing of samples containing bit errors.
In an effort to mitigate this degradation, forward error correction (FEC) or other advanced signal processing concepts could be used to potentially improve the quality of the received voice band signals during periods of fading and interference. For example, a block diagram of a personal communications system using ADPCM and FEC coding is shown in FIG. 3 and a graphical representation of the waveform processing using the FEC coding is shown in FIG. 4. The ADPCM encoder 2 and decoder 20, modulator 8, transmitter 10, antenna 12, and demodulator 14 perform the same functions as described above in connection with FIG. 1. The CRC processors 4 and 18 are replaced by the FEC processors 34 and 36 respectively. The need for the multiplexer 6 and demultiplexer 16 may be eliminated when using FEC coding because either the entire data block is coded so that parity bits are not required or the FEC processors internally multiplex and demultiplex the data with error correction bits as appropriate. FEC coding not only provides the capability of detecting errors, but also provides a limited capability for correcting some of the detected errors. When an error is detected and can not be corrected by the FEC receive processor 36, switch 38 is opened to prevent the samples received in the active block to be processed by the ADPCM decoder 20.
FIG. 4 is a graphical depiction of voice waveform processing using an FEC coding technique. As shown in FIG. 4, the sampled voice waveform 22 is processed into transmission blocks 40 to which FEC coding has been applied to the samples to be transmitted. The FEC receive processor may detect errors 30 in some of the received blocks, for example blocks 44 and 46. When no errors are detected in a received block, such as block 42, that block is output to the ADPCM decoder and the output voice waveform 32 corresponding to that block can be reconstructed. However, when errors are detected, the FEC receive processor may be capable of correcting some of the detected errors as is well known. Block 46, for example, is shown to contain only correctable errors such that those errors are corrected to produce a substantially error-free block 48. Thus, once detected errors have been corrected, block 48 can be processed to reconstruct the voice waveform 32. Where the detected errors cannot be corrected by the FEC receive processor, as in the case of block 44, that block of data is then muted to produce a period of silence for the duration of the transmitted block as shown in FIG. 4.
Although FEC techniques may result in a reduction of the number of muted blocks of voice data, blocks of data containing uncorrectable errors still produce periods of silence in the reconstructed voice waveform. Moreover, undetected errors still may produce objectionable distortion when the data having errors is processed.
To combat fading and interference some personal communication systems may employ two or more antennas. Each antenna would receive a different standing wave pattern of the transmitted data. The PCS receiver attempts to select the antenna with the stronger signal path. This technique is generally referred to as space diversity.
A block diagram of a PCS employing space diversity is shown in FIG. 5. For exemplary purposes, the system shown in FIG. 5 uses CRC processing. However, it should be understood that FEC coding could also be used in a diversity system. The functions performed by the ADPCM encoder 2, CRC transmit processor 4, multiplexer 6, modulator 8, and transmitter 10 are substantially the same as described above in connection with FIG. 1. In the diversity system shown in FIG. 5, two antennas 12 and 13 each receive the transmitted blocks. Demodulators 14 and 15 down-convert and demodulate the received blocks of data. The demodulated data from each receive chain (i.e., antenna 12 and demodulator 14 represent one receive chain and antenna 13 and demodulator 15 represent a second receive chain), is output to the respective CRC receive processors 18 and 19. As described above, the CRC receive processors 18 and 19 generate a new set of parity bits derived from the ADPCM samples received and then create a syndrome by comparing the generated parity bits with the received parity bits. These syndromes which will be referred to as diversity syndromes are output from the respective CRC processors 18 and 19 to the CRC selection logic processor 60. The CRC selection logic processor 60 operatively controls switches 62 and 64 based on the syndromes so that the ADPCM samples from one of the demultiplexers 16 or 18 is processed by the ADPCM decoder 20 or muted to produce the periods of silence shown in FIG. 2.
FIG. 6 is a flow diagram representing the processing steps performed by the CRC selection logic processor 60. The CRC selection logic processor checks the diversity syndromes to determine whether any errors were detected in the block of data received by each of the receive chains by determining whether the diversity syndromes are zero as shown at step 70. If both syndromes are zero, then the CRC selection logic processor sets switch 62 to allow the ADPCM samples from either demultiplexer to be output to the ADPCM decoder at step 72. If the first syndrome (i.e., corresponding to the block of data received by antenna 12, demodulator 14, and demultiplexer 16) is zero and the second syndrome (i.e., corresponding to the block of data received by antenna 13, demodulator 15, and demultiplexer 17) is non-zero as determined at step 74, the CRC selection logic processor sets the switch 62 so that the ADPCM samples from demultiplexer 16 are output to the ADPCM decoder at step 76. If the CRC selection logic processor determines at step 78 that the second syndrome is zero and the first syndrome is non-zero, then switch 62 is set to permit the ADPCM samples from demultiplexer 17 to be output to the ADPCM processor. When both syndromes are non-zero, the CRC selection logic processor sets switch 64 so that any samples output from either demultiplexer are muted in that they are not processed by the ADPCM decoder thereby creating a period of silence for the duration of that block.
It should be understood that by adding additional diversity channels to the personal communication system receiver, the number of periods of silence may be reduced. However, such diversity does not eliminate these lengthy periods of silence which significantly degrade the subjective quality of the reconstructed voice waveform. Moreover, undetected errors still create undesirable "pops" and "clicks" in the reconstructed voice waveform since all of the samples in a block of data are processed when no errors are detected.
Therefore, there is a need to provide coding and decoding techniques capable of improving the subjective quality of the reconstructed voice waveform in a wireless communication system while still eliminating the so-called "pops" and "click" resulting from the processing of data that contains errors.

ADPCM coding and decoding techniques for personal communication systems


A flat panel display includes a pixel electrode having an opening portion formed on an insulating substrate, a semiconductor layer formed over a surface of the insulating substrate, spaced apart from the pixel electrode, having source and drain regions formed to both end portions thereof, a first insulating layer formed over the surface of the insulating substrate excluding the opening portion of the pixel electrode, a gate electrode formed on the first insulating layer over the semiconductor layer, and a second insulating layer formed over the surface of the insulating substrate excluding the opening portion of the pixel electrode. The present invention provides an organic EL display manufactured with reduced mask processes which has excellent electrical characteristics and improved light transmittance.

