text
stringlengths 0
1.67M
|
|---|
Dynamic optical reflector and interrogation system |
A retro-reflective identification tag capable of modulating an optical signal whereby to support bi-directional communication with an associated remote optical interrogation device. The tag comprises a MOEMS modulating layer over a retro-reflective substrate, giving the tag a wide angle of effective operation. The tag modulator may optionally be switched on only responsive to detection of a precursor beam from the interrogation system in order to save power. The interrogation device may make use of multiple optical wavelengths for communicating with the tag. |
1. A modulator for modulating an optical signal, the modulator comprising a spacing-controllable etalon and a retro-reflector arranged to retro-reflect light received via the etalon back through the etalon. 2. A modulator according to claim 1 in which the etalon comprises a coherent planar MOEMS structure. 3. A modulator according to claim 1 in which the retro-reflector comprises an array of one or more corner-cube reflectors. 4. A modulator according to claim 1 arranged to be modulated at a fixed frequency. 5. A modulator according to claim 1 in which the cavities in the etalon are vacuum cavities. 6. A modulator according to claim 1 comprising a self-contained electrical power supply. 7. An optical detector arrangement comprising a plurality of photo-detectors with associated means for restricting the light acceptance angle, the means being so arranged as to allow determination, based on outputs from the photo-detectors, of a direction of incidence of light from a remote source. 8. A reflective tag comprising one or more modulators according to claim 1. 9. A reflector tag according to claim 8 comprising a detector arrangement coupled to the modulator. 10. A reflective tag according to claim 8 in which detection of a precursor signal causes the modulator to be activated. 11. A reflective tag according to claim 8 comprising attachment means. 12. An optical interrogator for use with a reflective optical tag, the interrogator comprising a laser source of light at two distinct wavelengths which are reflected by the tag substantially in anti-phase one with the other. 13. An interrogator according to claim 12 in which the source of light comprises two laser sources. 14. An interrogator according to claim 12 comprising a detector arranged to receive reflected light emitted from the interrogator. 15. An interrogator according to claim 14 comprising an erbium filter arranged to discriminate between light at the two distinct wavelengths. 16. A remote optical interrogation system comprising an optical interrogator according to claim 12. 17. A remote interrogation system according to claim 16 comprising at least one modulator arrangement or reflective tag. 18-20. (canceled) 21. A reflective tag comprising an etalon and a retro-reflector arranged to retro-reflect light received via the etalon back through the etalon. 22. A modulator according to claim 1 comprising an input or output port for local communication. |
<SOH> BACKGROUND TO THE INVENTION <EOH>It is known to provide dynamic optical tagging systems based on a number of different technologies. Such tags have a wide variety of applications including, for example, identification and/or tracking of vehicles (road tolling), equipment (cargo container tracking), or people and in access control systems (for example in employee identification badges used to control access to specific areas). Such applications include both military and civilian use. Known tagging systems have in common the basic concept of utilising a compact optically reflective tag which may be affixed, for example, to a vehicle, device, or person, etc. The tag may then be illuminated by means of a remote laser light source (preferably operating at a power and a wavelength which is not damaging to eyesight). Light reflected from tags in the area of illumination may then be detecting by means of a suitable optical detector and subsequently analysed so as to identify the location and possibly other information associated with those tags. Specific tag designs vary, and each has associated limitations. Such tags may also incorporate the ability to modulate the reflected light so as to further identify the tag, or convey other information according to the complexity of programming of the tag. A number of ways is known to provide such modulation. In particular U.S. Pat. No. 6,519,073 “Micromechanical Modulator and Methods for Fabricating the Same” (K. W. Goosen) and U.S. Pat. No. 5,500,761 “Micromechanical Modulator” (K. W. Goosen) disclose surface-normal micromechanical optical modulators. These modulators are arranged to reflect and modulate specific wavelengths only in a direction substantially normal to the of the device. Incident light arriving from a direction other than the normal to the surface of the device, will be reflected in a direction different from that of arrival. Furthermore, the wavelength of the light passed by such modulators varies as the angle of incidence deviates from the normal owing to the increase in optical path length within the device itself. For these reasons at least, such devices are in general not suitable for use as general purpose identification tags, particularly in situations in which an interrogating light source and detector may be arbitrarily located relative to the light-receiving surface of the tag. Other known dynamic optical tags for such applications are based on a number of concepts based on optically switched retro-reflectors exploiting technologies such as liquid crystal and multiple quantum well modulators. Another approach utilises micro electromechanical corner cube retro-reflectors, the reflected signal being modulated by deforming the corner cubes which are fabricated using silicon Microsystems. However, such techniques are unable to provide reliable communication links at data rates in excess of 50 kbps over a wide range of operating temperatures and the devices themselves costly to manufacture. Furthermore at ranges of, for example, 10 km between light source and reflector, calculations indicate that the diffuse return from background objects will be of a magnitude similar to that of any returns from such retro-reflectors. These returns act as a significant source of noise in the detection and interrogation process, thereby limiting both the effective data rate and the useful range of the devices. A further disadvantage of known tags, especially those utilising liquid crystal components or multiple quantum well (MQW) components, is that their effective operating temperature range is undesirably limited. Consequently, in order to support reliable operation over a wide range to of temperatures, for example −40 C to +70 C, either explicit temperature stabilisation mechanisms are required, or the interrogator must be widely tuneable in order to surmount the band-edge of the MQW material with ambient temperature. Known tags based on combinations of refractive or diffractive mirrors or lenses also suffer from a restricted effective field of view which can make remote interrogation difficult. |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention provides a compact dynamic optical tag and free-space optical communication system for data transmission between the tag and remote laser interrogator. The interrogation system incorporates an optical tracker which can be used to locate the tag autonomously at ranges of up to 10 km and to maintain effective communication channels over a wide range of approach geometries. According to a first aspect of the present invention there is provided a modulator for modulating an optical signal, the modulator comprising a spacing-controllable etalon and a retro-reflector arranged to retro-reflect light received via the etalon back through the etalon. Advantageously, light incident upon the arrangement is substantially reflected back towards its source whilst at the same time being filtered by the action of the etalon. Furthermore, by providing a construction which avoids use of liquid crystal components and multiple quantum well structures, the effective operating temperature range (without the need for temperature stabilisation mechanisms) of the device is greatly enhanced. Consequently, overall power consumption requirements for the device are also reduced. In addition, the modulator is able to operate effectively over a wide field of view of approximately 120°. Preferably, the etalon comprises a coherent planar MOEMS structure. Advantageously, the structure allows fast operation of the modulator leading to high data transfer rates. Preferably, the retro-reflector comprises an array of one or more corner-cube reflectors. Advantageously, corner cubes arrays are well known, reliable, durable, and relatively easy to produce at low cost with predictable reflective characteristics. Preferably, modulator is arranged to be modulated at a fixed frequency. Advantageously, the viewing angle associated with reflected light at a specific wavelength is enhanced. The wavelength reflected is determined by the internal optical path length and, by modulating the MOEMS membrane over a predetermined range, the path length over a wide range of viewing angles can be made to traverse the required path length at some point in the modulation. Preferably, the cavities in the etalon are vacuum cavities. Advantageously, this avoids the damping effect on the MOEMS membrane of air/gas in the cavities. Preferably, the modulator comprises a self-contained electrical power supply. Advantageously, such a modulator may be used without the need to couple it, in use, to an external source of electrical power. Such self-contained power supplies include, but are not limited to, electrical power cells, solar power units, etc. According to a further aspect of the present invention there is provided optical detector arrangement comprising a plurality of photo-detectors with associated means for restricting the light acceptance angle, the means being so arranged as to allow determination, based on outputs from the photo-detectors, of a direction of incidence of light from a remote source. Advantageously, the detector arrangement may be used to provide an initial indication of the relative position of a source of laser light directed towards a tag comprising such a detector. The invention is also directed to a reflective tag comprising one or more modulators according to the first aspect. Advantageously, the divergence of transmitted light is not limited by the size of a single MOEMS element, but by the size of the separate retro-reflective aperture. This construction allows the tag to overcome the limitations associated with a single MOEMS mirror. The reflective tag may comprise a detector arrangement coupled to the modulator. Advantageously, the modulator may be operated responsive to detection of an incoming optical signal. Preferably, detection of a precursor signal causes the modulator to be activated. Advantageously, power may be conserved while the tag is not being interrogated. The precursor signal may carry timing information which may be used to predict when the interrogator signal for activated a predetermined time interval after receipt of the incoming wake-up” signal, and not necessarily instantaneously. Advantageously, the stable dynamic behaviour of a modulator which has only two stable spacings may be exploited by activating the modulator a predetermined time interval before the interrogation pulse arrives. In this way the modulator can be at a precisely predicted intermediate position when the interrogation pulse arrives. This overcomes the fact that the optimum spacing of the modulator varies with angle of incidence on the tag. Advantageously, the tag will be fully activated by the precursor tag and ready to respond when the interrogator beam strikes the tag during the search phase. Preferably, the reflective tag comprises attachment means. Advantageously, such a tag may be readily attached to an item to be tracked. Such attachment means includes, but is not limited to, self-adhesive means, hook-fastening means (e.g. Velcro®), or clip means. According to a further aspect of the present invention there is provided an optical interrogator for use with a reflective optical tag, the interrogator comprising a laser source of light at two distinct wavelengths which are reflected by the tag substantially in anti-phase one with the other. Advantageously, by taking the returns from both lasers into account, the signal-to-noise ratio of the signal received from the tag at the interrogator is greatly improved relative to system employing only a single interrogation wavelength. The interrogator comprises two detectors, one for each wavelength. The interrogator source of light may comprise two laser sources. The interrogator may also comprise a detector arranged to receive reflected light emitted from the interrogator. The interrogator may also comprise an erbium filter arranged to discriminate between light at the two distinct wavelengths. According to a further aspect of the present invention there is provided a remote optical interrogation system comprising an optical interrogator. The remote interrogation system may comprise at least one modulator arrangement or reflective tag according to the present invention. According to a further aspect of the present invention there is provided a modulator for an optical signal substantially as described in the foregoing description or with reference to the accompanying drawings. According to a further aspect of the present invention there is provided a optical detector arrangement substantially as described in the foregoing description or with reference to the accompanying drawings. According to a further aspect of the present invention there is provided a optical remote interrogation system substantially as described in the foregoing description or with reference to the accompanying drawings. According to a further aspect of the present invention there is provided a reflective tag comprising an etalon and a retro-reflector arranged to retro-reflect light received via the etalon back through the etalon. According to a further aspect of the present invention there is provided a modulator according comprising an input or output port for local communication. The invention also provides for a system for the purposes of optical communications which comprises one or more instances of apparatus embodying the present invention, together with other additional apparatus. The invention is also directed to methods by which the described apparatus operates and including method steps for carrying out every function of the apparatus. The invention further provides for programs for computers (optionally on a machine-readable carrier) arranged, in operation, to control and/or carry out functions of the apparatus and/or methods and including software used to define circuitry utilised in implementing the apparatus or methods. The invention is also directed to special signals employed by the apparatus, methods, and programs. The preferred features may be combined as appropriate, as would be apparent to a skilled person, and may be combined with any of the aspects of the invention. |
Method to deter softwear tampering using interlinked sub-processes |
A method is disclosed for deterring the reverse engineering of computer software code. The method involves the recognition of an unauthorized access attempt by one of a plurality of linked sub-processes embedded in the computer software code. In response to the unauthorized attempt, each of the sub-processes begins a recursive execution, resulting in computer system resources being increasingly diverted to the linked sub-processes, making it difficult to continue unauthorized attempts to access the computer software code. |
1. A method to deter tampering of software code on a computer system comprising the steps of: recognizing an unauthorized attempt to access one of a plurality of linked sub-processes in said software code; and initiating a recursive execution of said plurality of linked sub-processes in response to said unauthorized attempt. 2. The method according to claim 1, wherein said recursive execution replicates said plurality of linked sub-processes. 3. The method according to claim 2, in which the initiating step includes the steps of: setting a tamper attempt status in said one of a plurality of linked sub-processes in response to said unauthorized attempt; communicating said tamper attempt status to said plurality of linked sub-processes; and executing recursively said plurality of linked sub-processes in response to said communication step. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Anti-tamper techniques are widely needed to protect software against tampering events. These techniques can protect valuable intellectual property resident in the code and can also satisfy the Department of Defense Anti-Tamper requirements. The Department of Defense is interested in protecting critical information associated with software applications or weapon systems from exploitation by foreign adversaries. In the commercial world, there are major incentives to develop methods for protecting software applications and other digital media from piracy. Without protection, computer software code is susceptible to attack from malicious users. There are techniques currently available to prevent tampering or reverse engineering of computer software code. Reverse engineering typically utilizes debugger or other software analysis tools. Prevention of the use of these tools is paramount in deterring unauthorized access. These techniques are generally associated with software protection that utilizes passive schemes, such as encryption or obfuscation. These passive techniques do not prevent the use of malicious tools. Furthermore, these passive techniques can oftentimes be overcome through lengthy, time-consuming processes that can break through the encryption or obfuscation and gain access to the computer software code. Accordingly, there is a need for anti-tamper techniques that can prevent the use of tools that can facilitate unauthorized access of computer software code. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention teaches a method to deter reverse engineering of computer software code. The disclosed technique changes the operating characteristics of the computer system attempting access. Importantly, by executing the linked sub-processes in response to an unauthorized access attempt, it is possible to exhaust all free memory of the computer system, thereby increasing the likelihood that the tamper attempt is unsuccessful. In an exemplary embodiment of the present invention, a plurality of sub-processes are inter-linked in the computer software code on a computer system. When an unauthorized access of the computer software code is attempted, the linked sub-processes detect the attempt and initiate a response by recursively executing all of the linked sub-processes. By executing all of the sub-processes in recursive fashion, computer system resources such as memory and processing power are increasingly diverted to the linked sub-processes, making it difficult to continue unauthorized attempts to access the computer software code. Advantageously, the present invention also minimizes the impact on execution time line by avoiding the encryption/decryption such, the computer software code will operate more efficiently in a non-hostile environment. The present invention is a versatile and effective means at prevent unauthorized access of computer software code. |
Target assignment projectile |
A projectile includes an ordnance portion configured to impact a target and a communication apparatus positioned rearward of the ordnance portion. The projectile is configured to rotate about and travel along a longitudinal axis after launch. |
1. A projectile comprising: an ordnance portion configured to impact a target; and a communication apparatus positioned rearward of the ordnance portion; wherein the projectile is configured to rotate about and travel along a longitudinal axis after launch. 2. The projectile of claim 1 wherein the ordnance portion includes a bullet. 3. The projectile of claim 1 wherein the ordnance portion includes a grenade. 4. The projectile of claim 1 wherein the ordnance portion is configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible. 5. The projectile of claim 1 wherein the ordnance portion is constructed of an energy absorbing material. 6. The projectile of claim 5 wherein the energy absorbing material is a thermoplastic. 7. The projectile of claim 5 wherein the energy absorbing material is a soft metal. 8. The projectile of claim 5 wherein the energy absorbing material encases a penetration device. 9. The projectile of claim 8 wherein the penetration device is constructed of a material chosen from the group consisting of: a ceramic material; a carbon fiber material; and a hard metal. 10. The projectile of claim 9 wherein the ceramic material is silicon carbide. 11. The projectile of claim 9 wherein the hard metal is tungsten. 12. The projectile of claim 8 wherein the penetration device is a threaded penetration device configured to attach the projectile to sheet metal. 13. The projectile of claim 1 further comprising one or more deployable fins that extend after leaving a barrel from which the projectile is launched. 14. The projectile of claim 1 further comprising one or more range-limiting fins. 15. The projectile of claim 1 further combining a sabot for encasing the projectile at the time the projectile is launched. 16. The projectile of claim 1 further comprising a power supply for providing energy to at least the communication apparatus. 17. The projectile of claim 16 wherein the power supply includes a use detection apparatus for activating the power supply after the occurrence of a use event. 18. The projectile of claim 17 wherein the use event is chosen from the group consisting of: a launch event, and an impact event. 19. The projectile of claim 17 wherein: the power supply is an electrochemical battery pack that generates electrical energy due to an electrochemical reaction between at least two components; and the use detection apparatus includes a membrane that separates the at least two components until the occurrence of the use event. 20. The projectile of claim 19 wherein: the battery pack is a zinc air (Zn/O2) battery pack; the at least two components include zinc, carbon and air; and the membrane separates the zinc and carbon from the air. 21. The projectile of claim 19 wherein: the battery pack is a lead acid (Pb/H2SO4) battery pack; the at least two components include lead, lead oxide and sulfuric acid; and the membrane separates the lead and lead oxide from the sulfuric acid. 22. The projectile of claim 19 wherein: the battery pack is an alkaline battery pack; the at least two components include zinc, manganese dioxide and potassium hydroxide; and the membrane separates the zinc and the manganese dioxide from the potassium hydroxide. 23. The projectile of claim 1 wherein the communication apparatus includes a reception device for receiving energy from a remote source. 24. The projectile of claim 23 wherein: the energy received is RF energy; and the reception device includes an antenna. 25. The projectile of claim 23 wherein: the energy received is infrared energy; and the reception device includes a photoreceptor. 26. The projectile of claim 23 wherein the energy received includes an encoded data signal configured to energize at least a portion of the communication apparatus. 27. The projectile of claim 26 wherein the energized portion of the communication apparatus includes a transmission device for transmitting energy to a remote receiver. 28. The projectile of claim 1 wherein the communication apparatus includes a transmission device for transmitting energy to a remote receiver. 29. The projection of claim 28 wherein: the transmitted energy is RF energy; and the transmission device includes an antenna. 30. The projectile of claim 28 wherein: the transmitted energy is infrared energy; and the transmission device includes one or more light emitting diode. 31. The projectile of claim 30 wherein the transmission apparatus further includes a lens assembly for refracting the infrared energy transmitted from the one or more light emitting diodes. 32. The projectile of claim 31 wherein the lens assembly is a convex lens assembly. 33. The projectile of claim 31 wherein the lens assembly is a concave mirror assembly. 34. The projectile of claim 30 wherein the one or more light emitting diodes includes a plurality of light emitting diodes, the transmission device further including a driver circuit for sequentially exciting each of the one or more light emitting diodes. 35. The projectile of claim 34 wherein the transmission apparatus further includes a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first radial angle; and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second radial angle. 36. The projectile of claim 34 wherein the transmission apparatus further includes a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first longitudinal angle; and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second longitudinal angle. 37. The projectile of claim 34 wherein the transmission apparatus further includes a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first longitudinal angle and a first radial angle; and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second longitudinal angle and a second radial angle. 38. The projectile of claim 1 wherein the communication apparatus is a passive communication apparatus. 39. The projectile of claim 38 wherein the passive communication apparatus includes a retroreflector. 40. The projectile of claim 1 wherein the communication apparatus is an active communication apparatus. 41. The projectile of claim 40 wherein the active communication apparatus is configured to substantially withstand the acceleration associated with launching the projectile from a launcher and the deceleration associated with the projectile striking the target. 42. The projectile of claim 41 wherein the active communication apparatus includes one or more surface mount electronic components mounted on a shock-resistant system board. 43. The projectile of claim 40 further comprising one or more interconnections for electrically coupling a plurality of electronic components internal to the projectile, wherein at least one interconnection is configured to allow a limited amount of relative movement between the plurality of electronic components. 44. The projectile of claim 42 wherein the active communication apparatus includes a system board for mounting one or more electronic components, wherein the system board is positioned within a plane that is essentially orthogonal to the longitudinal axis of the projectile. 45. The projectile of claim 42 wherein the communication apparatus includes an essentially planar mounting structure that is essentially orthogonal to the longitudinal axis of the projectile, wherein the essentially planar mounting structure is configured to receive a system board containing one or more electronic components. 46. The projectile of claim 1 wherein an exterior surface of the projectile is configured to engage an interior surface of a barrel from which the projectile is launched. 47. The projectile of claim 46 wherein the interior surface of the barrel includes spiral rifling that engages the exterior surface of the projectile and rotates the projectile about the longitudinal axis after launch. 48. A projectile comprising: a communication apparatus including a transmission device for transmitting energy to a remote receiver; and an ordnance portion positioned forward of the communication apparatus and configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible; wherein the projectile is configured to rotate about and travel along a longitudinal axis after launch. 49. A projectile comprising: a communication apparatus including a transmission device for transmitting energy to a remote receiver, and a receiving device for receiving energy from a remote transmitter; and an ordnance portion positioned forward of the communication apparatus and configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible; wherein the projectile is configured to rotate about and travel along a longitudinal axis after launch, and one or more interconnections for electrically coupling a plurality of electronic components internal to the projectile, wherein at least one interconnection is configured to allow a limited amount of relative movement between the plurality of electronic components. |