1. Field of the Invention
The present invention relates to a flat panel display and a method of manufacturing the same. More particularly, the present invention relates to an organic electroluminescence (EL) display and a method of manufacturing the same.
2. Description of the Related Art
Electroluminescence (EL) displays have recently attracted considerable attention as a flat panel display. The EL displays generally use a thin film transistor (TFT) as a switching element.
FIG. 1 is a cross-sectional view illustrating a conventional EL display. The conventional EL display of FIG. 1 is manufactured as follows. First, a first insulating layer 11 is formed on the whole surface of a transparent insulating substrate 10. The first insulating layer 11 serves as a buffer layer. The transparent insulating substrate 10 is made of a glass or a synthetic resin. A polysilicon layer is deposited on the buffer layer 11 and patterned into a semiconductor layer 13 using a first mask.
A second insulating layer 15 is formed over the whole surface of the transparent insulating substrate 10 and covers the semiconductor layer 13. The second insulating layer 15 serves as a gate insulating layer.
A first metal layer is deposited on the first insulating layer 15 and patterned into a gate electrode 16 and a first capacitor electrode 17 using a second mask.
An n-type or a p-type impurity is ion-doped into the semiconductor layer 13 to form source and drain regions 13-1 and 13-2. A portion 13-3 of the semiconductor layer 13 under the gate electrode 16 serves as an active area.
A third insulating layer 19 is formed over the whole surface of the transparent insulating substrate 10 and covers the gate electrode 16 and the first capacitor electrode 17. The insulating layer 19 serves as an inter-insulating layer.
Subsequently, the second and third insulating layers 15 and 19 are etched using a third mask to form first and second contact holes 20-1 and 20-2. The first contact hole 20-1 exposes a portion of the source region 13-1, and the second contact hole 20-2 exposes a portion of the drain region 13-2.
A second metal layer is deposited over the whole surface of substrate and patterned into source and drain electrodes 22-1 and 22-2 and a second capacitor electrode 22-3 using a fourth mask. The source electrode 22-1 contacts the source region 13-1 through the first contact hole 20-1, and the drain electrode 22-2 contacts the drain region 13-2 through the second contact hole 20-2. The second capacitor electrode 22-3 extends from either of the source and drain electrodes 22-1 and 22-2, for example the source electrode 22-1. Consequently, a TFT 51 and a capacitor 52 of the conventional EL display are completed.
At this point, a portion of the third insulating layer 19 between the first and second capacitor electrodes 17 and 22-3 serves as a dielectric layer of the capacitor 52.
Thereafter, a fourth insulating layer 25 is formed over the whole surface of the transparent insulating substrate 10. The fourth insulating layer 25 serves as a passivation layer. The passivation layer 25 is etched to form a via hole 26 at a region corresponding a portion of either of the source and drain electrodes 22-1 and 22-2 using a fifth mask. In FIG. 1, the via hole 26 exposes a portion of the drain electrode 22-2.
A transparent material layer is deposited on the passivation layer 25 and patterned into a pixel electrode 27 using a sixth mask. The pixel electrode 27 is made of a transparent conductive material such as indium tin oxide (ITO) or indium zinc oxide (IZO). The pixel electrode 27 electrically contacts the drain electrode 22-2 through the via hole 26. The pixel electrode 27 is used as an anode electrode.
A fifth insulating layer 28 is formed over the whole surface of the transparent insulating substrate 10. The fifth insulating layer 28 serves as a planarization layer. The planarization layer 28 is etched using a seventh mask to form an opening portion 28-1. The opening portion 28-1 exposes a portion of the anode electrode 27.
An organic EL layer 29 is formed on the exposed portion of the anode electrode 27 and the planarization layer 28. A third metal layer, i.e., a cathode electrode 30 is deposited to cover the whole display area, completing the conventional organic EL display 53.
However, the conventional organic EL display has the following disadvantages. Since seven complicated mask processes are used to manufacture the organic EL display, production cost is high and manufacturing yield is low. Also, during an etching process to form the anode electrode 27, an etching solution can soak into the source and drain electrodes 22-1 and 22-2, whereupon the source and drain electrodes 22-1 and 22-2 can be damaged, thereby deteriorating electrical characteristics of the TFT. Furthermore, light emitted from the organic EL layer 29 is reflected from an interface between the gate insulating layer 15 and the inter-insulating layer 19, and an interface between the inter-insulating layer 19 and the passivation layer 25, thereby lowering a light transmittance.

Flat panel display device and method of manufacturing the same


Methods, systems, and apparatus, including computer programs encoded on computer storage media, for securing data. One of the methods includes receiving, by a computer system, a network packet for analysis. The method includes determining, by the computer system, to examine the network packet for private data. The method includes identifying, by the computer system, private data in payload of the packet. The method includes encrypting the private data. The method includes storing the encrypted private data in a location separate from the payload. The method also includes obfuscating the private data by adding a reference to the location of the encrypted private data in the payload.

Information privacy, or data privacy (or data protection), can be considered the relationship between collection and dissemination of data, technology, the public expectation of privacy, and the legal and political issues surrounding them.
Privacy concerns exist wherever private information is collected and stored—in digital form or otherwise. Data privacy issues can arise in response to information from a wide range of sources, such as healthcare records, insurance information, financial transactions, biological traits, such as genetic material, residence and geographic records, ethnicity, government identification, tax records, and contact information.

Third-party platform for tokenization and detokenization of network packet data

United Services Automobile Association (USAA)


An embodiment of the present invention is a method for wafer level IC packaging that includes the steps of: (a) forming compliant, conductive bumps on metalized bond pads or conductors; and (b) surrounding the compliant, conductive bumps in a supporting layer.

The present invention pertains to the field of forming interconnects and, in particular, to the field of wafer packaging.
Prior art conventional Direct Flip Chip (xe2x80x9cDFCxe2x80x9d) packaging technology and Chip Scale Package (xe2x80x9cCSPxe2x80x9d) packaging technology provide integrated circuit (xe2x80x9cICxe2x80x9d) assemblies that address Original Equipment Manufacturer (xe2x80x9cOEMxe2x80x9d) requirements for smaller, thinner, lighter, denser, and lower cost packages for ICs. However, reliability and cost of these prior art, conventional packaging technologies continue to be important issues. A brief outline of the above-identified prior art conventional packaging technologies and the problems they face follows with reference to FIGS. 1 and 2.
In particular, FIG. 1 shows, in pictorial form, underfilled Flip Chip Assembly 100 that is fabricated in accordance with prior art DFC packaging technology. As shown in FIG. 1, wafer die 110 (having a coefficient of thermal expansion (xe2x80x9cCTExe2x80x9d) of about 3 ppm/xc2x0 C.) is bonded to interconnect joints 1201-1205 and interconnect joints 1201-1205 are bonded, in turn, to (mounted on) printed circuit board (xe2x80x9cPCBxe2x80x9d) 140 (having a CTE of about 14 to 21 ppm/xc2x0 C.). In addition, underfill material 130 is disposed between wafer die 110 and PCB 140 to surround interconnect joints 1201-1205. Thermal mismatch between the various package materials (for example, CTE differences between wafer die 110 and PCB 140) causes high residual stresses, resulting in device failure at connections between vias and interconnect joints 1201-1205 and at connections between PCB 140 and interconnect joints 1201-1205. In accordance with this prior art packaging technology, stress is reduced, and reliability is thereby enhanced, by surrounding interconnect joints 1201-1205 with underfill material 130 (for example, a thermo-set polymer). However this prior art method of stress reduction does not reduce device-to-board interfacial stresses (i.e., stresses between wafer die 110 and PCB 140), instead, it redistributes them into a greater area to reduce stress and strain at interconnect joints 1201-1205. Unfortunately, this prior art method of stress reduction has the following drawbacks: (a) inherent processing problems with underfill material 130 relating to dispensing/injection and (b) the fact that, after underfill material 130 is cured, encapsulated interconnect joints 1201-1205 cannot be reworked in case of failure. The fact that encapsulated interconnect joints 1201-1205 cannot be reworked in case of failure drives a need to have a xe2x80x9cKnown Good Diexe2x80x9d (xe2x80x9cKGDxe2x80x9d) before surface mounting it to PCB 140. This can be very costly for assembly manufacturers.
Lastly, the above-identified problems necessitate that an interposer (flexible or rigid) of some kind be used in addition to the DFC packing technology. Unfortunately, this adds to the size and cost of the package, while decreasing device functional performance.
Flip Chip Technologies, Inc. of Phoenix, Ariz. has adopted an Ultra Chip Scale Package (xe2x80x9cCSPxe2x80x9d) packing technology to enhance the strength of interconnect joints either by increased joint geometry (height) or by utilizing new, and more expensive, solder joint alloys having greater mechanical strength. The purpose is to increase the life expectancy of the device at the solder interconnect joints. However, underfill material is still needed in the package assembly so that solder interconnect joints pass more than 200 thermal cycles (xe2x88x9240xc2x0 C. to 125xc2x0 C.) when larger die size is required. See an article by D. S. Patterson, P. Elenius, and J. A. Leal entitled xe2x80x9cWafer Bumping Technologiesxe2x80x94A Comparative Analysis of Solder Deposition Processes and Assembly Considerations, EEPxe2x80x94Vol. 19-1, Advances in Electronic Packagingxe2x80x941997 Volume 1 ASME 1997, pp. 337-351.
FIG. 2 shows, in pictorial form, xcexcBGA(copyright) CSP Assembly 200 that is fabricated in accordance with prior art xcexcBGA(copyright) CSP packaging technology of Tessera Inc. of San Jose, Calif. (xe2x80x9cTesseraxe2x80x9d). As shown in FIG. 2, wafer die 210 (having a CTE of about 3 ppm/xc2x0 C.) is encapsulated in compliant elastomer layer 220. In accordance with this packaging technology, compliant elastomer layer 220 is supposed to provide a decoupling mechanism between wafer die 210 and PCB 250. As further shown in FIG. 2, compliant elastomer layer 220 is bonded to interposer 230, and interposer 230 is bonded, in turn, to interconnect joints 2401-2405. As still further shown in FIG. 2, interconnect joints 2401-2405 are bonded to PCB 250 (having a CTE of about 14 to 21 ppm/xc2x0 C.). In addition, first level interconnects 225 and 226 are highly compliant leads that are formed in an xe2x80x9cSxe2x80x9d shape.
Although this prior art packaging technology allows wafer die 210 to move independently of PCB 250, it significantly reduces device reliability because of the high CTE of compliant elastomer layer 220, i.e., the bonded leads are forced into excessive deflection by compliant elastomer layer 220. As shown in FIG. 2, Tessera""s solution to this problem was to construct highly compliant leads (xe2x80x9cSxe2x80x9d shaped first level interconnects 225 and 226) to take up these large strains. Unfortunately, this prior art packaging technology has tight process windows, which results in low assembly yields, higher costs, and low first level interconnect reliability.
In addition, the prior art CSP packaging technology requires the use of interposer 230 (for example, Flex or TAB tape) which adds to the cost of the package and reduces assembly yields. In further addition, the prior art CSP packaging technology requires customized equipment for high volume manufacturing, which customized equipment can be very costly.
As one can readily appreciate from the above, a need exists in the art for a method for wafer level IC packaging that: (a) can eliminate underfill layers; (b) enables rework to be done at board and chip level assembly; (c) minimizes the effects of thermal mismatches between PCBs and chip assemblies in a cost effective manner; (d) enables testing at the wafer level; and (e) can eliminate the need for an interposer.
Embodiments of the present invention advantageously satisfy the above-identified need in the art and provide a method for forming interconnects that can be applied to provide wafer level IC packaging. In accordance with the present invention, one can provide wafer level IC packaging that: (a) can eliminate underfill layers, thereby enhancing packaging reliability; (b) enables rework to be done at board and chip level assembly; (c) minimizes the effects of thermal mismatches between printed circuit boards(xe2x80x9cPCBsxe2x80x9d) and chip assemblies in a cost effective manner; (d) enables testing at the wafer level; (e) can eliminate the need for an interposer, thereby reducing material and processing cost; and (f) can be fully integrated into existing semiconductor manufacturing lines. Further embodiments of the present invention: (a) enable high density of packaging at the wafer level by enabling the size of interconnect joints to be minimized without reducing their mechanical integrity; (b) provide a chip size, high density, high power package with an integral, low profile, fin heat sink on the backside of the wafer; (c) eliminate solder paste printing, solder ball mounting, and flux cleaning by forming contact metallurgy using wet or dry processing methods such as, for example and without limitation, physical vapor deposition and high deposition rate electroplating of various metal alloys; and (d) depending on the outer joints, reduce device damage from alpha particles emitted by lead-containing solder interconnects.
An embodiment of the present invention is a method for forming interconnects that comprises: (a) forming compliant, conductive bumps on metalized bond pads or conductors; and (b) surrounding the compliant, conductive bumps in a supporting layer. A further embodiment of the present invention comprises forming conductive bumps over the compliant, conductive bumps.


A brake (10) includes a housing (12) formed from a first housing portion (14) capable of receiving a second housing portion (16). The first housing portion (14) houses a piston (18) and a plurality of springs (20), and the second housing portion (16) houses an alternating arrangement of discs (52) for enacting a braking function. The second housing portion (16) further includes torque pin holes (80) for receiving torque pins (82) therein. Each torque pin (82) is secured with a plug (84) to secure stationary discs (54A, 54B, 54C) in place. The stationary discs (54A, 54B, 54C) have extending ears (74) positioned between torque pin grooves (76), which further receive the torque pins (82).

Scissor lift and telehandler vehicles are known to use spring applied, hydraulically released brakes as a parking brake. These vehicles generally use multi-disc parking brakes located at the wheels of the vehicle. These brakes generally utilize hydraulic fluid to create hydraulic pressure in order to release the brake. The source of this hydraulic pressure is usually from vehicle hydraulics, since these vehicles generally include a hydraulic system. Brakes for these vehicles are generally built using several sand cast iron components, which are then machined to a finished state. This is expensive and inefficient. Brakes for these vehicles also must be compact with regard to space as available space for the brakes is limited. When considering replacement brakes for these vehicles, the available space cannot be changed or increased.
Thus, there is a need for a brake that offers one or more improvements over the prior art, such as optimization of available space within a brake housing and a reduction of materials over known brakes.

Spring applied, hydraulically released wheel-mount brake having improved stationary disc support


A collapsible helmet including an elliptic headband and an arc-shaped strap hingedly attached to the headband, the strap extending laterally across the crown of a wearer when deployed in its upright operative position so as to define a head protecting shell and lying co-planar with the headband when deployed in its folded inoperative position so as to define a relatively thin compact package. The helmet further includes a pair of arc-shaped ribs hingedly attached to the headband, the pair of ribs extending longitudinally across the crown of a wearer when deployed in their upright operative positions and lying co-planar with the headband when deployed in their folded inoperative positions. The helmet still further includes a face guard hingedly attached to the headband, the face guard extending laterally across the chin of a wearer when deployed in its downward inclined operative position and lying co-planar with the headband when deployed in its folded inoperative position.