<SOH> BACKGROUND <EOH>It is often desirable to remotely monitor people and places. This monitoring activity was traditionally accomplished by planting a “bug”, such that the “bug” is a covert microphone or video camera, for example. Unfortunately, this activity requires that a person (e.g., a spy, a soldier, or a detective, for example) enter the place that they wish to monitor so that the “bug” can be planted. Naturally, there are risks associated with such a procedure. Further, the use of smart munitions (e.g., laser-guided missiles and bombs, for example) have greatly increased the accuracy of munitions. Typically, the target is illuminated (i.e., designated or “painted”) using a laser source, and the laser-guided weapon uses that laser light painting the target as a homing beacon. Unfortunately, in order to illuminate a target, a laser must be aimed at and maintained on the target until the missile/bomb strikes the target. Again, this requires one or more soldiers to be in harm's way prior to and during the bombing mission. |
<SOH> SUMMARY OF THE DISCLOSURE <EOH>According to an aspect of this disclosure, a projectile includes an ordnance portion configured to impact a target, and a communication apparatus positioned rearward of the ordnance portion. The projectile is configured to rotate about and travel along a longitudinal axis after launch. One or more of the following features may also be included. The ordnance portion may include a bullet or a grenade. The ordnance portion may be configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible. The ordnance portion may be constructed of an energy absorbing material, such as: thermoplastic; or a soft metal. The energy absorbing material may encase a penetration device. The penetration device may be constructed of a material chosen from the group consisting of: a ceramic material (e.g., silicon carbide); a carbon fiber material; and a hard metal (e.g., tungsten). The penetration device may be a threaded penetration device configured to attach the projectile to sheet metal. One or more deployable fins may extend after leaving a barrel from which the projectile is launched. The projectile may include one or more range-limiting fins. A sabot may encase the projectile at the time the projectile is launched. A power supply may provide energy to at least the communication apparatus. The power supply may include a use detection apparatus for activating the power supply after the occurrence of a use event. The use event may be chosen from the group consisting of: a launch event, and an impact event. The power supply may be an electrochemical battery pack that generates electrical energy due to an electrochemical reaction between at least two components, and the use detection apparatus may include a membrane that separates the at least two components until the occurrence of the use event. The battery pack may be a zinc air (Zn/O 2 ) battery pack, the at least two components may include zinc, carbon and air; and the membrane may separate the zinc and carbon from the air. The battery pack may be a lead acid (Pb/H 2 SO 4 ) battery pack; the at least two components may include lead, lead oxide and sulfuric acid; and the membrane may separate the lead and lead oxide from the sulfuric acid. The battery pack may be an alkaline battery pack; the at least two components may include zinc, manganese dioxide and potassium hydroxide; and the membrane may separate the zinc and the manganese dioxide from the potassium hydroxide. The communication apparatus may include a reception device for receiving energy from a remote source. The energy received may be RF energy, and the reception device may include an antenna. The energy received may be infrared energy, and the reception device may include a photoreceptor. The energy received may include an encoded data signal configured to energize at least a portion of the communication apparatus. The energized portion of the communication apparatus may include a transmission device for transmitting energy to a remote receiver. The communication apparatus may include a transmission device for transmitting energy to a remote receiver. The transmitted energy may be RF energy, and the transmission device may include an antenna. The transmitted energy may be infrared energy, and the transmission device may include one or more light emitting diode. The transmission apparatus may further include a lens assembly for refracting the infrared energy transmitted from the one or more light emitting diodes. The lens assembly may be a convex lens assembly or a concave mirror assembly. The one or more light emitting diodes may include a plurality of light emitting diodes, the transmission device may further include a driver circuit for sequentially exciting each of the one or more light emitting diodes. The transmission apparatus may include a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first radial angle, and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second radial angle. The transmission apparatus may include a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first longitudinal angle, and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second longitudinal angle. The transmission apparatus may include a lens assembly configured to: project the infrared energy transmitted from a first of the plurality of light emitting diodes at a first longitudinal angle and a first radial angle, and project the infrared energy transmitted from a second of the plurality of light emitting diodes at a second longitudinal angle and a second radial angle. The communication apparatus may be a passive communication apparatus, such as a retroreflector. The communication apparatus may be an active communication apparatus. The active communication apparatus may be configured to substantially withstand the acceleration associated with launching the projectile from a launcher and the deceleration associated with the projectile striking the target. The active communication apparatus may include one or more surface mount electronic components mounted on a shock-resistant system board. One or more interconnections may electrically couple a plurality of electronic components internal to the projectile, such that at least one interconnection is configured to allow a limited amount of relative movement between the plurality of electronic components. The active communication apparatus may include a system board for mounting one or more electronic components, such that the system board is positioned within a plane that may be essentially orthogonal to the longitudinal axis of the projectile. The communication apparatus may include an essentially planar mounting structure that is essentially orthogonal to the longitudinal axis of the projectile, such that the essentially planar mounting structure is configured to receive a system board containing one or more electronic components. An exterior surface of the projectile may be configured to engage an interior surface of a barrel from which the projectile is launched. The interior surface of the barrel may include spiral rifling that engages the exterior surface of the projectile and rotates the projectile about the longitudinal axis after launch. According to another aspect of this disclosure, a projectile includes a communication apparatus including a transmission device for transmitting energy to a remote receiver. An ordnance portion is positioned forward of the communication apparatus and configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible. The projectile is configured to rotate about and travel along a longitudinal axis after launch. According to another aspect of this disclosure, a projectile includes a communication apparatus including a transmission device for transmitting energy to a remote receiver. A receiving device receives energy from a remote transmitter, and an ordnance portion is positioned forward of the communication apparatus and configured to partially penetrate a target such that at least a portion of the communication apparatus is remotely visible. The projectile is configured to rotate about and travel along a longitudinal axis after launch. One or more interconnections electrically couple a plurality of electronic components internal to the projectile, wherein at least one interconnection is configured to allow a limited amount of relative movement between the plurality of electronic components. The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features and advantages will become apparent from the description, the drawings, and the claims. |
Sensing System |
Described herein is an improved sensing system (30) and its method of operation. The system (30) includes a camera (16) for viewing an external scene, the camera comprising one or more detector(s) and has a field of view (40) which overlaps with the path (32) of a pulsed laser (12). The laser path (32) and radiation from the scene viewed (40) share a beamsplitter (36) and a window (38). In order to substantially reduce back-scattered radiation from the laser path (32) affecting operation of the detector(s) of the camera (16), the detector(s) is (are) switched in accordance with the operation of the laser (12) to be ‘off’ or non-receiving when the laser (12) is ‘on’ or firing. |
1-19. (canceled) 20. A method of operating a sensing system which comprises a sensor for viewing an external scene, the sensor comprising at least one detector and having a field of view which overlaps with the path of a pulsed laser, the method comprising the step of: switching the detector between a ‘stare’ period and a ‘readout’ period in accordance with operation of the pulsed laser to at least substantially reduce back-scattered radiation on overlapping portions of the laser path and the sensor field of view. 21. A sensing system comprising: a sensor for viewing a viewed scene, the sensor comprising at least one detector and having a field of view which overlaps with a path of a pulsed laser; and control means for controlling the operation of the detector, the control means including switching means for switching the detector between a ‘stare’ period and a ‘readout’ period in accordance with operation of the laser to at least substantially reduce back-scattered radiation on overlapping portions of the laser path and the sensor field of view. 22. A system according to claim 21, wherein each detector comprises a charge-coupled device. 23. A system according to claim 22, wherein the sensor is a multi-element sensor. 24. A system according to claim 23, wherein the multi-element sensor is in the form of a focal plane array. 25. A system according to claim 24, wherein the control means includes a readout circuit for reading and processing information received at the detector. 26. A system according to claim 21, wherein each detector comprises a charge-coupled device. 27. A system according to claim 26, wherein the sensor is a multi-element sensor. 28. A system according to claim 27, wherein the multi-element sensor is in the form of a focal plane array. 29. A system according to claim 28, wherein the control means includes a readout circuit for reading and processing information received at the detector. 30. A system according to claim 21, wherein the sensor is a multi-element sensor. 31. A system according to claim 30, wherein the multi-element sensor is in the form of a focal plane array. 32. A system according to claim 31, wherein the control means includes a readout circuit for reading and processing information received at the detector. 33. A system according to claim 21, wherein the control means includes a readout circuit for reading and processing information received at the detector. 34. A system according to claim 21, wherein the control means includes a readout circuit for reading and processing information received at the detector. 35. A system according to claim 22, wherein the control means includes a readout circuit for reading and processing information received at the detector. 36. A system according to claim 23, wherein the control means includes a readout circuit for reading and processing information received at the detector. 37. In a sensing system for viewing an external scene, the sensing system comprising a pulsed laser for repetitively transmitting light pulses along an outgoing light path, and a sensor comprising an array of detectors for detecting pulsed laser light reflected from the external scene along an incoming light path, wherein the incoming light path and the outgoing light path overlap and share at least one common optical component, the method comprising the steps of: repetitively transmitting light pulses from the laser; and switching each detector to an off condition so that it cannot detect back scattered light during the transmission of each light pulse along the outgoing light path; switching the detectors so as to receive light along the incoming light path when laser light is not being transmitted along the outgoing path and during the period between outgoing light pulses; and monitoring the detectors to record the amount of light record the amount of light recorded by each detector. 38. A sensing system comprising: a pulsed laser for repetitively transmitting output light pulses, and an outgoing light path for transmitting the light pulses to the scene to be viewed; a sensor for viewing the scene including an incoming light path for conducted laser light pulses from the scene; and control means for controlling the operation of the sensor in synchronism with the laser; wherein the outgoing light path and the incoming light path have at least a portion which overlap and include at least one shared optical component; wherein the sensor comprises a plurality of detector elements; and wherein, during the period that a laser light pulse is being transmitted on the outward path, each detector element is switched off to prevent detection of back scattered light, and during a period between the transmission of laser pulses on the outgoing light path, the detector elements are switched to on to monitor reflected light on the incoming light path, and signals an the detector elements are monitored. |
System for providing alert-based services to mobile stations in a wireless communications network |
System for providing alert-based communication services for which corresponding alert conditions to be met by mobile stations are defined. The system includes an alert engine capable of firing alerts associated with the alert-based communication services if location data regarding the mobile stations is indicative of the mobile stations meeting the alert conditions corresponding to the alert-based communication services. A requirements engine is provided for determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station and outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. Also provided is a scheduler for receiving expiry times data indicative of a plurality of expiry times relating to respective location requests, processing the expiry times data for determining an order for servicing the location requests by positioning determining equipment (PDE) at least in part on a basis on the expiry times of the location requests and an output for interfacing with the PDE, allowing it to service the location requests according to the order determined. |
1. Computer-readable media tangibly embodying a program of instructions executable by a computing device to implement a method, the computing device being capable of interfacing with a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, the method comprising: determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. 2. Computer-readable media as defined in claim 1, wherein determining the expected earliest future time includes: estimating a minimum travel time between a last known location of the particular mobile station and a target location associated with the at least one alert condition. 3. Computer-readable media as defined in claim 2, wherein estimating a minimum travel time between the last known location of the particular mobile station and the target location includes: determining a distance between the last known location of the particular mobile station and the target location; determining a speed of the particular mobile station; computing the quotient of the distance and the speed to obtain an estimated minimum travel time between the last known location of the particular mobile station and the target location. 4. Computer-readable media as defined in claim 3, wherein the speed is an instantaneous speed. 5. Computer-readable media as defined in claim 3, wherein the speed is an average speed within an interval of time. 6. Computer-readable media as defined in claim 3, wherein the speed is the greater of an instantaneous speed and an average speed within an interval of time. 7. Computer-readable media as defined in claim 2, wherein estimating a minimum travel time between the last known location of the particular mobile station and the target location includes: determining the shortest path from the last known location of the particular mobile station to the target location via a set of existing roads; and determining the least amount of time required to travel the shortest path. 8. Computer-readable media as defined in claim 1, the method further including: outputting a second data element indicative of a requirement to obtain updated location data about the particular mobile station dating back no later than the current time. 9. Computer-readable media as defined in claim 1, the method further comprising: outputting a second data element indicative of a requirement to obtain updated location data about the particular mobile station dating back no later than a predetermined time in the past. 10. Computer-readable media as defined in claim 1, the method further comprising: outputting a second data element indicative of a requirement to obtain updated location data about the particular mobile station no earlier than a predetermined time in the future. 11. Computer-readable media as defined in claim 1, the method further comprising: receiving location data about the particular mobile station; wherein the steps of determining and outputting are executed after executing the step of receiving. 12. Computer-readable media as defined in claim 11, wherein the method further comprises: repeatedly executing the steps of receiving, determining and outputting. 13. Computer-readable media as defined in claim 1, wherein determining an expected earliest future time at which at least one alert condition is capable of being met by the particular mobile station includes determining an expected earliest future time at which any of a plurality of alert conditions is capable of being met by the particular mobile station. 14. Computer-readable media as defined in claim 1, wherein determining an expected earliest future time includes: estimating a minimum travel time between a last known location of the particular mobile station and the closest amongst a plurality of target locations associated with a plurality of alert conditions. 15. Computer-readable media as defined in claim 1, wherein determining the expected earliest future time includes: for the alert condition for which the expected earliest future time was minimum, finding a new expected earliest future time; for all other alert conditions, if the earliest expected future time for that alert condition is before the new expected earliest future time, computing a second new expected earliest future time and setting the new expected earliest future time equal to the least of the new expected earliest future time and the second new expected earliest future time. 16. A method for use in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, comprising: determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. 17. A system for use in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, comprising: means for determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and means for outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. 18. A computer readable storage medium containing a program element for execution by a computing device to implement a method in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, the program element including: program code means for determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and program code means for outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. 19. A data processing device for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: an input capable of receiving updated location data about the mobile stations; and a processing unit connected to the input, said processing unit being capable of: determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire of an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. 20. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located within a predetermined maximum distance from a target location at a predetermined future time. 21. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located within a predetermined maximum distance from a target location during a predetermined time range. 22. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station having entered a predetermined target geographic area. 23. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station having exited a predetermined target geographic area. 24. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located within a predetermined target geographic area at a predetermined time. 25. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located outside a predetermined target geographic area at a predetermined time. 26. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located within a predetermined target geographic area for a predetermined duration. 27. A data processing device as defined in claim 26, wherein the predetermined duration is defined as a predetermined number of consecutive times updated location data is received at the input. 28. A data processing device as defined in claim 26, wherein the predetermined duration is defined as a predetermined length of time. 29. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located within one of a plurality of increasingly peripheral target geographic areas relative to a central target location for a corresponding predetermined duration. 30. A system as defined in claim 29, wherein the predetermined duration corresponding to a peripheral target geographic area is directly related to the degree to which that peripheral target geographic area is peripheral relative to the central target location. 31. A system as defined in claim 30, wherein the predetermined duration corresponding to a peripheral target geographic area is defined as a predetermined number of consecutive times the updated location data is indicative of the mobile station being in that peripheral target geographic area. 32. A system as defined in claim 30, wherein the predetermined duration corresponding to a peripheral target geographic area is defined as a predetermined length of time. 33. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being headed towards a particular direction or location. 34. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being headed away from a particular direction or location. 35. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being headed towards an area congested with traffic. 36. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located in an area with traffic congestion. 37. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being located on a congested road. 38. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station being headed towards a congested portion of a pre-defined travel route. 39. A data processing device as defined in claim 19, wherein firing of an alert associated with at least one alert-based service is triggered only if the particular mobile station is a member of a selected group of mobile stations. 40. A data processing device as defined in claim 19, wherein the selected group of mobile stations includes a group of mobile stations associated with users sharing a predefined set of at least one common demographic characteristic. 41. A data processing device as defined in claim 19, wherein he selected group of mobile stations includes a group of mobile stations subscribed to a common alert-based service. 42. A data processing device as defined in claim 19, wherein the selected group of mobile stations includes a group of mobile stations associated with users having a common behavioural characteristic. 43. A data processing device as defined in claim 19, wherein firing of an alert associated with at least one alert-based service is conditional upon an alert associated with the at least one alert-based service not having been fired during a predetermined length of time. 44. A data processing device as defined in claim 19, wherein generating a trigger to fire an alert associated with at least one of the alert-based services is conditional upon the current time falling within a predetermined range. 45. A data processing device as defined in claim 19, wherein the alert condition corresponding to at least one alert-based service is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station having a speed outside a predetermined range. 46. A data processing device as defined in claim 19, further comprising a primary memory and a secondary memory, the processing unit further being capable of: maintaining a set of data structures in the secondary memory, each set of data structures being associated with a time interval, wherein each data structure in a particular set of data structures contains information relevant to a respective subset of alert conditions that require a current time to be in the time interval associated with that set of data structures; if the primary memory does not contain the set of data structures associated with the time interval containing the current time, overwriting the content of the primary memory with the set of data structures associated with the time interval containing the current time; wherein the step of determining is effected on the basis of the alert conditions limited to those alert conditions belonging to the subset of alert conditions for which relevant information is contained in the set of data structures associated with the time interval containing the current time. 47. A data processing device as defined in claim 46, wherein each alert condition is considered as having been met by a particular mobile station if the updated location data about the particular mobile station is indicative of the particular mobile station having entered a corresponding alert region, wherein each data structure in each set of data structures includes data indicative of the closest alert region to different locations in the network. 48. A data processing device as defined in claim 47, wherein each data structure in each set of data structures is created by: dividing the network into nodes; computing for each node the nearest alert region; and merging together into cells, those nodes having the same nearest alert region. 49. A data processing device as defined in claim 48, the processing unit being further capable of smoothening out boundaries of the cells resulting from the merge of two or more nodes. 50. A data processing device as defined in claim 49, wherein computing for each node the nearest alert region includes computing a set of Voronoi regions for the nodes. 51. A data processing device as defined in claim 50, wherein the processing unit is further capable of responding to the appearance of a new alert region by: a) finding the set of nodes for which the new alert region is closer than the nearest alert region previously associated with the node in question; and b) creating at least one polygon enclosing only the set of nodes found in a). 