The present invention relates to helmets in general and in particular to collapsible helmets including a number of segments hinged in a manner movable between an expanded operative position and a folded inoperative position.
Personnel engaged in occupations or activities with high levels of danger are required to wear headgear to protect the wearers' heads against impact. Such headgear typically provides one of two levels of protection depending on which parts of the wearers' head are to be protected. The first level of protection is provided by "half helmets" for protecting the crown of a wearer whereas the second level of protection is provided by "full helmets" for protecting both the crown and the face of the wearer.
Such headgear typically includes a rigid shell helmet with a flexible internal rigging for supporting the shell in spaced relation to the wearers' heads. Rigid shell helmets suffer from a number of disadvantages. First, that they are relatively heavy when worn. Second, that they are inconvenient to carry when not in use. And third, they are inconvenient to store when not in use.
A number of collapsible helmets have been suggested to overcome some of these disadvantages as now described hereinbelow:
U.S. Pat. No. 3,987,495 to Holley describes a motorcycle helmet having two halves which may be detachably secured together for use or separated for easy storage. The halves come together at the central vertical plane that extends from the front of the helmet to the rear and thereby divides it into a right half and a left half that are mirror images of each other. PA1 U.S. Pat. No. 4,587,676 to Estadella describes a collapsible helmet including two supplemental portions which are mutually joined at two pivot points. The supplemental portions rotate about the rotating points and engage one inside the other in a folded position and engage along a line which extends parallel to a line which defines the bottom perimeter of the helmet. PA1 U.S. Pat. No. 4,827,537 to Villa describes a helmet having a plurality of segments which are interhinged for swinging movement between an expanded operating position and a collapsed non-operating position. The segments have cooperating ribs and recesses to maintain them in the expanded operating position. PA1 U.S. Pat. No. 4,091,470 to Ryunishin describes a collapsible helmet composed of several inwardly curved fan-shaped sections. The helmet can be folded into a nested position so as to assume the size of one of the sections.
Such developments suffer from a number of disadvantages including that they typically include a large number of elements and complicated mechanisms, they are cumbersome during conversion from their expanded operative positions to their folded inoperative positions and vice versa, and packages formed by the collapsible helmets are large and awkwardly shaped.
Therefore, there is a need for a collapsible helmet which overcomes the disadvantages of conventional collapsible helmets.


A fiber-reinforced resin composition includes a polyarylene sulfide (A), a carbodiimide compound (B) and carbon fibers (C) in specific blending amounts and in which the carbon fibers (C) are surface-treated with a sizing agent (D), the carbodiimide compound (B) is an aliphatic carbodiimide compound, and the sizing agent (D) is a compound having three or more specific functional groups in one molecule; and a fiber-reinforced composite material includes a thermoplastic resin (A′), an adhesive compound (B′) and reinforcing fibers (C′) and in which the adhesive compound (B′) is a compound having two or more specific structures in one molecule, the thermoplastic resin (A′) is a thermoplastic resin containing an element other than carbon in a repeating unit structure of a main chain, and an abundance ratio Rb of the adhesive compound (B′) is 1.2 or more.

Fiber-reinforced resin compositions including a thermoplastic resin and reinforcing fibers are easily molded and processed by virtue of the characteristics of the thermoplastic resin, do not require a load in storage unlike thermosetting resins, and are excellent in recyclability. As these fiber-reinforced resin compositions, those in a variety of forms are known such as thermoplastic prepregs in which reinforcing fibers are arranged in the form of a sheet, and pellets in which reinforcing fibers are randomly dispersed. Fiber-reinforced resin compositions are excellent in balance between lightness and dynamic characteristics, and are therefore widely used as structural members of aircraft, automobiles, watercraft and the like, electronic equipment housings, sporting goods, and industrial materials such as building materials.
Among thermoplastic resins, a polyarylene sulfide is particularly excellent in heat resistance and chemical resistance so that a fiber-reinforced resin composition produced using the resin can be expected to be applied as an alternative to a metal material. However, when a fiber-reinforced resin composition produced using a polyarylene sulfide is developed as an alternative to a metal material, further improvement of the dynamic characteristics, particularly the tensile strength and elongation, of the fiber-reinforced resin composition is desired. This is because, since the tensile elongation of a general polyarylene sulfide is lower than the tensile elongation of reinforcing fibers (e.g. about 2% in the case of carbon fibers), the reinforcing effect of reinforcing fibers cannot be sufficiently utilized in the fiber-reinforced resin composition.
A general method of improving the tensile strength and elongation of a fiber-reinforced resin composition is enhancement of the elongation of a polyarylene sulfide to be used. However, tensile elongation of a polyarylene sulfide correlates to its molecular weight and hence its melt viscosity and, when the tensile elongation of the polyarylene sulfide is improved, the melt viscosity increases so that there is a risk of considerably impairing the molding processability of a fiber-reinforced resin composition. It is well known that it becomes harder to combine a polyarylene sulfide with reinforcing fibers as the melt viscosity of the polyarylene sulfide increases. In that case, it is necessary to make the process temperature higher, and therefore a polyarylene sulfide is not suitable to easily produce a fiber-reinforced resin composition with high productivity. For these reasons, it is an important technical challenge to improve the tensile strength and elongation while securing productivity and molding processability in a fiber-reinforced resin composition produced using a polyarylene sulfide.
Japanese Patent Laid-open Publication No. 2008-231291 discloses a molding material in which a high-molecular-weight thermoplastic resin is disposed in contact with a composite including a polyarylene sulfide prepolymer and continuous reinforcing fibers. In that molding material, a continuous reinforcing fiber bundle is impregnated with a low-molecular-weight material, and a high-molecular-weight material is used for a matrix resin so that dynamic characteristics as well as productivity are secured. The polyarylene sulfide prepolymer is an excellent material easily impregnated in a reinforcing fiber bundle to improve productivity of a molding material and easily dispersed in or made compatible with a matrix resin in a molding step to improve dispersion of reinforcing fibers in a molded article. However, the polyarylene sulfide prepolymer has a low molecular weight, and therefore has the problem that the added amount thereof and the dynamic characteristics of the resulting molded article are in a trade-off relationship.
On the other hand, various substances have been studied as additives to be added in a polyarylene sulfide. Japanese Patent Laid-open Publication No. 10-168290 discloses a composition in which a polyarylene sulfide, a cyclic polyolefin resin and a polycarbodiimide are combined to improve adhesion with a metal material and an organic material. For that composition, however, reinforcing fibers are intended to impart rigidity to the composition, and are not intended to improve dynamic characteristics such as the tensile strength and elongation of the fiber-reinforced resin composition, and it is not intended to secure those dynamic characteristics as well as productivity and molding processability.
Japanese Patent Laid-open Publication No. 2004-91504 discloses a composition including a polyarylene sulfide, an aromatic polycarbodiimide-based resin and an inorganic filler. However, that composition is intended to improve moisture resistance and chemical resistance without considerably deteriorating dynamic characteristics, and while the dynamic characteristics of the composition are disclosed, a phenomenon in which the tensile strength and elongation of the composition is dramatically improved is not conceived. Further, it is not intended to secure those dynamic characteristics as well as productivity and molding processability.
Fiber-reinforced composite materials (FRPs) are light and excellent in dynamic characteristics, and are widely used in electric and electronic device applications, civil engineering and building applications, machine and mechanism component applications, robot applications, two-wheeled vehicle and automobile applications and aerospace applications. As reinforcing fibers to be used in those FRPs, metal fibers such as aluminum fibers and stainless fibers, organic fibers such as aramid fibers and PBO fibers, inorganic fibers such as silicon carbide fibers, and carbon fibers are used, and carbon fibers are suitably used because they are excellent particularly in specific strength and specific rigidity, and ensure outstanding lightness.
Typical forms of FRPs such as carbon fiber-reinforced composite materials (CFRPs) include molded articles produced by press-molding a prepreg, or a preform obtained by laminating prepregs (a molding method in which a prepreg or preform is defoamed under a pressurizing force, and shaped). The prepreg is generally produced by a method in which a reinforcing fiber base material with continuous reinforcing fibers arranged in one direction or processed into a woven fabric is impregnated with a resin, but discontinuous reinforcing fibers may also be used.
The molded article obtained by molding a prepreg produced using continuous reinforcing fibers has excellent dynamic characteristics, but it is not suitable to form a complicated shape because the reinforcing fibers are used in the form of a continuous body, and the use applications of the molded article are limited due to economic burden of the lamination step because its characteristics are greatly influenced by the lamination angle of the prepreg.
On the other hand, sheet molding compounds (SMCs) and glass mat base materials (GMT) produced using discontinuous reinforcing fibers are materials suitable for press molding, but their use applications are limited due to the problem that their dynamic characteristics such as specific strength and specific rigidity are low, adaptation to a thin molded article such as a prepreg is difficult, the rein considerably flows during molding so that isotropic dynamic characteristics are not achieved, and characteristics considerably vary, or the like.
Bondability between reinforcing fibers and a matrix resin influences the dynamic characteristics such as the tensile strength of the fiber-reinforced composite material, and therefore design of an interface between the reinforcing fibers and the matrix resin is very important in development of the fiber-reinforced composite material.
Japanese Patent Laid-open Publication No. 5-106163 proposes carbon fibers with a carbodiimide reagent deposited on the surface, and describes that the carbon fibers are excellent in bondability to a thermoplastic resin as a matrix resin, leading to improvement of the bending strength, but there is a problem in terms of interfacial strength between the reinforcing fibers and the matrix resin, and it is desired to further improve the strength.
Further, Japanese Patent Laid-open Publication No. 5-311069 discloses a technique relating to a surface modifier for carbon fibers including an organic compound having two or more carbodiimide bonds in the molecule, and carbon fibers modified with the modifier, but similarly, there is a problem in terms of interfacial strength between the reinforcing fibers and the matrix resin, and it is desired to further improve the strength of the molded article.
Further, Japanese Patent Laid-open Publication No. 2005-239917 discloses a resin composition including an aliphatic polycarbodiimide-based resin as a polyarylene sulfide resin and fibers as an inorganic filler, but the tensile strength of the molded article is insufficient, and it is desired to further improve the strength.
It could therefore be helpful to provide a fiber-reinforced resin composition having dynamic characteristics such as the tensile strength and elongation as well as productivity and molding processability, to provide a fiber-reinforced composite material excellent in dynamic characteristics such as the tensile strength.

This patent is subject to a terminal disclaimer.

Fiber-reinforced resin composition, and fiber-reinforced composite material


An electrophotographic process uses a developer in which the colorant is dispersed in an electrically insulating organic material being solid at room temperature and liquified by heating. The developer is superior in ease of handling and capable of producing stable images at all times. An electrostatic latent image is wet developed by the developer. For recording and preserving the developed image, it is transferred to a transfer substrate. The developed image is transferred by contact of a photoconductor with the transfer substrate, or by peeling a film from a photoconductor.

1. Field of the Invention
This invention relates to an electrophotographic process for recording and preserving an electrostatic latent image developed by wet development.
2. Description of the Related Art
In the field of image formation, a system in which a uniformly charged photoconductor is selectively irradiated with light as a function of image signals and an electrostatic latent image thus formed is developed is generally termed an electrophotographic process. This process may be roughly classified into either a dry developing method or a wet developing method.
The dry developing method has an advantage in that it is superior in the ease of handling and the stability of the toners used for development, since it is based on the principle that colorant particles are simply spread and affixed to an electrostatic latent image. However, dry developing is second to the wet development method in meeting the recent demand for high quality images, as exemplified by a video printer for taking an electronic still photograph.
On the other hand, the wet developing method makes use of a liquid developer which is produced by dispersing the dyestuff or pigment as the colorant in an insulating medium. According to the wet developing method, a resolution and gradation comparable to those of a silver halide photograph may be obtained, while the image exhibits superior weatherability when a pigment is used as the colorant.
The developer used in the conventional wet developing method contains an insulating medium which is liquid at room temperature, such as "Isopar G", a saturated hydrocarbon produced by Esso Inc., so that it is naturally liquid at room temperature (see FIG. 23).
However, the developing method employing a developer 5' which is liquid at room temperature is inconvenient to use since the developer can be handled only with difficulty and frequent maintenance is required for maintaining stable image formation.
In the preservation and supply of the wet developer, disadvantages are presented in connection with changes in the concentration thereof caused by cohesion or precipitation of the colorant particles and disposal of waste liquids.
The Japanese Kokai (Published Application) No. 25670/1988 discloses a method of developing an electrostatic latent image formed on the surface of a sensitized material wherein a toner is solidified and applied under pressure to the peripheral surface of a developing roll and the thus coated toner is dissolved by a developer and caused to flow into a space between the sensitized material and the developing roll.
In this reference, a developer such as "Isopar" is required for dissolving the solid toner, while a stable image cannot be obtained unless the supply of the developer is adjusted constantly.
For recording and preserving the electrostatic latent image in the visible form, it is preferably transferred to a suitable substrate. However, the conventional wet developing method is not necessarily suited to the purpose of forming a high quality image since the adsorption between the colorant particles and the sensitized material is so strong that the transfer efficiency is thereby lowered.

Electrophotographic process using melted developer


A brake actuator for a railway brake which provides both service and parking braking comprises a cylinder having an operating cavity. A piston assembly extends into the operating cavity and has a stepped bore including second and smaller third cavities. A first hydraulic supply admits pressurized hydraulic fluid into the operating cavity to extend the piston assembly to apply the service brake. A spring applies a retracting force on the piston smaller than the hydraulic force. A hollow parking brake piston carried in the second cavity extends to react against the cylinder and extend the piston assembly in response to the supply of pressurized fluid to the second cavity from a second hydraulic supply to apply the parking brake. A mechanical lock, comprising a one-way clutch utilizing ramps and rollers, locks the piston extended from the piston assembly cylinder to maintain the parking brake applied upon removal of the second hydraulic supply force. An unlocking member is responsive to the supply of pressurized fluid to the third cavity from a third hydraulic supply to disable the clutch and enable the spring to retract the parking brake piston and the piston assembly to release the parking brake. A gripper ring grips the exterior of the piston assembly with a friction force which enables slippage on the piston assembly upon engagement with a cylinder abutment upon extension to provide adjustment for brake wear. Ring engagement with another cylinder abutment limits piston assembly retraction to provide slack.