52. A method for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: receiving updated location data about the mobile stations; determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. 53. A system for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: means for receiving updated location data about the mobile stations; means for determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and means for generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. 54. Computer-readable media tangibly embodying a program of instructions executable by a computing device to implement a method in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, the method comprising: receiving updated location data about the mobile stations; determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. 55. A system for providing alert-based communication services for which corresponding alert conditions to be met by mobile stations are defined, comprising: an alert engine capable of firing alerts associated with the alert-based communication services if location data regarding the mobile stations is indicative of the mobile stations meeting the alert conditions corresponding to the alert-based communication services. 56. A system as defined in claim 55, further comprising: a requirements engine capable of specifying time conditions to be satisfied by the receipt of updated location data regarding the mobile stations; and a scheduler capable of ensuring that the receipt of the updated location data regarding the mobile stations satisfies the time conditions. 57. A system as defined in claim 56, wherein the alert engine is adapted to verify whether a particular alert condition is met by a particular mobile station upon receipt of the updated location data regarding the particular mobile station. 58. A system as defined in claim 57, wherein the alert engine is adapted to verify whether a particular alert condition is met by a particular mobile station upon receipt of the updated location data and only upon satisfaction of the time condition to be satisfied by the receipt of the updated location data regarding the particular mobile station. 59. A method of accessing a data structure for obtaining an earliest expected travel time between a current location and a plurality of alert regions, the data structure containing data regarding a subdivision of a network into cells for which a respective alert region is the nearest to all points in the cell, the method comprising: (a) using a point-location data structure to determine which cell contains the current location; (b) using the table to determine the alert region associated with the cell found in step (a); and (c) using a cost function to determine the travel time from the current location to the alert region found in step (b). 60. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) an input for receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; b) a scheduler processing the expiry times data for determining an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; c) an output for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by said scheduler. 61. An apparatus as defined in claim 60, wherein said scheduler includes a storage medium defining a sequence of slots for holding data elements according to the order for servicing the location requests by the PDE. 62. An apparatus as defined in claim 61, wherein each data element in said storage medium is associated to a location request. 63. An apparatus as defined in claim 61, wherein said scheduler is operative to re-compute the order of the data elements in said storage medium when new expiry times data associated with a new location request is received at said input. 64. An apparatus as defined in claim 63, wherein each slot in said sequence of slots corresponds to a point in time at which the position determination equipment is expected to service the location request of a data element stored in the slot. 65. An apparatus as defined in claim 64, wherein the re-computation includes for a new location request identifying a slot in said sequence of slots that corresponds to a point in time for servicing the new location request that is within the expiry time of the new location request. 66. An apparatus as defined in claim 65, wherein the re-computation includes identifying a slot in said sequence of slots that corresponds to a latest point in time for servicing the new location request, without exceeding the expiry time of the location request. 67. An apparatus as defined in claim 66, wherein if the slot that corresponds to the latest point in time for servicing the new location request is vacant, said scheduler is operative for storing a data element associated to the new location request in the slot that corresponds to the latest point in time. 68. An apparatus as defined in claim 67, wherein if the slot that corresponds to the latest point in time for servicing the new location request is occupied by a data element associated with a prior location request, then said scheduler is operative for: a) displacing the data element associated with the prior location request to a slot corresponding to an earlier point in time for servicing the prior location request to vacate the slot containing the data element associated with the prior location request; b) inserting the data element associated with the new location request in the vacated slot. 69. An apparatus as defined in claim 61, wherein the data elements are arranged according to a search tree. 70. An apparatus as defined in claim 69, wherein each data element is associated to a location request and each data element is represented by a node in said search tree. 71. An apparatus as defined in claim 70, wherein the nodes of said search tree are ordered according to the expiry times of the respective location requests. 72. An apparatus as defined in claim 71, wherein each data element includes a first label containing information about a number of descendants of the node associated with the data element. 73. An apparatus as defined in claim 72, wherein each data element includes a second label containing information identifying a time slot at which a location request is to be serviced. 74. An apparatus as defined in claim 73, wherein said scheduler is operative to compute an actual time to service a given location request based at least in part on the first and second labels of nodes in said search tree. 75. A computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a) a scheduling module for accepting as input expiry times data indicative of a plurality of expiry times relating to respective location requests for computing an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; b) an output module for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by said scheduler. 76. A computer readable storage medium as defined in claim 75, wherein said scheduling module is operative to insert and remove data elements in a storage medium defining a sequence of slots such that the data elements are arranged according to the order for servicing the location requests computed by said scheduling module. 77. A computer readable storage medium as defined in claim 76, wherein each data element is associated to a location request. 78. A computer readable storage medium as defined in claim 77, wherein said scheduling module is operative to re-compute the order of the data elements in the storage medium when new expiry times data associated with a new location request is received by said scheduling module. 79. A computer readable storage medium as defined in claim 78, wherein each slot in the sequence of slots corresponds to a point in time at which the PDE is expected to service the location request of a data element stored in the slot. 80. A computer readable storage medium as defined in claim 79, wherein the re-computation includes for a new location request identifying a slot in the sequence of slots that corresponds to a point in time for servicing the new location request that is within the expiry time of the location request. 81. A computer readable storage medium as defined in claim 80, wherein the re-computation includes identifying a slot in the sequence of slots that corresponds to a latest point in time for servicing the new location request, without exceeding the expiry time of the new location request. 82. A computer readable storage medium as defined in claim 80, wherein if the slot that corresponds to the latest point in time for servicing the new location request is vacant, said scheduling module is operative for storing a data element associated to the new location request in the slot that corresponds to the latest point in time. 83. A computer readable storage medium as defined in claim 82, wherein if the slot that corresponds to the latest point in time for servicing the new location request is occupied by a data element associated with a prior location request, then said scheduling module is operative for: a) displacing the data element associated with the prior location request to a slot corresponding to an earlier point in time for servicing the prior location request to vacate the slot containing the data element associated with the prior location request; b) inserting the data element associated with the new location request in the vacated slot. 84. A computer readable storage medium as defined in claim 76, wherein the data elements are arranged according to a search tree. 85. A computer readable storage medium as defined in claim 84, wherein each data element is associated to a location request and each data element is represented by a node in said search tree. 86. A computer readable storage medium as defined in claim 85, wherein the nodes of said search tree are ordered according to the expiry times of the respective location requests. 87. A method for scheduling servicing of location requests by a PDE, comprising: a) receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; b) processing the expiry times data for determining an order for servicing the location requests by the position determination equipment at least in part on a basis on the expiry times of the location requests; c) interfacing with the PDE for allowing the PDE to service the location requests according to the determining. 88. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) an input for receiving data elements from an entity, the data elements indicative of respective location requests; b) the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; c ) a scheduler for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; d) an output for interfacing with the PDE allowing the PDE to service the location requests according to the determining. 89. An apparatus as defined in claim 88, wherein the determining is such that the servicing of the delayed-type location requests is postponed artificially without exceeding the expiry-time data of the respective delayed-type location requests. 90. An apparatus as defined in claim 88, wherein said scheduler includes a storage medium defining a sequence of slots for holding data elements according to the determining. 91. An apparatus as defined in claim 90, wherein each data element in said storage medium. is associated to a location request. 92. An apparatus as defined in claim 91, wherein said scheduler is operative to re-compute the order of the data elements in said storage medium when new expiry times data associated with a new location request is received at said input. 93. An apparatus as defined in claim 89, wherein the data elements are arranged according to a search tree. 94. An apparatus as defined in claim 93, wherein each data element is associated to a location request and each data element is represented by a node in said search tree. 95. An apparatus as defined in claim 94, wherein the nodes of said search tree are ordered according to the expiry times of the respective location requests. 96. A method for scheduling servicing of location requests by a PDE, comprising: a) receiving data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; b) determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; c) interfacing with the PDE allowing the PDE to service the location requests according to the determining. 97. A method as defined in claim 96, wherein the determining is such that the servicing of the delayed-type location requests is postponed artificially without exceeding the expiry time data of the respective delayed-type location requests. 98. A computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a) a scheduling module for accepting as input data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data, said scheduling module being operative for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; b) an output module for interfacing with the PDE allowing the PDE to service the location requests according to the determining. 99. A computer readable storage medium as defined in claim 98, wherein the determining is such that the servicing of the delayed-type location requests is postponed artificially without exceeding the expiry time data of the respective delayed-type location requests. 100. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) an input for receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests; b) the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; c) a scheduler for: i) identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: ii) determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; d) an output for issuing the common location query. 101. A method for scheduling servicing of location requests by a PDE, comprising: i) receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; ii) identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: iii) determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (ii) when to issue the common location query to the PDE; iv) issuing the common location query. 102. A computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a) a scheduling module for accepting a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data, said scheduling module being operative for: i) identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: ii) determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; b) an output module for issuing the common location query. 103. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) Input means for receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; b) Scheduler means for processing the expiry times data for determining an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; c) output means for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by said scheduler. 104. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) input means for receiving data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; b) scheduling means for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; c) output means for interfacing with the PDE allowing the PDE to service the location requests according to the determining. 105. An apparatus for scheduling servicing of location requests by a PDE, comprising: a) input means for receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; b) scheduling means for: i) identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: ii) determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; c) output means for issuing the common location query. 106. A memory for storing data for access by an application program being executed on a data processing device used in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: a secondary memory for holding a plurality of data structures, the data structures being associated with respective non-overlapping time intervals, each of the data structures containing information relevant to a respective category of alert conditions that requires a current time to be included in the time interval associated with that data structure; a primary memory for storing the one data structure associated with the time interval that includes the current time. 107. A method of creating a data structure for access by an application program being executed on a data processing device used in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, each alert condition corresponding to an alert region, comprising: defining a subdivision of the network into nodes; computing, for each node, the nearest alert region; merging together into a single cell for each alert region, those nodes having that alert region as the nearest alert region; maintaining a data structure that is indicative of the locations covered by each cell and the alert condition associated with that cell. 108. A method as defined in claim 107, each alert condition further corresponding to an alert time, the method further comprising: maintaining separate data structures for at least two sets of alert conditions corresponding to respective disjoint time blocks, each set of alert conditions including those alert conditions corresponding to alert times contained within the respective time block. 109. A method of delivering an alert-based communications service relevant to a mobile station in a communications network, wherein the alert-based communications service is associated with an alert condition to be satisfied by the mobile station, comprising: obtaining location data about the mobile station for a first time instant; predicting location data about the mobile station for a second time instant after the first time instant based on the location data about mobile station for the first time instant; if the mobile station is predicted to be within the alert region at the second time instant, triggering the firing of an alert at or after the second time instant. 110. A method as defined in claim 109, wherein predicting location data is based on recent information regarding the mobile station. 111. A method as defined in claim 109, wherein predicting location data is based on historical information regarding the mobile station. 112. A method as defined in claim 109, wherein predicting location data is based on current information regarding other mobile stations in the network. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the current age of significant telecommunications competition, mobile network operators continuously seek new and innovative ways to create differentiation and increase profits. One of the best ways to accomplish this goal is through the delivery of highly personalized services, such as location-based services (LBS). Moreover, mobile network operators are required under the laws of certain national governments to equip their infrastructure with the ability to provide LBS, particularly having regard to emergency services. In all, there are at least four major categories of LBS, namely location-based information, location-sensitive billing, emergency services and tracking. A popular feature of LBS is the capability to support alert-based services (ABS). In an alert-based application, registered mobile stations within the wireless network are monitored, and alerts are triggered for each mobile station based on the location of the mobile station. When an alert fires for a particular mobile station reaching or entering a predetermined location, at least one specific action is taken, such as the transmission of a message to the particular mobile station or the updating of a database. The appeal of ABS is wide-ranging, from commercial to government sectors, for the purposes of marketing, advertising, law enforcement, emergency monitoring and communication-based services, among others. As the adoption rates of wireless LBS grow, network operators and other mobile location data providers will be required to provide an increasing amount of mobile location data to a variety of alert-based applications. These alert-based applications vary widely in their location data requirements. More specifically, some applications, such as a driving directions application or a merchant finder application, require timely data, initiated by the mobile station user. Other types of applications performing some kind of user tracking may require data only sporadically, with the delay between location requests varying as a function of mobile station position. One of the most obvious and important aspects of ABS is positioning, i.e., the ability to determine the position of a mobile station in the network. One example of a widely recognized positioning technology is the Global Positioning System (GPS). In addition to GPS, other positioning techniques typically rely on various means of triangulation of the signal from cell sites serving a mobile station. In addition, the serving cell site can be used as a fix for location of the user. Geographic data is another important aspect of any location system. Geographic Information Systems (GIS) provide the tools to provision and administer base map data such as man-made structures (streets, buildings) and terrain (mountains, rivers). GIS is also used to manage point-of-interest data such as location of gas stations, restaurants, nightclubs, etc. Finally, GIS information also includes information about the radio frequency characteristics of the mobile network. This allows the system to determine the serving cell site of the user. Finally, it is not enough to be able to position the mobile user and know the map data around that position. There must also be provided a location management function to process positioning and GIS data on behalf of ABS applications. The location management function is middleware that acts as a gateway and mediator between positioning equipment and the LBS/ABS infrastructure. Among other things, the location management function may be employed to convert positioning information into useful location information and make it available for various ABS applications. In conventional wireless networks, a request/answer mechanism involving the location management function and one or more network entities is used to determine position information regarding a mobile station in the network. Network entities that can receive location requests and thus may be involved in the request/answer mechanism include base station controllers (BSC), mobile switching centers (MSC), home location registers (HLR), visited location registers (VLR), gateway mobile location centers (GMLC), serving mobile location centers (SMLC), mobile positioning centers (MPC) and positioning determining entities (PDE), among other possibilities. The request/answer mechanism is typically implemented by leveraging the signaling that is supported by both of today's prevailing wireless network protocols, namely American National Standards Institute (ANSI)-41 and Global System for Mobility (GSM). Although the prevailing SS7 signaling is able to support this request/answer mechanism, other transport mechanisms may also be used for this purpose. For example, the Wireless Intelligent Network (WIN) standard—also known as IS-848 and based on the ANSI-41 protocol—provides for the position of a mobile station to be obtained in the following manner. The location management function at a given service control point interrogates an HLR using a specific position request (PosReq) message. The HLR knows the last VLR that served the mobile user. Accordingly, the HLR launches a request to this VLR for position information (such as a cell site identifier) and, upon receiving this information, sends it back to the service control point in a PosReq response message. As can be appreciated, conventional techniques require that the network be capable of specifically addressing each location request soon after it is generated. Moreover, in order for most ABS applications to be of any value, it will be necessary to request user location information at intervals of minutes or less. It is therefore apparent that the network will become increasingly, if not overly, congested as it attempts to satisfy frequent requests on behalf of each ABS application, for each user of interest. As a result, the switching and transport capacity of a wireless network will be eroded by the burdensome requirements of obtaining location information in a conventional manner. Against this background, there is clearly a need to enable ABS applications by obtaining and using valuable location information without surpassing available bandwidth and load limits within the wireless communications network. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to a first broad aspect, the present invention provides computer-readable media tangibly embodying a program of instructions executable by a computing device to implement a method, the computing device being capable of interfacing with a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, the method comprising: determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. According to a second broad aspect, the present invention provides a method for use in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, comprising: determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. According to a third broad aspect, the present invention provides a system for use in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, comprising: means for determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and means for outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. According to a fourth broad aspect, the present invention provides a computer readable storage medium containing a program element for execution by a computing device to implement a method in a communications network adapted to provide alert-based services defined for a plurality of mobile stations and a variety of alert conditions, the program element including: program code means for determining an expected earliest future time at which at least one alert condition is capable of being met by a particular mobile station; and program code means for outputting a data element indicative of a requirement to obtain updated location data about the particular mobile station in advance of the expected earliest future time. According to a fifth broad aspect, the present invention provides a data processing device for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: an input capable of receiving updated location data about the mobile stations; and a processing unit connected to the input, the processing unit being capable of: determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire of an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. According to a sixth broad aspect, the present invention provides a method for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: receiving updated location data about the mobile stations; determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. According to a seventh broad aspect, the present invention provides a system for use in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: means for receiving updated location data about the mobile stations; means for determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and means for generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. According to an eighth broad aspect, the present invention provides computer-readable media tangibly embodying a program of instructions executable by a computing device to implement a method in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, the method comprising: receiving updated location data about the mobile stations; determining, on the basis of the updated location data about a particular mobile station, for which alert-based services, if any, at least one corresponding alert condition is met by the particular mobile station; and generating a trigger to fire an alert associated with each alert-based service for which at least one corresponding alert condition has been met by the mobile station. According to a ninth broad aspect, the present invention provides a system for providing alert-based communication services for which corresponding alert conditions to be met by mobile stations are defined, comprising: an alert engine capable of firing alerts associated with the alert-based communication services if location data regarding the mobile stations is indicative of the mobile stations meeting the alert conditions corresponding to the alert-based communication services. According to a tenth broad aspect, the present invention provides a method of accessing a data structure for obtaining an earliest expected travel time between a current location and a plurality of alert regions, the data structure containing data regarding a subdivision of a network into cells for which a respective alert region is the nearest to all points in the cell, the method comprising: using a point-location data structure to determine which cell contains the current location; using the table to determine the alert region associated with the cell found in step (a); and using a cost function to determine the travel time from the current location to the alert region found in step (b). According to an eleventh broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: an input for receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; a scheduler processing the expiry times data for determining an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; an output for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by the scheduler. According to a twelfth broad aspect, the present invention provides a computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a scheduling module for accepting as input expiry times data indicative of a plurality of expiry times relating to respective location requests for computing an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; an output module for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by the scheduler. According to a thirteenth broad aspect, the present invention provides a method for scheduling servicing of location requests by a PDE, comprising: receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; processing the expiry times data for determining an order for servicing the location requests by the position determination equipment at least in part on a basis on the expiry times of the location requests; interfacing with the PDE for allowing the PDE to service the location requests according to the determining. According to a fourteenth broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: an input for receiving data elements from an entity, the data elements indicative of respective location requests; the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; a scheduler for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; an output for interfacing with the PDE allowing the PDE to service the location requests according to the determining. According to a fifteenth broad aspect, the present invention provides a method for scheduling servicing of location requests by a PDE, comprising: receiving data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; interfacing with the PDE allowing the PDE to service the location requests according to the determining. According to a sixteenth broad aspect, the present invention provides a computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a scheduling module for accepting as input data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data, the scheduling module being operative for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; an output module for interfacing with the PDE allowing the PDE to service the location requests according to the determining. According to a seventeenth broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: an input for receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests; the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; a scheduler for: identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; an output for issuing the common location query. According to an eighteenth broad aspect, the present invention provides a method for scheduling servicing of location requests by a PDE, comprising: receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (ii) when to issue the common location query to the PDE; issuing the common location query. According to a nineteenth broad aspect, the present invention provides a computer readable storage medium including a program element for execution by a processor to implement an apparatus for scheduling servicing of location requests by a PDE, comprising: a scheduling module for accepting a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data, the scheduling module being operative for: identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; an output module for issuing the common location query. According to a twentieth broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: Input means for receiving expiry times data indicative of a plurality of expiry times relating to respective location requests; Scheduler means for processing the expiry times data for determining an order for servicing the location requests by the PDE at least in part on a basis on the expiry times of the location requests; output means for interfacing with the PDE allowing the PDE to service the location requests according to the order determined by the scheduler. According to a twenty-first broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: input means for receiving data elements from an entity, the data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; scheduling means for determining when location requests are to be serviced, the determining being such that the servicing of at least some delayed-type location requests is postponed artificially; output means for interfacing with the PDE allowing the PDE to service the location requests according to the determining. According to a twenty-second broad aspect, the present invention provides an apparatus for scheduling servicing of location requests by a PDE, comprising: input means for receiving a plurality of data elements from an entity, the plurality data elements indicative of respective location requests, the location requests including delayed-type location requests, a location request data element associated with a delayed-type location request including expiry time data; scheduling means for: identifying among the delayed-type location requests, two or more delayed-type location requests that can be serviced by a common location query to the PDE: determining at least in part on the basis of the respective expiry times of the delayed-type location requests identified at (i) when to issue the common location query to the PDE; and output means for issuing the common location query. According to a twenty-third broad aspect, the present invention provides a memory for storing data for access by an application program being executed on a data processing device used in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, comprising: a secondary memory for holding a plurality of data structures, the data structures being associated with respective non-overlapping time intervals, each of the data structures containing information relevant to a respective category of alert conditions that requires a current time to be included in the time interval associated with that data structure; a primary memory for storing the one data structure associated with the time interval that includes the current time. According to a twenty-fourth broad aspect, the present invention provides a method of creating a data structure for access by an application program being executed on a data processing device used in a communications network adapted to provide alert-based services for which corresponding alert conditions to be met by mobile stations are defined, each alert condition corresponding to an alert region, comprising: defining a subdivision of the network into nodes; computing, for each node, the nearest alert region; merging together into a single cell for each alert region, those nodes having that alert region as the nearest alert region; maintaining a data structure that is indicative of the locations covered by each cell and the alert condition associated with that cell. According to a twenty-fifth broad aspect, the present invention provides a method of delivering an alert-based communications service relevant to a mobile station in a communications network, wherein the alert-based communications service is associated with an alert condition to be satisfied by the mobile station, comprising: obtaining location data about the mobile station for a first time instant; predicting location data about the mobile station for a second time instant after the first time instant based on the location data about mobile station for the first time instant; if the mobile station is predicted to be within the alert region at the second time instant, triggering the firing of an alert at or after the second time instant. These and other aspects and features of the present invention will now become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying drawings. |
Quinoline derivatives and their use as tyrosine kinase inhibitors |
The invention concerns quinoline derivatives of Formula (I) wherein each of Z, m, R1, n and R3 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease. |
1. A quinoline derivative of the Formula I wherein Z is an O, S, SO, SO2, N(R2) or C(R2)2 group, wherein each R2 group, which may be the same or different, is hydrogen or (1-6C)alkyl; m is 0, 1, 2, 3 or 4; each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula: Q1-X1— wherein X1 is a direct bond or is selected from O, S. SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (1-6C)alkyl, and Q1 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R1)m is (1-3C)alkylenedioxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CH═CH and C≡C wherein R5 is hydrogen or (1-6C)alkyl or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═ or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula: Q2-X2— wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (1-6C)alkyl, and Q2 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)allyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula: —X3-Q3 wherein X3 is a direct bond or is selected from 9, S, SO, SO2, N(R7), CO, CH(R7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (1-6C)alkyl, and Q3 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C) alynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula: —X4—R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C)alkyl, (2-SC)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; n is 0, 1, 2 or 3; and R3 is halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-SC)alkyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)allkl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)allcyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula: —X6—R11 wherein X6 is a direct bond or is selected from O and N(R12), wherein R12 is hydrogen or (1-6C)alkyl, and R11 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1−6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula: —X7-Q5 wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R13), CO, CH(OR13), CON(R13), N(R13)CO, SO2N(R13), N(R13)SO2, C(R13)2O, C(R13)2S and N(R13)C(R13)2, wherein R13 is hydrogen or (1-6C)alkyl, and Q5 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy, and any heterocyclyl group within Q5 optionally bears 1 or 2 oxo or thioxo substituents, or a pharmaceutically-acceptable salt thereof. 2. A quinoline derivative of the Formula I as claimed in claim 1 wherein m is 1 or 2, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-0.6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino and N-(1-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula: Q1-X1— wherein X1 is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (1-6C)alkyl, and Q1 is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-16C)alkyl or X1 is a direct bond and Q1 is aryl-(1-6C)alkyl, cycloalkyl-(1-6C)allyl, heteroaryl-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CH═CH and C≡C wherein R5 is hydrogen or (1-6C)alkyl, or, when the inserted group is N(R5), R5 may also be (2-6C)alkanoyl, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno groups or a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-0.6C)alkanoyloxy, (2-6C)alkanoylamino and N-(1-6C)alkyl-(2-6C)alkanoylamino, or from a group of the formula: —X3-Q3 wherein X3 is a direct bond or is selected from O, N(R6), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (1-6C)alkyl, and Q3 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulphonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and (2-6C)alkanoyl, or optionally bears 1 substituent selected from a group of the formula: —X4—R8 wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl, and from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, N(R10) and CO, wherein R10 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl which optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents. 3. A quinoline derivative of the Formula I as claimed in claim 1 wherein R1 substituents may only be located at the 5-, 6- and/or 7-positions on the quinoline ring. 4. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH; m is 1 and the R1 group is located at the 5-, 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pent-4ynyloxy, hex-5-ynyloxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyranyloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidinylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(Me), CH═CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, N-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl or homopiperazin-1-yl group within a R1 substituent is optionally N-substituted with allyl, methylsulphonyl, acetyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3group, if present, is located at the 5- or 6-position of the 2,3-methylenedioxyphenyl group and is selected from fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 5. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH; m is 1 and the R1 group is located at the 6- or 7-position or m is 2 and each R1 group, which may be the same or different, is located at the 5- and 7-positions or at the 6- and 7-positions and R1 is selected from hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, 2-imidazol-1-ylethoxy, 2-(1,2,4-triazol-1-yl)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4piperidinobutoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, piperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 3-piperidin-3-ylpropoxy, 2-piperidin-4-ylethoxy, 3-piperidin-4-ylpropoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 4-piperazin-1-ylbutoxy, 2-homopiperazin-1-ylethoxy and 3-homopiperazin-1-ylpropoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CH═CH and C≡C, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more chloro groups or a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-isopropyl-N-methylamino, N-methyl-N-propylamino and acetoxy; and wherein any heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, Nt-methylcarbamoyl and N,N-dimethylcarbamoyl and a pyrrolidin-2-yl, piperidin-3-yl, piperidinyl, piperazin-1-yl or homopiperazin-1-yl-group within a R1 substituent is optionally N-substituted with 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl, the last 8 of which substituents each optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, methyl and methoxy, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; and n is 0 or 1 and the R3 group, if present, is located at the 5- or 6-position of the 2,3-methylenedioxyphenyl group and is selected from fluoro, chloro, trifluoromethyl, cyano, hydroxy, methyl, ethyl, vinyl, allyl, ethynyl, methoxy and ethoxy; or a pharmaceutically-acceptable acid-addition salt thereof. 6. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is O or NH; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 4-dimethylaminobutoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy, 4diethylaminobutoxy, 2-diisopropylaminoethoxy, 3-diisopropylaminopropoxy, 4diisopropylaminobutoxy, 2-(N-isopropyl-N-methylamino)ethoxy, 3-(N-isopropyl-N-methylamino)propoxy, 4-%-isopropyl-N-methylamino)butoxy, 2-(N-isobutyl-N-methylamino)ethoxy, 3-(N-isobutyl-N-methylamino)propoxy, 4-(N-isobutyl-N-methylamino)butoxy, 2-N(N-allyl-N-methylamino)ethoxy, 3-(N-allyl-N-methylamino)propoxy, 4-(N-allyl-N-methylamino)butoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 4-pyrrolidin-1-ylbutoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 4-morpholinobutoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 4-piperidinobutoxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, N-cyanomethylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, N-cyanomethylpiperidin-4-ylmethoxy, 2-piperidin-3-ylethoxy, 2-V-methylpiperidin-3-yl)ethoxy, 3-piperidin-3-ylpropoxy, 3-(N-methylpiperidin-3-yl)propoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-piperidin-4-ylpropoxy, 3-(N-methylpiperidin-4-yl)propoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 4-homopiperidin-1-ylbutoxy, 2-piperazin-1-ylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-piperazin-1-ylpropoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-piperazin-1-ylbutoxy, 4-(4-methylpiperazin-1-yl)butoxy, 2-(4-cyanomethylpiperazin-1-yl)ethoxy, 3-(4-cyanomethylpiperazin-1-yl)propoxy, 4-(4-cyanomethylpiperazin-1-yl)butoxy, 2-(2-piperazin-1-ylethoxy)ethoxy, 2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy, 2-chloroethoxy, 3-chloropropoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-tetrahydropyran-4-ylethoxy, 3-tetrahydropyranylpropoxy, 2-pyrrol-1-ylethoxy, 3-pyrrol-1-ylpropoxy, 2-(2-pyridyloxy)ethoxy, 3-(2-pyridyloxy)propoxy, 2-(3-pyridyloxy)ethoxy, 3-(3-pyridyloxy)propoxy, 2-(4-pyridyloxy)ethoxy, 3-(4-pyridyloxy)propoxy, 2-pyridylmethoxy, 3-pyridylmethoxy and 4-pyridylmethoxy, and wherein any CH2 group within the second R1 group that is attached to two carbon atoms optionally bears a hydroxy group on said CH2 group, and wherein any heteroaryl group within the second R1 group optionally bears 1 or 2 substituents selected from chloro, cyano, hydroxy and methyl, and any heterocyclyl group within the second R1 group optionally bears 1 or 2 substituents selected from hydroxy, methyl and oxo; and n is 0 or n is 1 and the R3 group is located at the 6-position of the 2,3-methylenedioxyphenyl group and is selected from chloro and bromo; or a pharmaceutically-acceptable acid-addition salt thereof. 7. A quinoline derivative of the Formula I as claimed in claim 1 wherein: Z is NH or O; m is 2 and the first R1 group is a 6-methoxy group and the second R1 group is located at the 7-position and is selected from hydroxy, methoxy, 2-bromoethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-hydroxy-3-methoxypropoxy, 2-(2-hydroxyethoxy)ethoxy, 2-prop-2-ynylaminoethoxy, 2-(E-methyl-N-prop-2-ynylamino)ethoxy, 3-N-methyl-N-prop-2-ynylamino)propoxy, 3-(2,5-dimethylpyrrol-1-yl)propoxy, 3-pyrrolidin-1-ylpropoxy, 3-(3-fluoropyrrolidin-1-yl)propoxy, 3-(3,3-difluoropyrrolidin-1-yl)propoxy, 3-(2,5-dimethyl-3-pyrrolin-1-yl)propoxy, 3-morpholinopropoxy, 2-hydroxy-3-morpholinopropoxy, 2-fluoro-3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 3-piperidinopropoxy, 3-(4-hydroxypiperidin-1-yl)propoxy, 3-(4-fluoropiperidin-1-yl)propoxy, 3-(4,4-difluoropiperidin 1-yl)propoxy, 0.3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy, 2-fluoro-3-(1,2,3,6-tetrahydropyridin-1-yl)propoxy, 4-(1,2,3,6-tetrahydropyridin-1-yl)butoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-fluoro-3-(4-methylpiperazin-1-yl)propoxy, 4-(4-methylpiperazin-1-yl)butoxy, 2-(4-allylpiperazin-1-yl)ethoxy, 3-(4-allylpiperazin-1-yl)propoxy, 3-(4-methylsulphonylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy, 3-(4-acetylpiperazin-1-yl)propoxy, 4-(4-acetylpiperazin-1-yl)butoxy, 3-(4-acetylpiperazin-1-yl)-2-hydroxypropoxy, 3-(4-cyanomethylpiperazin-1-yl)propoxy, 3-chloropropoxy and 3-bromopropoxy; and n is 0, 1 or 2 and each R3 group, if present, is selected from fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, ethynyl, methylthio, methylsulphonyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl, 2-cyanoethyl, dimethylaminomethyl, phenyl, benzyl, 5-oxazolyl and morpholinomethyl; or a pharmaceutically-acceptable acid-addition salt thereof. 8. A process for the preparation of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 which comprises (a) for the production of those compounds of the Formula I wherein Z is an O, S or N(R2) group, the reaction of a quinoline of the Formula II wherein L is a displaceable group and m and R1 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a compound of the Formula III wherein Z is O, S, or N(R2) and n, R3 and R2 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means; (b) for the production of those compounds of the Formula I wherein at least one R1 group is a group of the formula Q1-X1— wherein Q1 is an aryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl group or an optionally substituted alkyl group and X1 is an oxygen atom, the coupling of a quinoline of the Formula V wherein m, R1, Z, n and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an appropriate alcohol wherein any functional group is protected if necessary whereafter any protecting group that is present is removed by conventional means; (c) for the production of those compounds of the Formula I wherein R1 is an amino-substituted (1-6C)alkoxy group, the reaction of a compound of the Formula I wherein R1 is a halogeno-substituted (1-6C)alkoxy group with a heterocyclyl compound or an appropriate amine; (d) for the production of those compounds of the Formula I wherein R1 is a hydroxy group, the cleavage of a quinoline derivative of the Formula I wherein R1 is a (1-6C)alkoxy or arylmethoxy group; (e) for the production of those compounds of the Formula I wherein an R1 group contains a primary or secondary amino group, the cleavage of the corresponding compound of the Formula I wherein the R1 group contains a protected primary or secondary amino group; (f) for the production of those compounds of the Formula I wherein an R1 group contains a (1-6C)alkoxy or substituted (1-6C)alkoxy group or a (1-6C)alkylamino or substituted (1-6C)alkylamino group, the alkylation of a quinoline derivative of the Formula I wherein the R1 group contains a hydroxy group or a primary or secondary amino group as appropriate; (g) for the production of those compounds of the Formula I wherein R1 is an amino-hydroxy-disubstituted (1-6C)alkoxy group, the reaction of a compound of the Formula I wherein the R1 group contains an epoxy-substituted (1-6C)alkoxy group with a heterocyclyl compound or an appropriate amine; (h) for the production of those compounds of the Formula I wherein an R1 group contains a hydroxy group, the cleavage of the corresponding compound of the Formula I wherein the R1 group contains a protected hydroxy group; (i) for the production of those compounds of the Formula I wherein Z is a SO or 802 group, wherein an R1 or R3 substituent is a(1-6C)alkylsulphinyl or (1-6C)alkylsulphonyl group or wherein an R1 or R3 substituent contains a SO or SO2 group, the oxidation of a compound of Formula I wherein Z is a S group or wherein an R1 or R3 substituent is a (1-6C)alkylthio group or wherein an R1 or R3 substituent contains a S group as appropriate; (j) for the production of those compounds of the Formula I wherein an R1 group contains a (1-6C)alkoxy or substituted (1-6C)alkoxy group or a (1-6C)alkylamino or substituted (1-6C)alkylamino group, the reaction of a quinoline derivative of the Formula VI wherein L is a displaceable group and Z, n and R3 have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an alcohol or amine as appropriate; or (k) the conversion of a compound of the Formula I wherein an R1 or R3 substituent is a halogeno group into a further compound of the Formula I wherein the R1 or R3 substituent is a cyano, ethynyl or phenyl group; and when a pharmaceutically-acceptable salt of a quinoline derivative of the Formula I is required, it may be obtained by reaction of said quinoline derivative with a suitable acid using a conventional procedure. 9. A pharmaceutical composition which comprises a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier. 10. A quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 for use in a method of treatment of the human or animal body by therapy. 11. The use of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1 in the manufacture of a medicament for use as an anti-invasive agent in the containment and/or treatment of solid tumour disease. 12. A method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a quinoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1. |
Processing system |
In a first aspect, a first substrate processing system is provided that includes (1) a chamber having a plurality of openings through which a substrate may be transported; (2) a substrate carrier opener coupled to a first one of the plurality of openings; (3) a thermal processing chamber coupled to a second one of the plurality of openings; and (4) a wafer handler contained within the chamber, having a substrate clamping blade and a blade adapted to transport high temperature substrates. Numerous other aspects are provided, as are methods and computer program products in accordance with these and other aspects. |