This invention relates generally to actuators for railway hydraulic braking systems and, more particularly, to an actuator for applying the service and parking brakes in such systems.
Railway braking systems have traditionally been operated by pneumatic actuators. These air brake systems are still in common use on long distance railways and on many subway systems. Such air brake systems are effective, but lack the ability to modulate braking effort sufficiently to provide consistently smooth stops.
Recently, braking requirements for rapid transit railway cars have resulted in the development of hydraulic friction service braking systems which are controllable to provide the desired smooth stops. Such a hydraulic braking system is disclosed in U.S. Pat. No. Re 29,096 to Jones. This patent relates a hydraulic friction braking system and a control system of a type currently in use on Washington Metropolitan Area Transit Authority (WMATA) transit cars. This system employs a brake actuator which hydraulically applies and releases the service brakes.
Parking brakes are required to apply and maintain the brakes applied for extended periods when the railway car is out of service and parked. Parking brake actuators have traditionally been mechanically applied and held. A hydraulic parking brake actuator has been developed, for use in the WMATA braking system, as shown in U.S. Pat. No. 4,083,436 to Straut. In this actuator, hydraulic pressure is utilized to extend a piston and apply the parking brake, while a mechanical lock holds the parking brake engaged. This mechanical lock is hydraulically released to enable a spring to retract the piston and release the brake.
In the Straut arrangement, a railway hydraulic actuator assembly includes separate actuators for applying both the service and parking brakes of a railway car. The service brake actuator applies the service brakes by spring force applied through service brake pistons; application of hydraulic pressure fluid supplied from a pump-fed accumulator releases the brakes.
A separate actuator applies the parking brake via hydraulic pressure created by a hand pump acting on a separate parking brake piston. The brake is held applied by a mechanical lock comprising a complex friction clutch which locks the piston extended when hydraulic pressure is removed; hydraulic pressure is again utilized to release the friction clutch and enable spring force to retract the piston and release the brake.
Although hydraulic railway service and parking brake actuators according to the above patents have been used successfully for many years, they are unduly bulky, complex and expensive to purchase and maintain. Accordingly, it would be desirable to reduce the complexity of railway hydraulic brake actuators.
Also, it would be desirable to provide a hydraulic railway service brake actuator having a slack adjustor of less complexity than the automatic rotary slack adjustor having a sprag clutch.
Further, it would be desirable to provide a parking brake actuator having a mechanical lock of reduced complexity.
In addition, it would be desirable to combine the parking brake and service brake actuators into a single actuator.

Railway service and parking brake actuator


The present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist. The present invention further provides novel compounds functional as selective iGluR5 receptor antagonists as well as compositions and formulations comprising said selective iGluR5 receptor antagonists.