1 A substrate processing system comprising: a chamber having a plurality of openings through which a substrate may be transported; a substrate carrier opener coupled to a first one of the plurality of openings; a thermal processing chamber coupled to a second one of the plurality of openings; and a wafer handler contained within the chamber, having a substrate clamping blade and a blade adapted to transport high temperature substrates. 2 The system of claim 1 wherein the substrate clamping blade and the blade adapted to transport high temperature substrates are vertically stacked. 3 The system of claim 2 wherein the wafer handler is adapted to elevate so as to position a desired one of the clamping blade and the blade adapted to transport high temperature substrates at a desired elevation. 4 The system of claim 1 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 5 The system of claim 1 wherein the substrate clamping blade comprises a sensor for detecting the presence of a substrate properly positioned thereon. 6 The system of claim 5 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 7 The system of claim 1 further comprising a track contained within the chamber and having the wafer handler mounted thereon so as to travel therealong. 8 The system of claim 1 further comprising a valve assembly for selectively sealing the second one of the plurality of openings, the valve assembly comprising: a housing comprising a first opening on a first side, and a threshold portion, the housing being adapted for coupling to a chamber surface having an opening therein, such that a substrate may be transferred through the first opening of the housing and the chamber opening and such that the threshold portion is positioned between the first opening of the housing and the chamber opening; the threshold portion having one or more inlets adapted to supply a curtain of gas across the chamber opening; and a sealing surface positioned within the housing to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough. 9 The system of claim 8 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon, and wherein the clamping blade comprises a sensor for detecting the presence of a substrate properly positioned thereon. 10 The system of claim 8 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 11 The system of claim 8 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 12 The system of claim 1 further comprising: a cooling station contained within the chamber. 13 The system of claim 12 wherein the cooling station comprises a plurality of cooling platforms. 14 The system of claim 13 wherein the plurality of cooling platforms are vertically stacked. 15 The system of claim 13 wherein the plurality of cooling platforms are cooled via a common fluid supply that supplies pressurized fluid thereto. 16 The system of claim 14 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon, and wherein the clamping blade comprises a sensor for detecting the presence of a substrate properly positioned thereon. 17 The system of claim 14 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 18 The system of claim 14 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 19 The system of claim 14 further comprising a valve assembly for selectively sealing the second one of the plurality of openings, the valve assembly comprising: a housing comprising: a first opening on a first side; and a threshold portion, the housing being adapted for coupling to a chamber surface having an opening therein, such that a substrate may be transferred through the first opening of the housing and the chamber opening and such that the threshold portion is positioned between the first opening of the housing and the chamber opening, the threshold portion having one or more inlets adapted to supply a curtain of gas across the chamber opening; and a sealing surface positioned within the housing and adapted to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough. 20 A substrate processing system comprising: a chamber having a plurality of openings through which a substrate may be transported; and a wafer handler contained within the chamber having a substrate clamping blade and a blade adapted to transport high temperature substrates. 21 The system of claim 20 wherein the substrate clamping blade and the blade adapted to transport high temperature substrates are vertically stacked. 22 The system of claim 21 wherein the wafer handler is adapted to elevate so as to position a desired one of the clamping blade and the blade adapted to transport high temperature substrates at a desired elevation. 23 The system of claim 20 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon, and wherein the clamping blade comprises a sensor fox detecting the presence of a substrate properly positioned thereon. 24 The system of claim 20 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 25 The system of claim 20 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 26 The system of claim 20 further comprising a track contained within the chamber and having the wafer handler mounted thereon so as to travel therealong. 27 The system of claim 20 further comprising: a valve assembly for sealing one of the plurality of openings in the chamber, comprising: a housing comprising: a first opening on a first side; and a threshold portion, the housing being adapted for coupling to a chamber surface having an opening therein, such that a substrate may be transferred through the first opening of the housing and the chamber opening and such that the threshold portion is positioned between the first opening of the housing and the chamber opening, the threshold portion having one or more inlets adapted to supply a curtain of gas across the chamber opening; and a sealing surface positioned within the housing to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough. 28 The system of claim 27 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon, and wherein the clamping blade comprises a sensor for detecting the presence of a substrate properly positioned thereon. 29 The system of claim 27 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 30. The system of claim 27 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 31 The system of claim 20 further comprising: a cooling station contained within the chamber. 32 The system of claim 31 wherein the cooling station comprises a plurality of cooling platforms. 33 The system of claim 32 wherein the plurality of cooling platforms are vertically stacked. 34 The system of claim 32 wherein the plurality of cooling platforms are cooled via a common fluid supply that supplies pressurized fluid thereto. 35 A substrate handler comprising: a substrate clamping blade; and a blade adapted to transport high temperature substrates. 36 The substrate handler of claim 35 wherein the substrate clamping blade and the blade adapted to transport high temperature substrates are vertically stacked. 37 The substrate handler of claim 36 wherein the wafer handler is adapted to elevate so as to position a desired one of the clamping blade and the blade adapted to transport high temperature substrates at a desired elevation. 38 The substrate handler of claim 35 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon, and wherein the clamping blade comprises a sensor for detecting the presence of a substrate properly positioned thereon. 39 The substrate handler of claim 35 wherein the blade adapted to transport high temperature substrates comprises a sensor for detecting the presence of a substrate properly positioned thereon. 40 The substrate handler of claim 35 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 41 The substrate handler of claim 39 wherein the sensor comprises an emitter and a detector, and wherein a non-refractive material is positioned adjacent the emitter and the detector so as to prevent an emitted signal from coupling through the blade to the detector. 42 A method of transporting a substrate, comprising: picking up a first substrate with a clamping blade of a substrate handler; clamping the first substrate via the clamping blade; transporting the first substrate to a thermal processing chamber via the clamping blade; processing the first substrate within the thermal processing chamber to thereby heat the first substrate; extracting the heated first substrate from the thermal processing chamber via a blade of the substrate handler that is adapted to transport a high temperature substrate; and transporting the heated first substrate via the high temperature blade. 43 The method of claim 42 wherein transporting the substrate to the thermal processing chamber via the clamping blade occurs at a higher speed than the speed at which the heated substrate is transported via the high temperature blade. 44 The method of claim 42 further comprising placing a second substrate in the thermal processing chamber via the clamping blade after the heated first substrate is extracted from the thermal processing chamber, and while the heated first substrate is held by the high temperature blade, such that the substrate exchange occurs without intermission. 45 The method of claim 44 further comprising sensing, via a clamping blade sensor, whether the clamping blade has properly clamped a substrate prior to transporting the substrate to another processing location. 46 The method of claim 44 further comprising sensing, via a high temperature blade sensor, whether a substrate is properly positioned on the high temperature blade prior to transporting the substrate via the high temperature blade. 47 The method of claim 45 wherein the clamping blade comprises a detector for detecting the presence of a substrate properly positioned thereon. 48 The method of claim 45 further comprising signaling an error if proper placement of a substrate is not sensed on the clamping blade and preventing transport of the improperly placed substrate. 49 The method of claim 46 further comprising signaling an error if proper placement of a substrate is not sensed on the high temperature blade and preventing transport of the improperly placed substrate. 50 The method of claim 44 further comprising transporting the first heated substrate to a cooling platform. 51 A valve assembly adapted to seal an opening in a chamber, comprising: a housing comprising: a first opening on a first side; and a threshold portion, the housing being adapted for coupling to a chamber surface having an opening therein, such that a substrate may be transferred through the first opening and the chamber opening and such that the threshold portion is positioned between the first opening and the chamber opening, the threshold portion having one or more inlets adapted to supply a curtain of gas across the chamber opening; and a sealing surface positioned within the housing to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough. 52 The valve assembly of claim 51 wherein the housing includes one or more openings adapted to exhaust gas from an interior region of the housing. 53 A system comprising: a chamber having an opening in a chamber surface; a valve assembly adapted to seal the opening in the chamber surface, comprising: a housing comprising: a first opening on a first side; and a threshold portion, the housing being adapted for coupling to the chamber surface having the opening therein, such that a substrate may be transferred through the first opening and the chamber opening and such that the threshold portion is positioned between the first opening and the chamber opening, the threshold portion having one or more inlets adapted to supply a curtain of gas across the chamber opening; and one or more openings adapted to exhaust gas from an interior region of the housing; a sealing surface positioned within the housing to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough; and a controller programmed to: control a flow of gas through the one or more inlets into the interior region of the housing; and control a flow of gas through the one or more openings out of the interior region of the housing. 54 A method comprising: providing a processing system having: a transfer chamber; a processing chamber coupled to the transfer chamber, the processing chamber having an opening that allows a substrate to be transferred between the transfer chamber and the processing chamber; and a valve assembly coupled to the processing chamber and adapted to selectively seal the opening of the processing chamber, the valve assembly having an interior region adjacent the opening of the processing chamber; vacuum pumping the interior region of the valve assembly; and exhausting any gas removed from the interior region of the valve assembly by the vacuum pumping. 55 The method of claim 54 wherein vacuum pumping the interior region of the valve assembly comprises vacuum pumping the interior region of the valve assembly to a vacuum level below that of the processing chamber and the transfer chamber. 56 The method of claim 55 wherein exhausting any gas removed from the interior region of the valve assembly by the vacuum pumping comprises removing gas emitted through the opening of the processing chamber before the gas enters the transfer chamber, 57 The method of claim 55 wherein vacuum pumping the interior region of the valve assembly to a vacuum level below that of the processing chamber and the transfer chamber comprises; flowing an inert gas into the interior region of the valve assembly at a first rate; and removing the inert gas from the interior region of the valve assembly at a second rate that is greater than the first rate. 58 The method of claim 55 wherein vacuum pumping the interior region of the valve assembly to a vacuum level below that of the processing chamber and the transfer chamber comprises: detecting a pressure level within the interior region of the valve assembly; and adjusting at least one of a flow rate of gas into the valve assembly and a flow rate of gas out of the valve assembly so that the vacuum level of the interior region of the valve assembly is below that of the processing chamber and the transfer chamber. 59 A method comprising: providing a processing system having: a processing chamber having an opening that allows a substrate to be loaded into the processing chamber; and a valve assembly coupled to the processing chamber and adapted to selectively seal the opening of the processing chamber, the valve assembly having an interior region adjacent the opening of the processing chamber; and flowing a gas through the interior region of the valve assembly so as to generate a curtain of gas across the opening of the processing chamber. 60 The method of claim 59 further comprising: vacuum pumping the interior region of the valve assembly; and exhausting any gas removed from the interior region of the valve assembly by the vacuum pumping. 61 The method of claim 59 wherein vacuum pumping the interior region of the valve assembly comprises vacuum pumping the interior region of the valve assembly to a vacuum level below that of the processing chamber. 62 A method comprising: providing a processing system having: a processing chamber having an opening that allows a substrate to be loaded into the processing chamber; and a valve assembly coupled to the processing chamber and adapted to selectively seal the opening of the processing chamber, the valve assembly having an interior region adjacent the opening of the processing chamber; and vacuum pumping the interior region of the valve assembly so as to remove gas emitted from the opening of the processing chamber. 63 An end effector for transporting a substrate, comprising: a blade adapted to support a substrate within a first plane defined by the blade; and a sensor for detecting the presence of a substrate on the blade, the sensor comprising an emitter adapted to emit a beam such that the beam is within the first plane and a detector adapted to receive and detect the beam, the emitter and detector being coupled to the blade such that a substrate supported by the blade within the first plane interrupts the beam. 64 The end effector of claim 63, wherein the beam is a light beam. 65 The end effector of claim 63, wherein the beam is a light beam, and wherein the blade comprises a refractive material that will allow light to couple therethrough. 66 The end effector of claim 65 wherein the refractive material is adapted to withstand a temperature greater than 70° C. 67 The end effector of claim 65 wherein the refractive material is adapted to withstand a temperature of 600° C. 68 The end effector of claim 65, wherein the refractive material of the blade comprises quartz. 69 The end effector of claim 65, further comprising a non-refractive material adjacent the sensor so as to prevent light from coupling with the refractive material of the blade. 70 The end effector of claim 69, wherein the non-refractive material comprises a coating. 71 The end effector of claim 69, wherein the non-refractive material comprises silicon carbide. 72 The end effector of claim 69, wherein the detector is at least partially surrounded by the non-refractive material so as to deter erroneous detection of reflected or refracted light from the light beam. 73 The end effector of claim 72, wherein the non-refractive material comprises metal. 74 The end effector of claim 64, wherein a beam gain threshold of the sensor is adjustable so as to allow compensation for reflection and refraction of the light beam. 75 The end effector of claim 74, wherein the blade comprises a refractive material that will allow light to couple therethrough. 76 The end effector of claim 69, wherein the emitter is at least partially surrounded by the non-refractive material so as to deter reflection or refraction of the light beam. 77 A method of positioning a substrate on a blade and determining whether the substrate is properly positioned thereupon, comprising: providing an end effector comprising: a blade comprising a refractive material, the blade being adapted to support a substrate within a first plane; and a sensor coupled to the blade for detecting the presence of a substrate on the blade, the sensor being adapted to emit a beam such that the beam is within the first plane and to receive and detect the emitted beam; positioning a substrate on the blade; and determining whether the substrate is properly positioned on the blade based on whether the sensor detects or fails to detect the beam. 78 The method of claim 77, further comprising preventing movement of the end effector if the sensor detects the beam. 79 The method of claim 77, further comprising providing a controller in communication with the sensor, adapted to prevent movement of the end effector if the sensor detects the beam. |
<SOH> BACKGROUND <EOH>In the field of substrate processing, improvements in substrate handling speed and reliability can translate into significant cost savings, and improved substrate quality. Likewise, a reduction in footprint (i.e., the projected floor space occupied by a processing system), and/or a reduction in equipment cost and complexity may result in reduced cost per substrate processed. Accordingly, substrate processing systems that improve throughput speed, reduce equipment cost and complexity and/or reduce the potential for substrates to be exposed to particles are desired. |
<SOH> SUMMARY <EOH>An inventive substrate processing system that transfers both hot and cold substrates is provided, as is an inventive method of transferring and processing substrates within the system. Also employed are inventive apparatuses and methods for sensing substrates on a substrate handler blade, for employing a ventilated valve assembly to deter toxic processing gases from entering an ambient environment, and/or for cooling substrates within a transfer chamber. Each such apparatus and method may be employed with the inventive system or with other processing systems and methods, as will be apparent from the figures and description provided below. More specifically, in a first aspect of the invention, a first substrate processing system is provided that includes (1) a chamber having a plurality of openings through which a substrate may be transported; (2) a substrate carrier opener coupled to a first one of the plurality of openings; (3) a thermal processing chamber coupled to a second one of the plurality of openings; and (4) a wafer handler contained within the chamber, having a substrate clamping blade and a blade adapted to transport high temperature substrates. In a second aspect of the invention, a second substrate processing system is provided that includes (1) a chamber having a plurality of openings through which a substrate may be transported; and (2) a wafer handler contained within the chamber having a substrate clamping blade and a blade adapted to transport high temperature substrates. In a third aspect of the invention, a substrate handler is provided that includes (1) a substrate clamping blade; and (2) a blade adapted to transport high temperature substrates. In a fourth aspect of the invention, a valve assembly is provided that is adapted to seal an opening in a chamber. The valve assembly includes a housing having a first opening on a first side and a threshold portion. The housing is adapted for coupling to a chamber surface having an opening therein, such that a substrate may be transferred through the first opening and the chamber opening and such that the threshold portion is positioned between the first opening and the chamber opening. The threshold portion has one or more inlets adapted to supply a curtain of gas across the chamber opening. The valve assembly further includes a sealing surface positioned within the housing to selectively (1) seal the chamber opening, and (2) retract from the chamber opening so as not to obstruct substrate passage therethrough. Numerous other aspects are provided, as are methods and computer program products in accordance with these and other aspects of the invention. Other features and aspects of the present invention will become more fully apparent from the following detailed description, the appended claims and the accompanying drawings. |
Polyphase motor |
A multiphase motor includes a fixed part or stator energized by electric coils and a mobile part or rotor including N pairs of poles radially magnetized in alternate directions, N being not less than 4 while being other than a multiple of 3, and the stator including P×9 identical poles spaced apart by 40°/P, the stator poles being assembled consecutively by three so as to define a phase with a W-shaped circuit, assembling three consecutive stator poles, the central stator pole bearing the winding of the phase. At least one element for detecting the positions of the rotor is arranged in a common stage with the stator poles, in a housing substantially equidistant between two consecutive stator poles not belonging to a common phase. |
1. Multiphase motor comprises: a fixed part or stator energized by electric coils, and, a mobile part or rotor having N pairs of poles radially magnetized in alternate directions, N being higher than or equal to 4 while being other than a multiple of 3, wherein said stator is comprised of P×9 identical poles, spaced apart by 40°/P, said stator poles being assembled consecutively three by three so as to define a phase comprised of a W-shaped circuit, grouping three consecutive stator poles, the central stator pole bearing winding of said phase, and wherein at least one element for detecting the position of the rotor is arranged in one and the same stage as the stator poles, in a housing substantially equidistant between two consecutive stator poles not belonging to one and the same phase. 2. Multiphase motor according to claim 1, further comprising a plurality of position-detection elements, numbering the same as there are phases positioned in a housing defined between each of these phases. 3. Multiphase motor according to claim 1, wherein said housing is defined by said consecutive stator poles not belonging to one and the same phase. 4. Multiphase motor according to claim 2, wherein said position-detection elements are further comprised of means for controlling the motor in auto-switching mode. 5. Multiphase motor according to claim 1, wherein said position-detection elements are Hall-effect probes. 6. Multiphase motor according to claim 5, wherein said probes have analog outputs. 7. Multiphase motor according to claim 5, wherein said probes have digital outputs. 8. Multiphase motor according to claim 1, wherein said central stator poles bearing the coil of a phase are comprised of elements inserted at the level of the stator structure. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Such motors are for example described in FR-2 754 953. Thus, reference is made in particular to a polyphase motor consisting, on the one hand, of a fixed part or stator, energized by electric coils and, on the other hand, a magnetized mobile part or rotor. The latter includes N 1 pairs of poles radially magnetized in alternate directions, N 1 being equal to 4 or 5. As to the stator, it includes N 2 identical poles, N 2 being equal to 9 so that these poles are spaced apart by 40°. Besides, they are assembled consecutively 3 by 3 so that each phase consist of a W-shaped circuit, grouping three consecutive stator poles. The central pole of the W bears the winding of said phase. Besides, the central poles of two W-shaped circuits are angularly spaced apart by 120°. These elements are arranged in a common stage, that is substantially in the game plane, in order to optimize costs and size of the parts they are comprised of, such as the magnets. For this type of motor, it is usual to detect the displacement of the mobile rotor part in the magnetic circuit. In fact, this rotor part induces a flow variation, a variation that can be detected by an electromagnetic type position sensor. Therefore, such actuators are capable of providing a representative image of the position of the load energized directly or, more frequently, through a reducing gear, thanks to a position control, therefore requiring an appropriate electronic control device and a position sensor for the mobile organ. This sensor is, in most cases, of the potentiometric, magnetic, or optic type, and it is mounted on the back of the actuator. Naturally, this position sensor requires, for this reason, an extra space at the level of the actuator, not to mention that some of its constituent elements have to be extended in order to permit this detection of the rotation of the mobile organ. In this context, moreover, one has to make sure that the presence of these sensors does not influence the propagation of the magnetic flows between different the stator poles. Furthermore, in such a construction, the electric connection of this or these sensors and that of the actuator to the electronic control card turns out to be relatively complex. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>Within the scope of a first inventive step, an attempt has been made to solve problems resulting from the externalization of the sensors, integrating them directly and ideally into the actuator, in particular in a same plane as the stator windings. In a second inventive step, one has tried to find a solution, not only capable of eliminating the above-mentioned constraints, but also not requiring any geometrical or generic modifications of the various elements which the actuator is comprised of, modifications that would be a handicap as regards costs of manufacturing and assembly, standardization and easy operation. To this end, the invention relates to a polyphase motor consisting, on the one hand, of a fixed part or stator energized by electric coils and, on the other hand, a mobile part or rotor including N pairs of poles radially magnetized in alternate directions, N being not higher than or equal to 4 while being other than a multiple of 3, and said stator having P×9 identical poles spaced apart by 40°/P, said stator poles being assembled consecutively three by three so as to define a phase consisting of a W-shaped circuit, grouping three consecutive stator poles, the central stator pole bearing the winding of said phase. According to the invention, it includes at least one element for detecting the position of the rotor arranged in a game stage as the stator poles, in a housing substantially equidistant between two consecutive stator poles not belonging to one and the game phase. Advantageously, said housing is delimited by said consecutive stator poles not belonging to one and the same phase. According to another feature of the invention, said position-detection elements are Hall-effect probes. According to another feature of the invention, said probes have analog outputs. According to another feature of the invention, said probes have digital outputs. According to another feature of the invention, the central stator poles bearing the winding of a phase are in the form of elements inserted at the level of the stator structure. Such a design has the advantage that the coils can be mounted on these central poles, not by a mere engagement, but by winding around the latter. Finally, this allows to increase the volume of copper, which results into generating more efficiency for the motor. Furthermore, it should be noted that this way of designing the stator structure of the motor also allows to increase the surface of these central poles in front of the rotor and, therefore, that of all stator poles. This invention will be better understood when reading the following description accompanied by the attached drawings referring to embodiments given by way of examples. |
Human mini-antibody cytotoxic for tumor cells which express the ERB-B2 receptor |
The invention refers to a fully human miniantibody (scFv), called Erbicin, specific for the receptor ErbB2, with a pharmacological, in particular antitumour, activity. It has been obtained from a larger fagmidic library (Griffin 1.) (19) of human synthetic scFv by panning (affinity selection on antigen) carried out on live cells that express various levels of ErbB2. The invention relates also to the DNA and aniino acid sequences of said antibody, to the procedure for isolating it, to its use in therapy. |