In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathways in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropic.xe2x80x9d This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), xcex1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). Molecular biological studies have established that AMPA receptors are composed of subunits (GluR1-GluR4), which can assemble to form functional ion channels. Five kainate receptors have been identified which are classified as either High Affinity (KA1 and KA2) or Low Affinity (GluR5, GluR6, and GluR7). Bleakman et al., Molecular Pharmacology, 49, No.4, 581,(1996).
The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of neurological disorders and conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders. For example, excitotoxicity has been linked with the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer""s Disease, Huntington""s Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson""s Disease, as well as ocular damage and retinopathy. Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction. In addition, it has also been reported that excitatory amino acid excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
The use of a neuroprotective agent, such as an excitatory amino acid receptor antagonist, is believed to be useful in treating or preventing these disorders and/or reducing the amount of neurological damage associated with these disorders. Excitatory amino acid receptor antagonists may also be useful as analgesic agents.
Early theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff (Arch. Neurol. Psychiatry, 39, 737-63 (1938)). They proposed that the cause of migraine headache is vasodilatation of extracranial vessels. This view is supported by knowledge that ergot alkaloids and sumatriptan contract cephalic vascular smooth muscle and are effective in the treatment of migraine. Sumatriptan is a hydrophilic agonist at the serotonin 5-HT-1-like receptors and does not cross the blood-brain barrier (Humphrey, et al., Ann. NY Acad. Sci., 600, 587-600 (1990)). Consequently, several series of compounds said to be useful for the treatment of migraine, have been developed to optimize the 5-HT1-like mediated vasoconstrictive activity of sumatriptan. However, sumatriptan""s contraindications, including coronary vasospasm, hypertension, and angina are also products of its vasoconstrictive activity (MacIntyre, P. D., et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, A. H., et al., Cardiovascular Research, 24, 932-937 (1990); Conner, H. E., et al., European Journal of Pharmacology, 161, 91-94 (1990)).
While the vascular mechanism for migraine has gained wide acceptance, there is not total agreement as to its validity. Moskowitz, for example, has shown the occurrence of migraine headaches, independent of changes in vessel diameter (Cephalalgia, 12, 5-7, (1992)). It is known that the trigeminal ganglion, and its associated nerve pathways, are associated with painful sensations from the face such as headache, in particular migraine. Moskowitz proposed that unknown triggers stimulate the trigeminal ganglia which innervate vasculature within cephalic tissue, giving rise to the release of vasoactive neuropeptides from axons innervating the vasculature. These neuropeptides initiate a series of events leading to neurogenic inflammation of the meninges, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan at doses similar to those required to treat acute migraine in humans. However, such doses of sumatriptan, as stated, are associated with contraindications as a result of sumatriptan""s attendant vasoconstrictive properties.(see supra.)
5-HT1D receptors have been implicated as mediating the blockade of neurogenic protein extravasation. (Neurology, 43(suppl. 3), S16-S20 (1993)). In addition, it has been reported that xcex12, H3, m-opioid and somatostatin receptors may also be located on trigeminovascular fibers and may block neurogenic plasma extravasation (Matsubara et al., Eur. J. Pharmacol., 224, 145-150 (1992)). Weinshank et al. have reported that sumatriptan and several ergot alkaloids have a high affinity for the serotonin 5-HT1F receptor, suggesting a role for the 5-HT1F receptor in migraine (WO93/14201).
European Patent Application Publication No. 590789A1 and U.S. Pat. Nos. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor antagonists and, as such, are useful in the treatment of many different conditions, including pain and migraine headache.
Recently, it has been reported that all five members of the kainate subtype, of ionotropic glutamate receptors, are expressed on rat trigeminal ganglion neurons. In particular, high levels of GluR5 and KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17), 6611 (1997)). Simmons et al. reported that the kainate GluR5 receptor subtype mediates the nociceptive response to formalin in a rat model of persistent pain.(Neuropharmacology, 37, 25 (1998). Further, WO98/45270 previously disclosed that antagonists selective for the iGluR5 receptor are useful for the treatment of pain, including; severe, chronic, intractable, and neuropathic pain. Noteworthy is the observation that kainate receptors have not previously been implicated in the etiology of migraine headache. In particular, selective iGluR5 receptor antagonists have not been previously reported as being useful for the treatment of migraine.
Surprisingly, and in accordance with this invention, Applicants have discovered that selective antagonists of the iGluR5 receptor subtype are efficacious in an animal model of neurogenic inflammation and, thus, could be useful for the treatment of migraine. Such antagonists could address a long felt need for a safe and effective treatment for migraine, without attending side effects. The treatment of neurological disorders is hereby furthered.
The present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist or a pharmaceutically acceptable salt thereof. More specifically, the present invention provides a method of treating or preventing dural protein extravasation comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist.
In addition, the present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a compound, or combination of compounds, which possesses the activity of a selective iGluR5 receptor antagonist.
In another embodiment, the present invention provides a method of treating or preventing a neurological disorder, or neurodegenerative condition, comprising administering to a patient in need thereof an effective amount of a selective iGluR5 receptor antagonist or a pharmaceutically acceptable salt thereof. Examples of such neurological disorders, or neurodegenerative conditions, include: cerebral deficits subsequent to cardiac bypass surgery and grafting; stroke; cerebral ischemia; spinal cord lesions resulting from trauma or inflammation; perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage; Alzheimer""s Disease; Huntington""s Chorea; inherited ataxias; AIDS-induced dementia; amyotrophic lateral sclerosis; idiopathic and drug-induced Parkinson""s Disease; ocular damage and retinopathy; muscular spasticity including tremors; drug tolerance and withdrawal; brain edema; convulsive disorders including epilepsy; depression; anxiety and anxiety related disorders such as post-traumatic stress syndrome; tardive dyskinesia; psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction; and acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain.
In a further aspect, the present invention provides a compound of Formula I
wherein R1 and R2 are each independently H, C1-C20 alkyl, C2-C6 alkenyl, C1-C6 alkylaryl, C1-C6 alkyl(C3-C10)cycloalkyl, C1-C6 alkyl-N,Nxe2x80x94C1-C6 dialkylamine, C1-C6 alkyl-pyrrolidine, C1-C6 alkyl-piperidine, or C1-C6 alkyl-morpholine; or a pharmaceutically acceptable salt thereof.
In yet another aspect, the present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a compound of Formula I.
In addition, the present invention provides pharmaceutical compositions useful for treating or preventing migraine comprising selective iGluR5 receptor antagonists in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present invention also provides the use of a selective iGluR5 receptor antagonist for the manufacture of a medicament for treating or preventing migraine.
The present invention provides a method for the treatment of migraine which can be demonstrated by a particular mechanism of action, inhibition of neurogenic dural protein extravasation. By treating a migraineur with a compound or composition which is a selective antagonist of the iGluR5 receptor relative to other excitatory amino acid receptors, the neurogenic extravasation which mediates migraine is inhibited without the attending side effects of agents designed to optimize the 5-HT1-like mediated vasoconstrictive activity of sumatriptan. In addition, the present invention provides compounds functional as selective iGluR5 receptor antagonists as well as pharmaceutically acceptable salts, prodrugs, and compositions thereof.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds provided by, or employed in the present invention which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described herein as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex1-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981.
The compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of Formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, xe2x80x9cStereochemistry of Organic Compoundsxe2x80x9d, John Wiley and Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
It should also be understood by the skilled artisan that all of the compounds useful for the methods of the present invention are available for prodrug formualtion. xe2x80x9cProdrugxe2x80x9d as used herein, refers to metabolically labile ester or diester derivative of the functional acid compounds(drugs) provided by, or employed in the methods of, the present invention. When administered to a patient, the prodrug undergoes enzymatic and/or chemical hydrolytic cleavage in such a manner that the parent carboxylic acid (drug), or as the case may be the parent dicarboxylic acid, is released. In all cases, the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of all of the compounds employed are encompassed in the names of the compounds herein.
As used herein the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of I to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term xe2x80x9cC1-C10 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term xe2x80x9cC1-C20 alkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like.
As used herein, the terms xe2x80x9cMexe2x80x9d, xe2x80x9cEtxe2x80x9d, xe2x80x9cPrxe2x80x9d, xe2x80x9ciPrxe2x80x9d, xe2x80x9cBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein the term xe2x80x9cC2-C6 alkenylxe2x80x9d refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C2-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
As used herein, the term xe2x80x9carylxe2x80x9d refers to monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
As used herein, the term xe2x80x9cC1-C6 alkylarylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkylarylxe2x80x9d are the following:
and the like.
As used herein the term xe2x80x9c(C3-C10)cycloalkylxe2x80x9d refers to a saturated hydrocarbon ring structure containing from three to ten carbon atoms. Typical C3-C10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It is understood that xe2x80x9c(C3-C8)cycloalkylxe2x80x9d and xe2x80x9c(C4-C6)cycloalkylxe2x80x9d is included within the term xe2x80x9c(C3-C10)cycloalkylxe2x80x9d.
As used herein, the term xe2x80x9cC1-C6 alkyl(C3-C10)cycloalkylxe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C3-C10)cycloalkyl attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkyl(C3-C10)cycloalkylxe2x80x9d are the following:
and the like.