1-54. (canceled) 55. An isolated recombinant single chain anti-ErbB2 antibody of human origin able to inhibit growth of cells expressing the ErbB2 receptor characterized in that it comprises at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences. 56. A recombinant antibody according to claim 55 further comprising as Complementarity Determining Regions (CDR) amino acid sequences corresponding to seq. ID N 4, 6 and 8 or amino acid sequences corresponding to seq. ID N 14, 16 and 18. 57. A recombinant antibody according to claim 55 able to inhibit the tyrosine kinase activity of the receptor. 58. A recombinant antibody according to claim 55 characterized in that it is capable of inhibiting the growth of SKBR3 cells by at least 65%. 59. A recombinant antibody according to claim 58 characterized in that it comprises a VH region corresponding to SEQ ID. N. 2 and a VL region corresponding to SEQ ID. N 12, covalently linked by a protein linker. 60. A recombinant antibody according to claim 59 comprising amino acid sequence SEQ ID. N 20. 61. A recombinant antibody according to claim 59 further comprising conservative amino acid substitutions. 62. A fusion protein characterized in that it comprises at least one of the amino acid sequences according to claim 55. 63. A fusion protein according to claim 62 wherein said amino acid sequences are fused to constant regions from human antibodies, or to toxins or to molecules with cytotoxic effect. 64. A fusion protein according to claim 63 wherein said constant regions from human antibodies are from immunoglobulins G1. 65. A fusion protein according to claim 63 capable to recognize specifically ErbB2-positive tumor cells and selectively kill them. 66. A fusion protein according to claim 62 wherein at least one of the sequences selected in the group consisting of: seq. ID N2, seq. ID N12, seq. ID N20 or amino acid sequences sharing at least 90% identity with said sequences are fused to a human enzyme with ribonuclease activity. 67. A fusion protein according to claim 66 wherein said human enzyme is the human pancreatic ribonuclease. 68. A fusion protein according to claim 67 characterized in that it is able to perform at least one of the following activities: (i) it specifically recognizes receptor-positive cells; (ii) it is endowed with enzymatic (ribonucleolytic) activity; (iii) tested on receptor-positive and receptor-negative cell lines it specifically kills receptor-positive cells, hence it is capable of discriminating between target and non-target cells. 69. An isolated nucleotide sequence encoding the recombinant antibody according to claim 55. 70. Nucleotide sequence according to claim 69 selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19. 71. Vector comprising at least one of the nucleotide sequences according to claim 70 or fragments thereof. 72. Vector according to claim 71 characterized in that it is an expression vector. 73. Vector according to claim 71 characterized in that it comprises SEQ. ID. N 19. 74. Vector according to claim 71 characterized in that it is a phagemid. 75. A bacteriophage vector according to claim 74 characterized in that it comprises at least one of the sequences selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19. 76. A bacteriophage according to claim 75 characterized in that it expresses on its surface at least one copy of the recombinant antibody comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences. 77. Cells transformed with the vector according to claim 71. 78. Pharmaceutical composition comprising as an active ingredient the antibody according to claim 55 in combination with suitable diluents and/or eccipients, and/or adjuvants. 79. Diagnostic composition comprising as an active ingredient the antibody according to claim 55. 80. Pharmaceutical composition comprising as an active ingredient the nucleotide sequences according to claim 70 in combination with suitable diluents and/or eccipients, and/or adjuvants. 81. Pharmaceutical composition comprising as an active ingredient the bacteriophage according to claim 75 in combination with suitable diluents and/or eccipients, and/or adjuvants. 82. Pharmaceutical composition comprising as an active ingredient the vector according to claim 71 in combination with suitable diluents and/or eccipients, and/or adjuvants. 83. A therapeutic method to inhibit the proliferation of cells overexpressing the Erb-B2 receptor comprising administering to a subject in need of the therapy a therapeutically effective amount of the antibody according to claim 55. 84. A therapeutic method according to claim 83 wherein said Erb-B2 overexpressing cells are selected from the group consisting of: mammary carcinomas, ovarian carcinomas, colon carcinomas, lung carcinomas, salivary glands tumor, gastric tumor. 85. A therapeutic method to inhibit the proliferation of cells overexpressing the Erb-B2 receptor comprising administering to a subject in need of the therapy a therapeutically effective amount of the bacteriophage according to claim 75. 86. A therapeutic method according to claim 85 wherein said Erb-B2 overexpressing cells are selected from the group consisting of: mammary carcinomas, ovarian carcinomas, colon carcinomas, lung carcinomas, salivary glands tumor, gastric tumor. 87. A kit for the preparation of the antibodies according to claim 55 comprising any one of the nucleotide sequences selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19. 88. A kit for the preparation of the vectors according to claim 72 comprising any one of the nucleotide sequences selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19. 89. A kit for the preparation of the bacteriophages according to claim 75 comprising any one of the nucleotide sequences selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19. 90. A process for the preparation of a bacteriophage expressing on its surface at least one copy of the recombinant antibody comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences comprising the following steps: transformation of an E. coli strain with the vector according to claim 74 selection of the E. coli strain superinfection with M13 phage purification of the scFv bacteriophage by precipitation with PEG. 91. A process according to claim 90 further comprising at least two cycles of subtractive selection, each consisting of a selection on cell lines expressing ErbB2 receptor, and on cell lines not expressing the ErbB2 receptor. 92. A process according to claim 91 wherein the former two selection cycles are performed with SKBR3 cell line from human mammary carcinoma expressing high levels of ErbB2, and with a cell line from human epidermoid carcinoma (A431), expressing low levels of ErbB2; the latter two selection cycles are performed using the same above mentioned combination. 93. A process according to claim 92 wherein SKBR3 and A431 cell lines are replaced by NIH3T3 cell line transfected with DNA encoding human ErbB2, and non-transfected NIH3T3, respectively. 94. A process according to claim 93 wherein each selection cycle comprises the steps of: labeling of positive cells with a fluorophore; phage incubation with a mixture of previously labeled positive cells and “negative”, non labeled cells; cell washings and isolation of fluorescent cells; phage elution at acid pH; cell infection of TG1 strain (E. coli), with the phages obtained from the elution; identification of clones specific for ErbB2 by an assay selected among: ELISA, Western blotting, and flow cytometric analyses; preparation of the isolated scFv expressing phages. 95. A process for the preparation of a recombinant single chain anti-ErbB2 antibody of human origin able to inhibit growth of cells expressing the ErbB2 receptor and comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences, characterized in that the vectors according to claim 17 are used. 96. A process according to claim 95 comprising the following steps: infection of E. coli cultures with a phagemid vector comprising at least one of the nucleotide sequences selected from the group consisting of: SEQ ID. N. 1, SEQ ID. N. 11, SEQ ID. N. 19, and nucleotide sequences characterized for being at least 80% identical to SEQ ID. N. 1, to SEQ ID. N. 11 or to SEQ ID. N. 19.; growth in culture medium containing antibiotics up to an absorbancy value of 1 O.D.; induction with IPTG; expression; preparation of the periplasmic extract; isolation of a recombinant single chain anti-ErbB2 antibody of human origin able to inhibit growth of cells expressing the ErbB2 receptor comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences from the periplasmic extract by affinity chromatography; purification by gel-filtration. 97. A process according to claim 96 wherein the periplasmic extract is prepared by incubating cells for 1 h on ice in 50 mM Tris HCl pH 7.4 containing 20% sucrose and 1 mM EDTA. 98. A process for the preparation of the fusion protein according to claim 64 comprising the following steps: (i) isolation of at least one of the nucleotide sequence encoding a single chain anti-ErbB2 antibody of human origin able to inhibit growth of cells expressing the ErbB2 receptor and comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences; (ii) fusion of said DNA sequence to a cDNA encoding the constant regions (CH2 and CH3) and the hinge peptide from human heavy chains of immunoglobulin G1; (iii) expression of the resulting fusion cDNA in eucaryotic cells. 99. A process for the preparation of the fusion protein according to claim 67 comprising essentially the following steps: (i) fusion of the nucleotide sequence encoding a single chain anti-ErbB2 antibody of human origin able to inhibit growth of cells expressing the ErbB2 receptor and comprising at least one of the following amino acid sequences: SEQ ID. N 2 (VH region), SEQ ID. N 12 (VL region), SEQ ID. N 20 or amino acid sequences with at least a 90% identity to said sequences to the cDNA encoding human pancreatic RNase, said fusion being preferably performed by interposing a DNA fragment encoding a spacer peptide according to SEQ ID N. 24; (ii) expression of the resulting fusion cDNA in Escherichia coli; (iii) isolation and characterization of the recombinant protein. 100. A method of treating Erb-B2 positive tumors in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 78. 101. A method of treating Erb-B2 positive tumors in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 80. 102. A method of treating Erb-B2 positive tumors in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 81. 103. A method of treating Erb-B2 positive tumors in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 81. |
<SOH> FIELD OF THE INVENTION <EOH>The present invention refers to a human mini-antibody cytotoxic for tumor cells that express the ErbB2 receptor, its corresponding sequence, the procedure for isolating it, and its use in therapy. |
<SOH> SUMMARY OF THE INVENTION <EOH>The object of the present invention is a fully human scFv, named Erbicin, specific for the ErbB2 receptor, with pharmacological, particularly antitumour, activity. Erbicin has been isolated from a very large phagemid library (Griffin.1 library) (19) of human synthetic scFv by panning (affinity selection on antigen) carried out on live cells that express different levels of ErbB2. It has been found that the single chain fragment of a human anti-ErbB2 antibody, called Erbicin, shows biological properties not described for other anti-ErbB2 scFv isolated so far. In fact Erbicin binds specifically to the ErbB2 receptor, it is internalized by target cells, it severely inhibits receptor phosphorylation, and displays a powerful growth inhibition of all ErbB2 positive cell lines tested. In addition, a clear cytotoxic effect was evidenced towards ErbB2 hyper-expressing SKBR3 cells, in which apoptotic death is induced. These features are present both in soluble Erbicin, and in its phage format (Ph-Erbicin). Another object of the invention are the isolated sequences listed in the description, relative to the corresponding variants, mutants and portions. Particularly relevant are the portions present in bold type within the sequences. Another object of the invention are the pharmaceutical compositions comprising as active principle Erbicin itself in its phage format (Ph-Erbicin), or Erbicin fused to constant regions from human antibodies, or to toxins, or to molecules with cytotoxic potential, such as enzymes with ribonuclease or protease activity (clearly known to the expert in the field). Another object of the invention is the use of the scFv according to the invention in therapy, particularly as an antitumour agent, more particularly for the treatment of tumors in which cells express the ErbB2 receptor, such as cells from mammary, ovary or lung carcinomas. Additional objects of the invention will be evident from the following detailed description of the invention. |
Depositing a tantalum film |
This invention relates to a method of depositing a tantalum film in which α-Ta dominates and to methods of electroplating copper using such films. The films have a thickness of less than 300 nm and are formed by depositing a seed layer of an organic containing low dielectric constant insulating layer and sputtering tantalum onto the seed layer at a temperature below 250° C. |
1 A method of depositing Ta film in which α-Ta dominates having a thickness <300 nm comprising depositing a seed layer of an organic-containing low dielectric constant insulating layer and sputtering Tantalum onto the seed layer at a temperature below 250° C. 2 A method as claimed in claim 1 wherein the seed layer is a methyl-doped silicon oxide. 3 A method as claimed in claim 1 wherein the seed layer is formed by reacting a silicon containing organic compound and an oxidising agent in the presence of a plasma and setting the resultant film such that the carbon containing groups are contained therein. 4 A method as claimed in claim 3 wherein the seed layer is set by exposing it to an hydrogen containing plasma. 5 A method as claimed in claim 1 wherein the surface of the seed layer has been etched away prior to tantalum deposition. 6 A method as claimed in claim 1 wherein the seed layer is heated prior to tantalum deposition. 7 A method as claimed in claim 1 wherein the tantalum source to substrate separation is at least 200 mm. 8 A method as claimed in claim 7 wherein the tantalum source to substrate distance is between 200 mm and 250 mm . 9 A method as claimed in claim 1 where the tantalum deposition is by unbalanced magnetron sputtering. 10 A method as claimed in claim 1 where the substrate is biased. 11 A method as claimed in claim 1 wherein copper is deposited on the Ta film. 12 A method as claimed in claim 1 wherein the seed layer is an inter metal dielectric layer. 13 A method as claimed in claim 1 wherein a significant proportion of the tantalum material arrives at the seed layer in an ionised state. 14 A method of electroplating copper on to a profiled surface of a semiconductor wafer or the like, including depositing a tantalum layer onto the profiled surface and electroplating a copper layer directly onto the barrier layer wherein the tantalum layer has a resistivity of less than 50 micro.ohm.cm. 15 A method as claimed in claim 14 wherein the tantalum layer is at least substantially alpha phase tantalum. 16 A method as claimed in claim 14 wherein the tantalum layer is deposited using a method as claimed in claim 1. 17 A method as claimed in claim 1 wherein the resistivity of the tantalum layer is between 20 and 40 micro.ohm.cm. 18 A method as claimed in claim 17 wherein the resistivity is about 25 micro.ohm.cm. 19 A method of electroplating copper onto a profiled surface of a semiconductor wafer to fill a recess in the surface, including depositing a tantalum barrier layer onto the profiled surface and electroplating a copper layer directly onto the barrier layer to achieve filling of the recess, wherein the tantalum layer has a resistivity of less than 50 micro.ohm.cm. |
Susceptor for epitaxial growth and epitaxial growth method |
A susceptor for use in an epitaxial growth apparatus and method where a plurality of circular through-holes are formed in the bottom wall of a pocket in an outer peripheral region a distance of up to about ½ the radius toward the center of the circular bottom wall. The total opening surface area of these through-holes is 0.05 to 55% of the surface area of the bottom wall. The opening surface area of each of the through-holes provided at this outer peripheral region is 0.2 to 3.2 mm2 and the density of the through-holes is 0.25 to 25 per cm2. After a semiconductor wafer is mounted in the pocket, epitaxial growth is carried out while source gas and carrier gas (i.e., reactive gas) is made to flow on the upper surface side of the susceptor and carrier gas is made to flow on the lower surface side. |
1. An epitaxial growth susceptor comprising a substantially circular bottom wall and a sidewall encompassing the bottom wall to form a pocket for mounting a semiconductor wafer, wherein a plurality of through-holes having a substantially circular or polygonal opening are provided in the bottom wall within a region of up to approximately half the radius of the bottom wall from the outer periphery to the center, in a radial direction, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted; and a total opening surface area of the plurality of through-holes is between 0.05 to 55% of the surface area of the bottom wall. 2. The epitaxial growth susceptor of claim 1, further provided with a support means at the bottom wall or the sidewall for supporting the semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. 3. The epitaxial growth susceptor of claim 1, wherein a SiC film is adhered to a surface of the susceptor and to inner wall surfaces of each of the through-holes. 4. The epitaxial growth susceptor of claim 1, wherein at least a portion of the bottom wall that includes the through-holes is made of a solid SiC material. 5. The epitaxial growth susceptor of claim 1, wherein the through-holes are inclined with respect to the thickness direction of the bottom wall. 6. An epitaxial growth susceptor comprising a substantially circular bottom wall and a sidewall encompassing the bottom wall to form a pocket for mounting a semiconductor wafer, wherein a plurality of through-holes having a substantially circular or polygonal opening are provided in the bottom wall within a region of up to approximately half the radius of the bottom wall from the outer periphery to the center, in a radial direction, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted; and the opening surface area of each through-hole is taken to be between 0.2 to 3.2 mm2, and the density of the through-holes is taken to be between 0.25 to 25 per cm2. 7. The epitaxial growth susceptor of claim 6, further provided with a support means at the bottom wall or sidewall for supporting the semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. 8. The epitaxial growth susceptor of claim 6, wherein a SiC film is adhered to a surface of the susceptor and to inner wall surfaces of each of the through-holes. 9. The epitaxial growth susceptor of claim 6, wherein at least a portion of the bottom wall that includes through-holes is made of a solid SiC material. 10. The epitaxial growth susceptor of claim 6, wherein the through-holes are inclined with respect to the thickness direction of the bottom wall. 11. An epitaxial growth method for growing an epitaxial film on a surface of a semiconductor wafer by mounting the semiconductor wafer within a susceptor pocket and supplying source gas and carrier gas to the upper surface side of the susceptor and supplying carrier gas to the lower surface side of the susceptor, wherein the susceptor comprises a substantially circular bottom wall and a sidewall encompassing the bottom wall to form a pocket for mounting the semiconductor wafer, wherein a plurality of through-holes having a substantially circular or polygonal opening are provided in the bottom wall within a region of up to approximately half the radius of the bottom wall from the outer periphery to the center, in a radial direction, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted. 12. The epitaxial growth method of claim 11, further provided with a support means at the bottom wall or sidewall for supporting the semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. 13. The epitaxial growth method of claim 11, wherein a SiC film is adhered to a surface of the susceptor and to the inner wall surfaces of each of the through-holes. 14. The epitaxial growth method of claim 11, wherein at least a portion of the bottom wall that includes the through-holes is made of a solid SiC material. 15. The epitaxial growth method of claim 11, wherein the carrier gas supplied to the lower surface side of the susceptor is hydrogen-containing gas supplied at between 3 to 100 liters per minute. 16. The epitaxial growth method of claim 11, wherein the through-holes are inclined with respect to the thickness direction of the bottom wall. 17. An epitaxial growth method for growing an epitaxial film on a surface of a semiconductor wafer by mounting the semiconductor wafer within a pocket of a susceptor and supplying source gas and carrier gas to the upper surface side of the susceptor and supplying carrier gas to the lower surface side of the susceptor, wherein the susceptor comprises a substantially circular bottom wall and a sidewall encompassing the bottom wall to form a pocket for mounting the semiconductor wafer, wherein a plurality of through-holes having a substantially circular or polygonal pattern are provided in the bottom wall within a region of up to approximately half the radius of the bottom wall from the outer periphery to the center, in a radial direction, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted; and the opening surface area of each through-hole is taken to be between 0.2 to 3.2 mm2, and the density of the through-holes is taken to be between 0.25 to 25 per cm2. 18. The epitaxial growth method of claim 17, further provided with a support means at the bottom wall or sidewall for supporting the semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. 19. The epitaxial growth method of claim 17, wherein a SiC film is adhered to a surface of the susceptor and to the inner wall surfaces of each of the through-holes. 20. The epitaxial growth method of claim 17, wherein at least a portion of the bottom wall that includes the through-holes is made of a solid SiC material. 21. The epitaxial growth method of claim 17, wherein the carrier gas supplied to the lower surface side of the susceptor is hydrogen-containing gas supplied at between 3 to 100 liters per minute. 22. The epitaxial growth method of claim 17, wherein the through-holes are inclined with respect to the thickness direction of the bottom wall. 23. An epitaxial growth susceptor comprising a substantially circular bottom wall and a sidewall encompassing the bottom wall to form a pocket for mounting a semiconductor wafer, wherein a plurality of through-holes having a substantially circular or polygonal opening are provided in the bottom wall within a region of up to approximately half the radius of the bottom wall from the outer periphery to the center, in a radial direction, wherein at least one row of through-holes is included within at least the region of the bottom wall on which the semiconductor wafer is mounted, adjacent holes in a row of said at least one row of through-holes being connected by a channel. 24. The epitaxial growth susceptor of claim 23, wherein said channel has a width that is up to 1.5 times the diameter of a through-hole and a depth such that a cross-sectional area of a channel is from about 50% to about 100% an opening surface area of a through-hole. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In recent years, epitaxial wafers where an epitaxial film is formed on the surface of a silicon wafer are widely used as silicon wafers for use with MOS devices. These epitaxial wafers provide improved yield for gate oxidation films of MOS devices, and have superior characteristics such as the reduction of parasitic capacitance, the prevention of soft errors, improved gettering performance, and improved mechanical strength. With this epitaxial wafer structure, in the prior art where a batch method is implemented so as to perform epitaxial growth process simultaneously on a plurality of silicon wafers, it has become difficult to maintain compatibility with large diameter silicon wafers and single wafer processing epitaxial growth apparatus have therefore mainly been employed. In recent years, epitaxial growth apparatus for use with large diameter wafers capable of performing epitaxial growth process on wafers of a diameter of 300 mm or more have been developed. With these single wafer type epitaxial growth apparatus, methods of transferring a wafer into and out of the apparatus, and onto a susceptor, can be classified into two types: a type where a wafer is transferred using a Bernoulli chuck method or elevating method using a transportation jig; and a type where the lower surface of the wafer is supported using pins, so that transfer is achieved by raising the pins. However, in each case, a semiconductor wafer is mounted on a single susceptor arranged horizontally in the apparatus. The wafer is then raised to a high temperature using a heat source such as infrared lamps, etc. located around the wafer. Epitaxial growth is then initiated at the wafer surface by flowing a reactive gas over the surface of the wafer at a high-temperature while rotating the susceptor. The following is a description, with reference to FIG. 19 to FIG. 23 , of a susceptor for epitaxial growth and an epitaxial growth method of the prior art. FIG. 19 is a cross-sectional view schematically showing an epitaxial growth apparatus of the prior art. FIG. 20 is a plane view schematically showing a susceptor for epitaxial growth of the prior art. FIG. 21 is a further cross-sectional view schematically showing a susceptor for epitaxial growth of the prior art. FIG. 22 is a further cross-sectional view schematically showing a design of a susceptor for epitaxial growth of the prior art. FIG. 23 is a further plane view schematically showing of a susceptor for epitaxial growth of the prior art. As shown in FIG. 19 to FIG. 22 , the epitaxial growth apparatus (hereinafter referred to as “apparatus”) 1 internally contains an epitaxial film forming chamber (hereinafter referred to as “film forming chamber”) 2 . This film forming chamber 2 is equipped with an upper dome 3 , a lower dome 4 , and a dome fitting 5 . The upper dome 3 and the lower dome 4 are made from a transparent material such as quartz, etc., with a susceptor 10 and silicon wafer W being heated using a plurality of halogen lamps 6 arranged above and below the apparatus 1 . The susceptor 10 is then rotated as a result of an outer part of the lower surface of the susceptor 10 engaging with a support arm 8 linked to a susceptor rotating shaft 7 . A carbon base material, coated on the surface with a SiC film, is adopted as the susceptor 10 . The susceptor 10 is disc-shaped as shown in FIG. 20 , or is disc-shaped having a recess as shown in FIG. 21 , and supports the entire rear surface of the silicon wafer W. This recess is comprised of a pocket 10 a housing the silicon wafer W and is comprised of a substantially circular bottom wall and a sidewall surrounding this bottom wall. A total of three through-holes 10 b are formed every 120 degrees around the outside of the susceptor 10 . Elevating pins 9 for raising and lowering the silicon wafer W are inserted loosely at each through-hole 10 b . Elevation of the elevating pins 9 is carried out by a lift arm 11 . A gas supply opening 12 and gas exhaust opening 13 are located facing each other at a position of the dome fitting 5 that faces the susceptor 10 . Reactive gas, that has been formed by diluting source gas such as SiHCl 3 , etc. with hydrogen gas (carrier gas) and mixed with a microscopic amount of dopant, is supplied from the gas supply opening 3 so as to flow parallel (in a horizontal direction) to the surface of the silicon wafer W. The provided reactive gas is exhausted to the outside of the apparatus 1 by gas exhaust outlet 13 after passing over the surface of the silicon wafer W to bring about epitaxial film growth. In recent years, uniform distribution of resistivity within epitaxial film surfaces has become an extremely important quantitative requirement for epitaxial wafers. However, high-temperature processing is required during epitaxial growth. This causes dopant within the wafer to be diffused outwards during the epitaxial growth process and causes a so-called “autodoping” phenomenon where dopant is diffused outwards and is incorporated into the epitaxial film. This causes unevenness in dopant concentration within the formed epitaxial film and causes the resistivity at the outer edge part of the epitaxial film to decrease, and resistivity distribution across the surface to be uneven. In particular, when epitaxial growth is carried out at a concentration lower than the dopant concentration of the silicon wafer W, this causes regions where the dopant concentration of the epitaxial film is outside of the required specifications to occur and causes device yield to decrease. In order to prevent the deterioration of the resistivity distribution within the epitaxial film, silicon wafers are coated with a protective film so that autodoping from the silicon wafer W is prevented. Silicon oxide films produced by CVD techniques are typically used as the protective films for preventing autodoping and a polycrystaline silicon film formed on the rear surface of the wafer can contribute to gettering capabilities and may also function as a protective film for reducing autodoping. Typically only the rear surface is coated with the silicon oxide film. The edges of the wafer are not coated, but any out diffusion of dopant from the wafer edge is minimal because of the small surface area. The use of a wafer having a protective film is therefore effective in suppressing autodoping. However, this requires dedicated equipment such as CVD processing tools, etc. and this requires additional processing. There are also cases that demand the use of an epitaxial wafer where the protective layer must be removed from the rear surface after the epitaxial growth process. This requirement depends on the type of processing required. In this case, it is necessary to perform additional processing such as polishing and etching, etc. in order to remove the protective film after the epitaxial growth process. This additional processing causes the cost of producing epitaxial wafers to increase and in recent years this increased cost has made it impossible to produce low cost epitaxial wafers. An epitaxial wafer that has been processed with an oxide backseal and then the oxide stripped, has a dopant concentration at the rear surface that is similar to the bulk of the substrate. An epitaxial wafer that has been processed without an oxide backseal has a rear surface that is depleted of dopant concentration. This depleted rear surface may be beneficial for subsequent processing by the device manufacturer. In order to resolve these problems, an epitaxial growth process method has been proposed that employs a susceptor 10 formed with a large number of through-holes 10 c over substantially the entire surface of the bottom wall of the pocket 10 a of the susceptor 10 , as shown, for example, in FIG. 23 . However, when there are through-holes 10 c dispersed over substantially the whole surface of the bottom wall of the pocket, degradation of the nanotopology of the surface of the epitaxial wafer occurs due to temperature differences between regions where through-holes 10 c are formed and regions where through-holes 10 c are not formed and these nanotopographical degradation regions occur across the entire wafer surface. In the prior art, a region from a central position of the bottom wall of this pocket to a radius of ½ is a region for measuring the temperature of the epitaxial growth process in the epitaxial growth apparatus. When through-holes 10 c are then formed in this region, variations occur in measurement of the process temperature and as a result there is an increased possibility that slip will occur in the wafer. On the other hand, uniform epitaxial film thickness is also an important quantitative demand placed upon epitaxial wafers. The aforementioned reactive gas is supplied to the film-forming chamber 2 in a manner parallel with respect to the surface of the silicon wafer W ( FIG. 22 ). Part of the reactive gas flowing into the film-forming chamber 2 therefore collides with the outer wall of the susceptor 10 . As a result, the gas flow of reactive gas is disturbed in the vicinity of the upper edge part of the susceptor 10 and it is therefore difficult for the reactive gas to make sufficient contact with the outer edge surface of the silicon wafer W. As a result, this causes a phenomenon to occur where the epitaxial film of this portion becomes thin compared with the surface portion. This phenomenon occurs regardless of whether or not a protective film for preventing autodoping is present at the rear surface of the silicon wafer W. Methods have therefore been disclosed in the prior art to prevent lowering of film thickness at the outer parts of the epitaxial film through control of the epitaxial growth process. To give concrete examples, there is a method (1) where the speed of growth of an epitaxial film is lowered, and a method (2) where the height D from the surface of the bottom wall of the susceptor 10 to the upper end surface of the sidewall is lowered. This height D is typically 0.55 to 1.00 mm. However, according to the method (1) of lowering the growth speed, a longer period of time is required to grow the epitaxial film, and this impacts the productivity with which the silicon wafers are produced. Further, when the susceptor height D is lowered in (2), the silicon wafer W being processed may become miscentered in the pocket 10 a as the result of small vibrations. Moreover, the through-holes 10 c in the prior art are formed in a direction perpendicular to the bottom wall of the susceptor 10 . When the through-holes are formed perpendicular to the susceptor pocket bottom wall, radiant heat can pass through the through-holes and can be absorbed directly on the rear surface of the silicon wafer. This can cause non-uniform heating of the silicon wafer. |
<SOH> SUMMARY OF THE INVENTION <EOH>In a first aspect of the invention, there is provided an epitaxial growth susceptor (hereinafter sometimes referred to simply as “susceptor”) with a pocket formed from a substantially circular bottom wall and a side wall encompassing the bottom wall, where a semiconductor wafer is to be mounted in the pocket. A plurality of through-holes with openings that are substantially circular or polygonal are provided at the bottom wall within an outer periphery region in a radial direction from the outer periphery of the bottom wall to the center, over a distance that is up to approximately {fraction (1/2)} of the radius, with the through-holes being included within at least a portion of the region of the bottom wall on which the semiconductor wafer is mounted. The total opening surface area of the plurality of through-holes is 0.05 to 55% of the surface area of the bottom wall. Circular, elliptical or a similar shape may be given as substantially circular shapes. Triangular, quadrangular, pentagonal, or other angular shapes may be given as polygonal shapes. The type of wafer is by no means limited. For example, a silicon wafer or gallium arsenide wafer or SOI or selectively grown epitaxial wafers may be used. If the total opening surface area of the plurality of through-holes is smaller than 0.05% of the surface area of the bottom wall, dopant that diffuses outwards from the rear surface of the wafer is not effectively exhausted. Further, when the total opening surface area exceeds 55%, slip begins to occur in the epitaxial wafer and the strength of the susceptor itself decreases due to a temperature difference between the central part and outer periphery of the wafer being large, and there are problems with the susceptor fracturing or the like during the epitaxial reaction. According to this first aspect of the invention, the plurality of though-holes are provided within an outer periphery region in a radial direction from the outside of the bottom wall to the center over a distance that is up to ½ of the radius. The through-holes are included within at least the region of the bottom wall on which the semiconductor wafer is mounted on. The total surface area of the openings of the through-holes is taken to be 0.05 to 55% of the surface area of the bottom wall. This improves uniformity of film thickness of the epitaxial film. Additionally, nanotopgraphically degraded regions of the epitaxial wafer surface that occur due to a temperature difference between the regions where a plurality of through-holes are formed in the bottom wall of the pocket and regions where the holes are not formed can be reduced., The slip caused by the forming of through-holes in the bottom wall of the pocket can also be prevented. Further, with semiconductor wafers where influence is exerted by autodoping from the rear surface of the wafer, it is possible to eliminate the influence of autodoping and to improve the uniformity of dopant concentration within the epitaxial film. In a second aspect of this invention, in the epitaxial growth susceptor there is further provided a support means at the bottom wall or sidewall for supporting the mounted semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. According to a susceptor structure where the entire rear surface of the semiconductor wafer is surface-supported, it is difficult for carrier gas such as hydrogen gas to become wrapped around the entire rear surface of the wafer. The effectiveness with which dopant is discharged from the rear surface of the wafer and is exhausted is therefore reduced. To this end, it is effective to form on the susceptor a support means for supporting the wafer by making surface contact, line contact or point contact with the outer periphery of the wafer so that a slight gap is formed between the rear surface of the wafer and the upper surface of the susceptor. In a third aspect of the invention, a SiC film is adhered to the surface of the susceptor and to inner wall surfaces of each of the through-holes. Exposed surfaces of the susceptor and inner surfaces of the through-holes are coated with a SiC film. Contamination from the susceptor base material, such as carbon contamination, etc., can therefore be reliably prevented. In a fourth aspect of the invention, at least the portion of the susceptor that includes the through-holes of the susceptor is made of a solid SiC material. The reason for making the portion of the susceptor that includes the through-holes of a solid SiC material is because it is difficult to coat all of the inside surfaces of the through-holes uniformly and because peeling of the SiC film tends to occur at parts of the inside surfaces of the through-holes. Contamination caused by the susceptor base material can be reliably prevented by forming the susceptor region where the through-holes are formed using a solid SiC material which is fabricated from solid SiC using a CVD technique, etc. It is also possible to form the entire susceptor from a solid SiC material. In a fifth aspect of the invention, the through-holes of the susceptor are inclined with respect to the thickness direction of the bottom wall. Namely, each of the through-holes is formed in the bottom wall inclined in such a manner that a central axis of each through-hole is not orthogonal with respect to the bottom wall plane but rather has a prescribed angle. The angle of inclination of (the central axes of) the through-holes with respect to the bottom wall surface is, for example, 20 to 70 degrees. The direction of inclination of the through-holes is by no means limited. Inclination from the upper surface of the bottom wall to the lower surface towards the inside of the bottom wall or towards the outside is possible. According to the fifth aspect of the invention, the radiant heat occurring at the part of the bottom wall where the through-holes are formed can therefore be decreased compared with the case where the through-holes are not inclined and the occurrence of uneven brightness at the rear surface of the semiconductor wafer can be suppressed. In a sixth aspect of this invention, there is provided an expitaxial growth susceptor with a pocket formed from a substantially circular bottom wall and a sidewall encompassing the bottom wall, where a semiconductor wafer is to be mounted within the pocket. A plurality of through-holes with openings that are substantially circular or polygonal are provided at the bottom wall within a region or a distance of up to approximately {fraction (1/2)} the radius from the outer periphery to the center in a radial direction, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is to be mounted. The opening surface area of each through-hole is taken to be 0.2 to 3.2 mm 2 , and the density of the through-holes is taken to be 0.25 to 25 holes per cm 2 . The reason the through-holes are not formed with an opening surface area less than 0.2 mm 2 is because of technical difficulties with mechanical machining precision. When through-holes where the opening surface area exceeds 3.2 mm 2 are formed, temperature distribution becomes uneven and nanotopographical degradation and the occurrence of slip becomes marked due to the opening surface area being too large. On the other hand, when the density of the through-holes is less than 0.25 holes per cm 2 , the amount of reactive gas flowing decreases and therefore a decrease of the film thickness at the outer periphery of the epitaxial film cannot be prevented, the effectiveness with which dopant discharged from the rear surface of the wafer is also small and therefore the influence of autodoping cannot be eliminated. When through-hole density exceeds 25 per cm 2 , the strength of the susceptor itself decreases and the susceptor may warp or fracture during the epitaxial growth process. According to the sixth aspect of the invention, the thickness uniformity of the epitaxial film is improved and the nanotopgraphically degraded regions of the epitaxial wafer surface that occur due to a temperature difference between the regions where a plurality of through-holes are formed in the bottom wall of the pocket and regions where the holes are not formed are reduced. The slip caused by the forming of through-holes in the bottom wall of the pocket can therefore be prevented. In the case of semiconductor wafers where influence is exerted by autodoping from the rear surface of the wafer, it is also possible to eliminate the influence of this autodoping and to improve the uniformity of dopant concentration within the epitaxial film surface. In a seventh aspect of this invention, the epitaxial susceptor according to the sixth aspect of the invention is further provided with a support means at the bottom wall or sidewall for supporting the mounted semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. In an eighth aspect of the invention, a SiC film is adhered to the surface of the susceptor of the sixth aspect of the invention and to inner wall surfaces of each of the through-holes. In a ninth aspect of the invention, at least the portion of the susceptor of the sixth aspect of the invention that includes the through-holes of the susceptor is made of a solid SiC material. In a tenth aspect of the invention, the through-holes of the susceptor of the sixth aspect of the invention are inclined with respect to the thickness direction of the bottom wall. In an eleventh aspect of the invention, there is provided an epitaxial growth method for growing an epitaxial film on a surface of a semiconductor wafer by mounting the semiconductor wafer within the susceptor pocket and supplying source gas and carrier gas to an upper surface side of the susceptor and supplying carrier gas to a lower surface side of the susceptor. The pocket is formed from a substantially round bottom wall and a sidewall encompassing the bottom wall, and a plurality of through-holes with openings that are substantially circular or polygonal are provided at the bottom wall within a region or a distance of up to approximately {fraction (1/2)} the radius from the outer periphery to the center, with through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted. The total opening surface area of the plurality of through-holes is 0.05 to 55% of the surface area of the bottom wall. A gas such as, for example, SiH 4 , SiH 2 Cl 2 , SiHCl 3 or SiCl 4 etc., is adopted as the source gas. Hydrogen gas or an inert gas may be adopted as the carrier gas. According to the eleventh aspect of the invention, after the semiconductor wafer is mounted within the pocket, epitaxial growth is carried out while flowing source gas and carrier gas on the upper surface side of the susceptor and flowing carrier gas on the lower surface side. Therefore, at the outer periphery of the susceptor, part of the source gas flowing on the upper surface side of the susceptor flows from a gap between the outer periphery of the semiconductor wafer and the sidewall of the susceptor down to the lower surface side of the susceptor via the through-holes as a result of negative pressure created by the carrier gas flowing on the lower surface side of the susceptor. A sufficient amount of source gas can therefore be supplied to the surface of the outer periphery of the wafer. This improves the thickness uniformity of the epitaxial film and reduces the nanotopographically degraded regions of the epitaxial wafer surface that occur due to a temperature difference between the regions where a plurality of through-holes are formed in the bottom wall of the pocket and regions where the holes are not formed because the through-holes are not formed in the region from the center of the bottom wall of the susceptor to a distance of at least ½ of the radius from the center. The slip caused by the forming of through-holes in the bottom wall of the pocket can therefore be prevented. Further, dopant is diffused outwards from the rear surface of a wafer during an epitaxial growth process when a semiconductor wafer with both front and rear surfaces constituted by a semiconductor single crystal surface is subjected to the epitaxial growth process. However, in the eleventh aspect of the invention dopant is discharged at the lower surface side of the susceptor due to the action of this negative pressure and it is difficult for this dopant to be incorporated into the epitaxial film. As a result, the influence of this autodoping from the rear surface of the wafer can be substantially eliminated and the uniformity of dopant concentration within the epitaxial film surface can be improved. This epitaxial growth process may also be applied to semiconductor wafers with oxide films or polycrystalline films formed on the rear surface thereof where the influence of autodoping is slight. Reduction in film thickness at the outer periphery of the epitaxial film can also be suppressed in this case. In a twelfth aspect of this invention, there is further provided an epitaxial growth method where the epitaxial growth susceptor in the eleventh aspect of the invention is provided with support means at the bottom wall or sidewall for supporting the mounted semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. In a thirteenth aspect of the invention, a SiC film is adhered to the surfaces of the susceptor of the eleventh aspect of the invention and to inner wall surfaces of each of the through-holes. In a fourteenth aspect of the invention, an epitaxial growth method is provided where at least the portion of the susceptor of the eleventh aspect of the invention that includes the through-holes of the susceptor is made of a solid SiC material. In a fifteenth aspect of the invention, an epitaxial growth method is provided where the carrier gas supplied to the lower surface side of the susceptor of the eleventh aspect of the invention is hydrogen containing gas supplied at 3 to 100 liters per minute. When the amount of carrier gas flowing at the lower surface side of the susceptor is less than 3 liters per minute, there is an insufficient amount of negative pressure generated and the dopant does not effectively flow through the susceptor through-holes. In this case the autodoping is excessive. When a flow of 100 liters per minute flow is exceeded, the effectiveness of exhausting the dopant is increased, but the carrier gas including the dopant is not discharged from the gas exhausting opening in an appropriate manner. Part of the carrier gas flows into the source gas and the distribution of resistivity within the epitaxial film deteriorates. In a sixteenth aspect of the invention, an epitaxial growth method is provided where the through-holes of the epitaxial growth susceptor of the eleventh aspect of the invention are inclined with respect to the thickness direction of the bottom wall. In a seventeenth aspect of the invention, there is provided an epitaxial growth method for growing an epitaxial film on a surface of a semiconductor wafer by mounting the semiconductor wafer within the susceptor pocket and supplying source gas and carrier gas to an upper surface side of the susceptor and supplying carrier gas to a lower surface side of the susceptor. The pocket is formed from a substantially round bottom wall and a sidewall encompassing the bottom wall, and a plurality of through-holes with openings that are substantially circular or polygonal are provided at the bottom wall within a region a distance of up to approximately ½ the radius from the outer periphery to the center, with the through-holes being included within at least the region of the bottom wall on which the semiconductor wafer is mounted. The opening surface area of each through-hole is taken to be 0.2 to 3.2 mm 2 , and the density of the through-holes is taken to be 0.25 to 25 per cm 2 . According to the seventeenth aspect of the invention, after the semiconductor wafer is mounted within the pocket of the susceptor, epitaxial growth is carried out while flowing source gas and carrier gas on the upper surface side of the susceptor and flowing carrier gas on the lower surface side. At this time, a negative pressure force acts at the outer peripheral part of the susceptor due to carrier gas flowing on the lower surface side of the susceptor causing part of the source gas flowing on the upper surface side of the susceptor to flow to the lower surface side of the susceptor via the through-holes. As a result, a sufficient amount of source gas can also be supplied to the surface of the outer periphery of the wafer, and the thickness of the epitaxial film can be made uniform. This uniformity of the epitaxial film can therefore be achieved regardless of whether or not a protective film for preventing autodoping is present at the rear surface of the silicon wafer. Nanotopographically degraded regions of the epitaxial wafer surface that occur due to a temperature difference between the regions where a plurality of through-holes are formed in the bottom wall of the pocket and regions where the holes are not formed can be reduced. The slip caused by the forming of through-holes in the bottom wall of the pocket can be prevented. Further, dopant is diffused outwards from the rear surface of the wafer during the epitaxial growth process in the case of a semiconductor wafer with both front and rear surfaces constituted by a semiconductor single crystal surface. However, dopant diffused outwards is exhausted to the lower surface side of the susceptor due to the action of the negative pressure. It is therefore difficult for the dopant to be taken into the epitaxial film. As a result, the influence of this autodoping from the rear surface of the wafer can be eliminated and the uniformity of dopant concentration within the epitaxial film surface can be improved. In an eighteenth aspect of this invention, there is further provided an epitaxial growth method where the epitaxial growth susceptor of the seventeenth aspect of the invention is provided with a support unit at the bottom wall or sidewall for supporting the mounted semiconductor wafer through surface contact, line contact or point contact with only the outer periphery of the semiconductor wafer. In a nineteenth aspect of the invention, an epitaxial growth method is provided where a SiC film is adhered to the surface of the susceptor of the seventeenth aspect of the invention and to inner wall surfaces of each of the through-holes in the epitaxial growth method. In a twentieth aspect of the invention, an epitaxial growth method is provided where at least the portion of the susceptor of the seventeenth aspect of the invention that includes the through-holes of the susceptor is made of a solid SiC material. In a twenty-first aspect of the invention, an epitaxial growth method is provided where the carrier gas supplied to the lower surface side of the susceptor of the seventeenth aspect of the invention is hydrogen containing gas supplied at 3 to 100 liters per minute. In a twenty-second aspect of the invention, an epitaxial growth method is provided where the through-holes of the susceptor of the seventeenth aspect of the invention are inclined with respect to the thickness direction of the bottom wall. |
Membrane electrode assembly of fuel cell |
In a MEA (membrane electrode assembly) of a fuel cell including an electrolyte membrane as an ion transfer medium arranged between a bipolar plate having a fuel side open groove in which fuel flows and a bipolar plate having an air side open groove in which air flows so as to form a fuel path with the fuel side open groove and form an air path with the air side open groove; and a catalyst electrode inserted into the fuel side open groove so as to be separated from the electrolyte membrane in order to form a fuel path with both sides thereof and induce electrochemical oxidation with the fuel, by activating action occurred on the fuel electrode in which fuel is supplied and the air electrode in which air is supplied, current generating efficiency can be improved. |
1. A MEA (membrane electrode assembly) of a fuel cell, comprising: an electrolyte membrane as an ion transfer medium interposed between a bipolar plate having a fuel side open groove in which fuel flows and a bipolar plate having an air side open groove in which air flows so as to form a fuel path with the fuel side open groove and form an air path with the air side open groove; and a catalyst electrode inserted into the fuel side open groove so as to be separated from the electrolyte membrane in order to form a fuel path with both sides thereof and induce reaction with the fuel. 2. The MEA of claim 1, wherein the catalyst electrode is formed as a corrugate shape having a certain thickness and area so as to increase a contact area with fuel. 3. The MEA of claim 2, wherein the catalyst electrode has a certain thickness and a section in which hemispheres are connected up and down. 4. The MEA of claim 1, wherein the catalyst electrode is formed as a folded shape having a certain thickness and area in order to increase a contact area with fuel. 5. The MEA of claim 4, wherein the catalyst electrode has a certain thickness and has a section formed as a saw tooth shape. 6. The MEA of claim 4, wherein the catalyst electrode has a certain thickness and a section formed as a rectangular shape in the length direction. 7. The MEA of claim 1, wherein the catalyst electrode is made of a fiber material. 8. The MEA of claim 1, wherein the catalyst electrode is made of a nickel micro fiber material. 9. The MEA of claim 1, wherein fuel is an electrolyte solution having a hydrogen forming agent. 10. The MEA of claim 1, wherein the catalyst electrode is made of hydrogen storage alloy. 11. The MEA of claim 1, wherein the air electrode placed on the air side open groove is attached to or detached from the electrolyte membrane. |