As used herein the term xe2x80x9cN,Nxe2x80x94C1-C6 dialkylaminexe2x80x9d refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term xe2x80x9cN,N-C1-C6 dialkylaminexe2x80x9d are xe2x80x94N(CH3)2, xe2x80x94N(CH2CH3)2, xe2x80x94N(CH2CH2CH3)2, xe2x80x94N(CH2CH2CH2CH3)2, and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-N,N-C1-C6 dialkylaminexe2x80x9d refers to straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N,N-C1-C6 dialkylamine attached to the aliphatic chain. Included within the term xe2x80x9cC1-C6 alkyl-N,N-C1-C6 dialkylaminexe2x80x9d are the following:
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-pyrrolidinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-pyrrolidinexe2x80x9d are the following:
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-piperidinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-piperidinexe2x80x9d are the following:
and the like.
As used herein the term xe2x80x9cC1-C6 alkyl-morpholinexe2x80x9d refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a morpholine attached to the aliphatic chain. Included within the scope of the term xe2x80x9cC1-C6 alkyl-morpholinexe2x80x9d are the following:
and the like.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page.
The designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page.
As used herein the term xe2x80x9ciGluR5xe2x80x9d refers to the kainate ionotropic glutamate receptor, subtype 5, of the larger class of excitatory amino acid receptors.
As used herein the term xe2x80x9cmigrainexe2x80x9d refers a disorder of the nervous system characterized by recurrent attacks of head pain (which are not caused by a structural brain abnormality such as those resulting from tumor or stroke), gasrointestinal disturbances, and possibly neurological symptoms such as visual distortion. Characteristic headaches of migraine usually last one day and are commonly accompanied by nausea, emesis, and photophobia.
Migraine is a xe2x80x9cchronicxe2x80x9d condition. The term xe2x80x9cchronicxe2x80x9d, as used herein, means a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease. Conversely, the term xe2x80x9cacutexe2x80x9d means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of migraine contemplates both acute events and chronic conditions. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease.
As used herein the term xe2x80x9cpatientxe2x80x9d refers to a mammal, such a mouse, gerbil, guinea pig, rat, dog or human. It is understood, however, that the preferred patient is a human.
It is understood that the term xe2x80x9cselective iGluR5 receptor antagonistxe2x80x9d as used herein, includes those excitatory amino acid receptor antagonists which selectively bind to the iGluR5 kainate receptor subtype, relative to the iGluR2 AMPA receptor subtype. Preferably the selective iGluR5 antagonist for use according to the method of the present invention has a binding affinity at least 10 fold greater for iGluR5 than for iGluR2, more preferably at least 100 fold greater. It is further understood that any selective iGluR5 antagonist, as appreciated by one of ordinary skill in the art, is included within the scope of the methods of the present invention. Such selective iGluR5 receptor antagonists are readily available to, or are readily prepared by, one of ordinary skill in the art following recognized procedures. Examples of selective iGluR5 receptor antagonists include, but are not limited to, the compounds provided in WO 98/45270, the entire contents of which is herein incorporated by reference.
It is further understood that the selective iGluR5 receptor antagonists may exist as pharmaceutically acceptable salts and, as such, salts are therefore included within the scope of the present invention.
As used herein, the terms xe2x80x9ctreatingxe2x80x9d or xe2x80x9cto treatxe2x80x9d each mean to alleviate symptoms, eliminate the causation of resultant symptoms either on a temporary or permanent basis, and to prevent, slow the appearance, or reverse the progression or severity of resultant symptoms of the named disorder. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
As used herein the term xe2x80x9ceffective amountxe2x80x9d refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the degree of involvement or the severity of the migraine involved; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of each compound used in the present method of treatment. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
The selective iGluR5 antagonists for use according to the methods of the present invention may be a single compound or a combination of compounds capable of functioning as a selective iGluR5 receptor antagonist. For example, it may be a combination of a compound capable of functioning as an antagonist at the iGluR5 receptor and one or more other glutamate receptors, in combination with one or more compounds capable of blocking its actions at the iGluR2 receptor. It is understood, however, that the selective iGluR5 antagonist for use in the methods of the present invention, is preferably a single compound.
Oral administration is a preferred route of administering the compounds employed in the present invention whether administered alone, or as a combination of compounds capable of acting as a selective iGluR5 receptor antagonist. Oral administration, however, is not the only route, nor even the only preferred route. Other preferred routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, or intrarectal routes. Where the selective iGluR5 receptor antagonist is administered as a combination of compounds, one of the compounds may be administered by one route, such as oral, and the other may be administered by the transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, or intrarectal route, as particular circumstances require. The route of administration may be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the caregiver.
The compounds employed in the present invention may be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating said compounds are important embodiments of the present invention. Such compositions may take any physical form which is pharmaceutically acceptable, but orally administered pharmaceutical compositions are particularly preferred. Such pharmaceutical compositions contain an effective amount of a selective iGluR5 receptor antagonist, which effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound, or may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit depends on the identity of the particular compound chosen for the therapy, and other factors such as the indication for which it is given. The pharmaceutical compositions of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.
Compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, more preferably about 5 to about 300 mg (for example 25 mg). The term xe2x80x9cunit dosage formxe2x80x9d refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
The inert ingredients and manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science may be used here. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches and suspensions. In general, compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used. The amount of the compound, however, is best defined as the xe2x80x9ceffective amountxe2x80x9d, that is, the amount of each compound which provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the present invention do not depend on the nature of the composition, hence, the compositions are chosen and formulated solely for convenience and economy.
Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances such as starches, powdered cellulose especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours, and similar edible powders.
Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
Tablets are often coated with sugar as a flavor and sealant. The compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
A lubricant is often necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
When it is desired to administer the compound as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with innumerable pores through which the drugs are pumped by osmotic action.
The following table provides an illustrative list of formulations suitable for use with the compounds employed in the present invention. The following is provided only to illustrate the invention and should not be interpreted as limiting the present invention in any way.
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
The components are blended and compressed to form tablets each weighing 665 mg.
The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
It is understood by one of ordinary skill in the art that the above procedures can also be applied to a method of treating migraine comprising administering to a patient an effective amount of a compound which possesses the activity of a selective iGluR5 receptor antagonist.
Inhibition of neuronal protein dural extravasation is an exemplary mechanism of action for the method of the present invention. The method further requires that compounds which exhibit such inhibition, also demonstrate selective binding and inhibition of the iGluR5 receptor. The panel of compounds used to illustrate the principle of the present invention, and the pharmacological assays employed to demonstrate the mechanistic effectiveness of the invention, are described below. It is believed that Compounds III, IV(a), and IV(b) herein, represent novel compounds and, as such, have not previously been described as selective iGluR5 receptor antagonists, nor reported as efficacious in treating migraine. Compounds III, IV(a), and IV(b) therefore, are provided as additional embodiments of the present invention.
The following examples illustrate the methods of the present invention. The reagents and starting materials are readily available to one of ordinary skill in the art. These examples are intended to be illustrative only and are not to be construed so as to limit the scope of the invention in any way. As used herein, the following terms have the meanings indicated: xe2x80x9ci.v.xe2x80x9d refers to intravenously; xe2x80x9cp.o.xe2x80x9d refers to orally; xe2x80x9ci.p.xe2x80x9d refers to intraperitoneally; xe2x80x9ceqxe2x80x9d or xe2x80x9cequiv.xe2x80x9d refers to equivalents; xe2x80x9cgxe2x80x9d refers to grams; xe2x80x9cmgxe2x80x9d refers to milligrams; xe2x80x9cLxe2x80x9d refers to liters; xe2x80x9cmLxe2x80x9d refers to milliliters; xe2x80x9cxcexcLxe2x80x9d refers to microliters; xe2x80x9cmolxe2x80x9d refers to moles; xe2x80x9cmmolxe2x80x9d refers to millimoles; xe2x80x9cpsixe2x80x9d refers to pounds per square inch; xe2x80x9cmm Hgxe2x80x9d refers to millimeters of mercury; xe2x80x9cminxe2x80x9d refers to minutes; xe2x80x9chxe2x80x9d or xe2x80x9chrxe2x80x9d refers to hours; xe2x80x9cxc2x0 C.xe2x80x9d refers to degrees Celsius; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; xe2x80x9cHPLCxe2x80x9d refers to high performance liquid chromatography; xe2x80x9cRfxe2x80x9d refers to retention factor; xe2x80x9cRtxe2x80x9d refers to retention time; xe2x80x9cxcex4xe2x80x9d refers to part per million down-field from tetramethylsilane; xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran; xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide; xe2x80x9cDMSOxe2x80x9d refers to dimethyl sulfoxide; xe2x80x9caqxe2x80x9d refers to aqueous; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9ciPrOAcxe2x80x9d refers to isopropyl acetate; xe2x80x9cMeOHxe2x80x9d refers to methanol; xe2x80x9cMTBExe2x80x9d refers to tert-butyl methyl ether; xe2x80x9cRTxe2x80x9d refers to room temperature; xe2x80x9cKixe2x80x9d refers to the dissociation constant of an enzyme-antagonist complex and serves as an index of ligand binding; and xe2x80x9cID50xe2x80x9d and xe2x80x9cID100xe2x80x9d refer to doses of an administered therapeutic agent which produce, respectively, a 50% and 100% reduction in a physiological response.

Selective iGluR5 receptor antagonists for the treatment of migraine