<SOH> BACKGROUND ART <EOH>Fuel cell has been presented as a substitute for fossil fuel. In the fuel cell, fuel including hydrogen is continually supplied, simultaneously air including oxygen is continually supplied, the hydrogen and the oxygen pass electrochemical reaction, and accordingly energy difference between before and after the reaction is directly converted into electric energy. Fuel cells can be classified into various kinds according to kinds of fuel, operational temperature and catalyst, etc. FIGS. 1 and 2 illustrate an example of the fuel cell. As depicted in FIGS. 1 and 2 , in the fuel cell, a MEA (membrane electrode assembly) 200 is inserted between a pair of bipolar plates 100 . Open grooves 110 , 120 in which a fluid flows are respectively formed on both sides or a side of the bipolar plate 100 . Inflow paths 130 , 140 and outflow paths 150 , 160 for making the fluid flow into/out of the open grooves 110 , 120 are respectively formed on both sides of the bipolar plate 100 . In the MEA 200 , a fuel electrode (anode) 220 contacted to fuel is formed on a side of an electrolyte membrane 210 having a certain area, and an air electrode (cathode) 230 contacted to air is formed on the other side of the electrolyte membrane 210 . With the open grooves 110 , 120 , a fuel path in which fuel flows and an air path in which air flows are respectively formed on both sides of the MEA 200 . Herein, the fuel electrode 220 is arranged on the fuel side open groove 410 , 110 , and the air electrode 230 is arranged on the air side open groove 420 , 120 . In the above-described fuel cell, when fuel flows into the inflow path 130 of the bipolar plate 100 , simultaneously air flows into the inflow path 140 of the other bipolar plate 100 . The fuel in the inflow path 130 flows through the open groove 110 and is discharged through the outflow path 150 . The air in the inflow path 140 flows through the open groove 120 and is discharged through the outflow path 160 . The fuel discharged through the outflow path 150 flows into the inflow path 130 by an additional device and is circulated. In the process for making the fuel flow in the open groove 110 , electrochemical oxidation reaction occurs on the fuel electrode 220 of the MEA 200 contacted to the open groove 110 , the hydrogen ions are moved to the air electrode 230 through the electrolyte membrane 210 , and the electrons are moved to the air electrode 230 through a load (not shown) connecting the fuel electrode 220 with the air electrode 230 . Simultaneously, while the air flows in the open groove, electrochemical reduction reaction occurs on the air electrode 230 of the MEA contacted to the open groove 120 , hydrogen ion is combined with oxygen, and accordingly water, heat of reaction and additional byproducts are generated. By continuing that process, electrons are moved from the anode (fuel electrode) to the cathode (air electrode) through a load, and electric energy is generated. The fuel electrode 220 and the air electrode 230 of the fuel cell on which oxidation and reduction reaction occur are generally constructed as a catalyst electrode having a catalyst for activating reaction. Reference numeral 300 is a collector plate. FIG. 3 illustrates a MEA of a fuel cell in accordance with the conventional art. As depicted in FIG. 3 , in the MEA of the fuel cell, a catalytic layer 221 , 231 is respectively coated on both sides of the electrolyte membrane 210 having a certain thickness and a rectangular area, and a coating layer 222 , 232 is respectively coated onto the catalytic layer 221 , 231 . The catalytic layer 221 and the coating layer 222 formed on a side of the electrolyte membrane 210 construct a fuel electrode, and the catalytic layer 231 and the coating layer 232 formed on the other side of the electrolyte membrane 210 construct the air electrode. In that structure, when fuel and air flow through the open grooves 110 , 120 respectively, while oxidation and reduction reaction occur on the fuel electrode 220 and the air electrode 230 of the MEA, reaction of fuel is activated by catalytic reaction of the catalytic layer 221 , and hydrogen ions are moved to the air electrode 230 through the electrolyte membrane 210 . Herein, when fuel in which hydrogen forming agent such as NaBH4, KBH4, LiAIH4, KH and NaH, etc. is dissolved in an alkali aqueous solution is used, because the fuel is an electrolyte solution, electrons generated with hydrogen ions are moved to the air electrode 230 through the electrolyte solution and the bipolar plate 100 . However, in the conventional structure, when hydrogen ions generated by catalytic reaction by the catalytic layer 221 of the fuel electrode 220 move to the air electrode 230 through the coating layer 222 , the catalytic layer 221 and the electrolyte membrane 210 , because the catalytic layer 221 of the fuel electrode 220 is coated onto the electrolyte membrane 210 , the coated catalytic layer 221 disturbs movement of hydrogen ions toward to the air electrode 230 through the electrolyte membrane 210 , ionic action (catalytic action) is active only on a side of the catalytic layer 221 , on the contrary, ionic action does not occur on a side contacted to the electrolyte membrane 210 , and accordingly current generating efficiency is lowered. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings: FIG. 1 is a sectional view illustrating a general fuel cell; FIG. 2 is an exploded-perspective view illustrating the general fuel cell; FIG. 3 is a sectional view illustrating a MEA (membrane electrode assembly) of a fuel cell in accordance with the conventional art; FIG. 4 is a sectional view illustrating a MEA of a fuel cell in accordance with the present invention; FIG. 5 is a perspective view illustrating a catalyst electrode of the MEA of the fuel cell in accordance with the present invention; FIGS. 6 and 7 are perspective views respectively illustrating modifications of a catalyst electrode of the MEA of the fuel cell in accordance with the present invention; and FIG. 8 is a sectional view illustrating an operation state of the MEA of the fuel cell in accordance with the present invention. detailed-description description="Detailed Description" end="lead"? |
Method for the preparation of escitalopram |
A novel method is provided for the manufacture of escitalopram. The method comprises chromatographic separation of the enantiomers of citalopram or an intermediate in the production of citalopram using a chiral stationary phase such as Chiralpak™ or Chiralcel™ OD. Novel chiral intermediates for the synthesis of Escitalopram made by said method are also provided. |
1. Method for preparation of escitalopram having the formula or pharmaceutically acceptable addition salts thereof comprising separation of the enantiomers of a compound selected from the group comprising citalopram having the formula and intermediate compounds in the preparation of citalopram, characterised in that said separation of enantiomers is performed by liquid chromatographic separation of enantiomers using a chiral stationary phase for the chromatography. 2. A method according to claim 1 comprising preparation of a compound of formula wherein X is a cyano group or halogen or any other group that may be converted to a cyano group, by optical resolution by chromatography of a racemic compound of formula wherein X is as defined above, and if X is not a cyano group then followed by conversion of the group X in the compound of formula (IV) to a cyano group followed by isolation of escitalopram or a pharmaceutically acceptable salt thereof. 3. Method according to claim 2, wherein the group X is cyano. 4. The method according to claim 2, wherein the group X is bromo. 5. A method according to claim 1 comprising optical resolution by chromatography of a compound of formula wherein X is a cyano group or halogen or any other group that may be converted to a cyano group and Z is hydroxy or a leaving group, to form the compound of formula and if Z is OH conversion of the group Z to a leaving group and then ring closure of the resulting compound of formula (VII) wherein Z is a leaving group to form a compound of formula wherein X is as defined above, and if X is not a cyano group then conversion of the group X in the compound of formula (IV) to a cyano group, followed by isolation of escitalopram or a pharmaceutically acceptable salt thereof. 6. Method according to claim 5, wherein the group X is cyano. 7. Method according to claim 5, wherein the group X is bromo. 8. The method according to claim 1, characterised in that the chiral stationary phase comprises a carbohydrate derivative. 9. Method according to claim 8, characterised in that the carbohydrate derivative is a polysaccharide derivative. 10. The method according to claim 8, characterised in that the carbohydrate derivative comprises phenyl carbamate substituents which optionally may be substituted with one or more C1-4-alkyl groups, preferably methyl groups. 11. The method according to claim 9, characterised in that the polysaccharide derivative is an amylose derivative. 12. Method according to claim 11, characterised in that the chiral stationary phase comprising an amylose derivative comprising optionally alkyl substituted phenyl carbamate substituents is a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carabamate groups. 13. The method according to claim 9, characterised in that the polysaccharide derivative is a cellulose derivative. 14. Method according to claim 13, characterised in that the chiral stationary phase comprising a cellulose derivative comprising optionally alkyl substituted phenyl carbamate substituents is a silica gel supported cellulose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carbamate groups. 15. The method according to claim 8, characterised in that the carbohydrate derivative is adsorbed on silica gel. 16. The method according to claim 1, characterised in that the chromatographic separation comprises a continuous chromatographic process, suitably Simulated Moving Bed technology. 17. The method according to claim 1, wherein a compound of formula(III), wherein X is halogen, in particular bromo, is converted to escitalopram by reaction of the compound of formula (IV) with CuCN followed by purification and isolation of escitalopram or a pharmaceutically acceptable salt thereof. 18. The method according to claim 1, wherein the compound of formula (IV), wherein X is halogen, in particular bromo, or CF3—(CF2)n—SO2—O—, wherein n is 0-8, is converted to escitalopram by reaction of the compound of formula (III) with a cyanide source in presence of a palladium catalyst followed by purification and isolation of escitalopram or a pharmaceutically acceptable salt thereof. 19. The method according to claim 1, wherein a compound of formula (IV) wherein X is halogen, in particular bromo, is converted to escitalopram by reaction of a compound of formula (III) with a cyanide source in presence of a nickel catalyst followed by purification and isolation of escitalopram or a pharmaceutically acceptable salt thereof. 20. An intermediate having the formula wherein Z is hydroxy or a leaving group; or a salt thereof. 21. (canceled) 22. The method according to claim 9, wherein the carbohydrate derivative comprises phenyl carbamate substituents which optionally may be substituted with one or more C1-4-alkyl groups, preferably methyl groups. 23. The method according to claim 10, wherein the polysaccharide derivative is an amylose derivative. 24. The method according to claim 22, wherein the polysaccharide derivative is an amylose derivative. 25. The method according to claim 23, wherein the chiral stationary phase comprising an amylose derivative comprising optionally alkyl substituted phenyl carbamate substituents is a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carabamate groups. 26. The method according to claim 24, wherein the chiral stationary phase comprising an amylose derivative comprising optionally alkyl substituted phenyl carbamate substituents is a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carabamate groups. 27. The method according to claim 10, wherein the polysaccharide derivative is a cellulose derivative. 28. The method according to claim 22, wherein the polysaccharide derivative is a cellulose derivative. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. Citalopram was first disclosed in DE 2,657,013, corresponding to U.S. Pat. No. 4,136,193. This patent publication i.a. outlines a process for the preparation of citalopram from the corresponding 5-bromo-derivative by reaction with cuprous cyanide in a suitable solvent. Further processes for the preparation of citalopram by exchange of 5-halogen or CF 3 —(CF 2 ) n —SO 2 —O—, n being 0-8, with cyano are disclosed in WO 0011926 and WO 0013648. The diol of formula II, 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile, and its use as an intermediate in the preparation of citalopram has been disclosed in e.g. U.S. Pat. No. 4,650,884. Escitalopram, the enantiomers of the diol II and methods for their preparation are disclosed in U.S. Pat. No. 4,943,590. Two routes to escitalopram are disclosed, both of them are starting with the racemic diol II. In the first route, the diol II is reacted with an enantiomerically pure acid derivative, such as (+) or (−)-α-methoxy-α-trifluoromethyl-phenylacetyl chloride to form a mixture of diastereomeric esters, which are separated by HPLC or fractional crystallization, whereupon the ester with the right stereochemistry is enantioselectively converted into escitalopram. In the second route, the diol II is separated into the enantiomers by stereoselective crystallization with an enantiomerically pure acid such as (+)-di-p-toluoyltartaric acid, whereupon the S-enantiomer of the diol II is enantioselectively converted to escitalopram. Both of these routes involve consumption of expensive, enantiomerically pure reagents and give relatively low yields resulting in that they are economically and environmentally infeasible for industrial production. The stereoselectivity of the pharmacological action of citalopram, i.e. the 5-HT-reuptake inhibition residing in the S-enantiomer, and accordingly, the antidepressant effect of said enantiomer is also disclosed in U.S. Pat. No. 4,943,590. Escitalopram has now been developed as an antidepressant. Hence, there is a desire for an improved method for preparation of escitalopram. It is known to those skilled in the art that two enantiomers in certain situations may be separated by liquid chromatography using a chiral stationary phase. The chiral stationary phase has to be found by screening of the available chiral stationary phases for one, which is effective in separating the pair of enantiomers in question, and there may not always be an available chiral stationary phase suitable for the purpose. Conventional liquid chromatography is a batch process consuming large amounts of solvents and, hence, is generally not economically feasible for industrial production. Chromatographic processes, which are advantageous by being continuous and generally consuming reduced amounts of solvents, are known to those skilled in the art. Simulated moving bed (SMB) chromatography is one such continuous chromatographic process. EP 563,388 discloses a simulated moving bed (SMB) chromatographic process wherein enantiomers of an optically active compound are separated and the stationary phase comprises silica gel coated with a chiral material such as a cellulose ester. Hence, there is a desire for a chiral stationary phase which is effective in separating the enantiomers of citalopram, or a compound which is an intermediate in the manufacture of citalopram. There is no method which enables one, a priori, to forecast which chiral stationary phase will be effective in separating a given pair of enantiomers. The chiral stationary phase for separation of a pair of enantiomers has to be found by laborious testing of chiral stationary phases selected from the vast amount of available chiral stationary phases. |
<SOH> SUMMARY OF THE INVENTION <EOH>As used herein, the terms ‘separation of enantiomers’ and ‘separation into enantiomers’ refer to any process resulting in two or more fractions wherein the ratio between the two enantiomers deviates from 1:1. The term ‘optically resolved’ refers to the product of any such process. As used herein, the term ‘purity’ means the purity of the enantiomer measured as percent enantiomeric excess (ee). As used herein, the term ‘carbohydrate derivative’ means any compound which principally can be derived from a carbohydrate by substitution of one or more hydroxyl groups with another substituent leaving the stereochemical structure intact. As used herein, the terms ‘intermediate for the manufacture of escitalopram’ and ‘intermediate compounds in the preparation of citalopram’ means any intermediate in any known process for the manufacture of escitalopram. Throughout the application, structural formula of chiral compounds refer to the racemates if the stereochemistry is not indicated. Laborious experimentation has now resulted in a new and inventive process for the manufacture of escitalopram comprising separation of the enantiomers of citalopram or an intermediate in the manufacture of citalopram by chromatography using a chiral stationary phase. Accordingly, the present invention relates to a novel process for the preparation of escitalopram having the formula comprising preparation of a compound of formula wherein X is a cyano group, halogen or any other group which may be converted to a cyano group by optical resolution by chromatography of the racemic compound of formula wherein X is as defined above; and if X is not a cyano group, then followed by conversion of X to a cyano group and thereafter isolation of escitalopram or a pharmaceutically acceptable salt thereof. In one preferred embodiment of the invention, citalopram is separated into its enantiomers by chromatography using a chiral stationary phase. Accordingly the present invention relates to a novel process for the preparation of escitalopram having the formula comprising optical resolution by chromatography of a compound of formula wherein X is a cyano group, halogen or any other group that may be converted to a cyano group and Z is hydroxy or a leaving group, to form the compound of formula and if Z is OH conversion of the group Z to a leaving group and then ring closure of the resulting compound of formula (VII) wherein Z is a leaving group to form a compound of formula wherein X is as defined above, and if X is not a cyano group, then followed by conversion of the group X in the compound of formula (III) to a cyano group, followed by isolation of escitalopram or a pharmaceutically acceptable salt thereof. In another preferred embodiment of the invention, the intermediate diol II 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzo-nitrile is separated into its enantiomers by chromatography using a chiral stationary phase. The obtained (S)-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile may be transformed into escitalopram by methods known to those skilled in the art, such as treatment with para-toluensulfonylchloride and a base, e.g. triethylamine, as disclosed in U.S. Pat. No. 4,943,590. The invention also relates to the intermediate having the formula wherein Z is as defined above. In a further embodiment, the present invention relates to the S-enantiomer of 5-Br-citalopram having the formula or salts thereof. The racemic compounds of formula (V) and (VI) may be resolved by liquid chromatography or super or sub critical chromatography using a chiral stationary phase. The chiral stationary phase may comprise an optically active high molecular compound, e.g. a polysaccharide derivative, such as esters or carbamates of cellulose or amylose, a polyacrylate derivative (e.g. a methacrylate derivative, such as poly(triphenylmethylmethacrylate)) or a polyamide derivative, a protein with an asymmetric or disymmetric chain (bovine serum albumin bonded to silica, cellulase covalently bonded to aldehyde silica), polymers with an asymmetric centre in its side chains etc. . . . Another possibility is a chiral stationary phase comprising a low molecular compound having optical resolution capability, e.g. crown ethers ((S) or (R)-18-crown-6-ether on silica) and cyclodextrin derivatives (alpha cyclodextrin bonded to silica). Other important chiral separation factors which may be comprised by the chiral stationary phase are amino acids and derivatives thereof, esters or amids of amino acids, acetylated amino acids and oligopeptides. Still another possibility is a particulate polysaccharide material, e.g microcrystalline cellulose triacetate. Chiral stationary phases including polysaccharide derivatives and polyamides useful for separation of enantiomers are described in EP 0 147 804, EP 0 155 637, EP 0 157 365, EP 0 238 044, WO 95/18833, WO 97/04011, EP 0656 333 and EP 718 625. Particles of polysaccharides useful for the separation of optical enantiomers are described in EP 0706 982. Preferably, the chiral stationary phase comprises a carbohydrate derivative, more preferred a polysaccharide derivative and most preferred an amylose or cellulose derivative. Suitably, the polysaccharide adsorbed on the silica gel carry groups such as phenylcarbamoyl, 3,5-dimethyl-phenylcarbamoyl, 4-chlorophenylcarbamoyl, 3,5-dichloro-phenylcarbamoyl, acetyl, benzoyl, cinnamoyl, 4-methyl-benzoyl or S-alpha-phenylethyl carbamoyl. Preferably, the carbohydrate derivative comprises phenyl carbamate substituents, which optionally may be substituted with one or more C 1-4 -alkyl groups, preferably methyl groups. The chiral compound, which is the chiral separating factor of the stationary phase, may suitably be adsorbed on a carrier, such as silica gel. Suitably, the chiral stationary phase is Chiralpak™ AD, a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carbamate groups, or Chiralcel™ OD, a silica gel supported cellulose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carbamate groups. Chiralpak™ AD and Chiralcel™ OD are both obtainable from Daicel Chemical Industries Ltd. Chiral stationary phases comprising amylose phenyl carbamate derivatives are especially suitable for resolvation of compounds of formula (VI). Exemplary of such chiral stationary phases is Chiralpak™ AD. Chiral stationary phases comprising cellulose phenyl carbamate derivatives are especially suitable for resolvation of compounds of formula (V). Exemplary of such chiral stationary phases is Chiralcel™ OD. The nature of the substituent X has little influence on the resolvation of the compounds as it is distant from the chiral center. Any liquid chromatographic separation method may be used for the separation of the enantiomers. Preferably, the chromatographic separation method comprises a continuous chromatographic technology, suitably simulated moving bed technology. The eluent is typically selected from the group comprising acetonitrile, alcohols, such as methanol, ethanol or isopropanol, and alkanes, such as cyclohexane, hexane or heptane, and mixtures thereof. An acid such as formic acid, acetic acid and trifluoroacetic acid and/or a base such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl-isopropyl-amine may be added to the eluent. Alternatively, super or sub critical carbon dioxide containing a modifier may be used as eluent. The modifier is selected from lower alcohols such as methanol, ethanol, propanol and isopropanol. An amine, such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl-isopropyl-amine and optionally an acid, such as formic acid, acetic acid and trifluoroacetic acid may be added. Suitably, the chromatographic method used is a liquid chromatographic method. A suitable eluent according to this embodiment of the invention is acetonitrile. Another suitable eluent according to this embodiment of the invention is a mixture of iso-hexane and isopropanol. A suitable mixture contains iso-hexane 98% vol and isopropanol 2% vol. Another suitable eluent according to the invention is super or sub critical carbon dioxide containing 10% vol methanol with 0.5% vol diethylamine and 0.5% vol trifluoroacetic acid. One embodiment of the invention comprises novel optically resolved intermediates for the manufacture of escitalopram. When Z is OH in the compound of formula (VII), the alcohol group, Z, may be converted to a suitable leaving group such as a sulfonate ester or a halide. The former is carried out by reaction with sulfonyl halides, such as methanesulfonyl chloride and p-toluensulfonyl chloride. The latter is achieved by reaction with halogenating agents such as thionyl chloride or phosphorus tribromide. Ring closure of the compounds of formula (VII), wherein Z is a leaving group, such as a sulfonate ester or halogen may thereafter be carried out by treatment with a base such as KOC(CH 3 ) 3 or other alkoxides, NaH or other hydrides, triethylamine, ethyldiisopropylamine or pyridine in an inert organic solvent, such as tetrahydrofuran, toluene, DMSO, DMF, t-butyl methyl ether, dimethoxyethane, dimethoxymethane, dioxane, acetonitrile or dichloromethane. The ring closure is analogous to the process described in U.S. Pat. No. 4,943,590. The compound of formula (IV) may be converted to escitalopram having the formula by a number of methods as described below. As mentioned above, X in the compound of formula (IV) may be a cyano group, halogen, preferably chloro or bromo, or any other compound which may be converted to a cyano group. Such other groups, X, which may be converted to a cyano group may be selected from the groups of formula CF 3 —(CF 2 ) n —SO 2 —O—, wherein n is 0-8, —OH, —CHO, —CH 2 OH, —CH 2 NH 2 , —CH 2 NO 2 , —CH 2 Cl, —CH 2 Br, —CH 3 , —NHR 1 , —COOR 2 , —CONR 2 R 3 , wherein R 1 is hydrogen or alkylcarbonyl, and R 2 and R 3 are selected from hydrogen optionally substituted alkyl, aralkyl or aryl, and a group of formula wherein Y is O or S; R 4 -R 5 are each independently selected from hydrogen and C 1-6 alkyl or R 4 and R 5 together form a C 2-5 alkylene chain thereby forming a spiro ring; R 6 is selected from hydrogen and C 1-6 alkyl, R 7 is selected from hydrogen, C 1-6 alkyl, a carboxy group or a precursor group for a carboxy group, or R 6 and R 7 together form a C 2-5 alkylene chain thereby forming a spiro ring. When X is halogen, in particular bromo or chloro, conversion of the compound of formula (IV) to form escitalopram may be carried out according to the procedures described in U.S. Pat. No. 4,136,193, WO 00/13648, WO 00/11926 and WO 01/02383 or other procedures suitable for such conversions. According to U.S. Pat. No. 4,136,193, conversion of the 5-bromo group may be carried out by reaction of a compound of formula (IV) wherein X is bromo, with CuCN. WO 00/13648 and WO 00/11926 describes the conversion of a 5-halogen or a triflate group to a cyano group by cyanation with a cyanide source in presence of a Pd or Ni catalyst. The cyanide source used according to the catalysed cyanide exchange reaction may be any useful source. Preferred sources are KCN, NaCN or (R′) 4 NCN, where (R′) 4 indicates four groups which may be the same of different and are selected from hydrogen and straight chain or branched C 1-6 alkyl. The cyanide source is used in stoichiometric amount or in excess, preferably 1-2 equivalents are used pr. equivalent starting material. (R′) 4 N 30 may conveniently be (Bu) 4 N 30 . The cyanide source is preferably NaCN or KCN or Zn(CN) 2 . The palladium catalyst may be any suitable Pd(0) or Pd(II) containing catalyst, such as Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd(PPh) 2 Cl 2 , etc. The Pd catalyst is conveniently used in an amount of 1-10, preferably 2-6, most preferably about 4-5 mol %. In one embodiment, the reaction is carried out in the presence of a catalytic amount of Cu + or Zn 2+ . Catalytic amounts of Cu + and Zn 2+ , respectively, means substoichiometric amounts such as 0.1-5, preferably 1-3 mol. Conveniently, about ½ eq. is used per eq. Pd. Any convenient source of Cu + and Zn ++ may be used. Cu + is preferably used in the form of CuI, and Zn 2+ is conveniently used as the Zn(CN) 2 salt. In a preferred embodiment, cyanation is carried out by reaction with ZnCN 2 in the presence of a Palladium catalyst, preferably Pd(PPh 3 ) 4 (tetrakis(triphenylphos-phine)palladium). The nickel catalyst may be any suitable Ni(0) or Ni(II) containing complex which acts as a catalyst, such as Ni(PPh 3 ) 3 , (σ-aryl)-Ni(PPh 3 ) 2 Cl, etc. The nickel catalysts and their preparation are described in WO 96/11906, EP-A-613720 and EP-A-384392. In a particularly preferred embodiment, the nickel(0) complex is prepared in situ before the cyanation reaction by reduction of a nickel(II) precursor such as NiCl 2 or NiBr 2 by a metal, such as zinc, magnesium or manganese in the presence of excess of complex ligands, preferably triphenylphosphin. The Ni-catalyst is conveniently used in an amount of 0.5-10, preferably 2-6, most preferably about 4-5 mol %. In one embodiment, the reaction is carried out in the presence of a catalytic amount of Cu + or Zn 2+ . Catalytic amounts of Cu + and Zn 2+ , respectively, means substoichiometric amounts such as 0.1-5, preferably 1-3%. Any convenient source of Cu + and Zn 2+ may be used. Cu + is preferably used in the form of CuI and Zn 2+ is conveniently used as the Zn(CN) 2 salt or formed in situ by reduction of a nickel (II) compounds using zinc. The cyanation reaction may be performed neat or in any convenient solvent, such solvent includes DMF, NMP, acetonitril, propionitrile, THF and ethylacetate. The cyanide exchange reaction may also be performed in an ionic liquid of the general formula (R″) 4 N + , Y − , wherein R″ are alkyl-groups or two of the R″ groups together form a ring and Y − is the counterion. In one embodiment of the invention, (R″) 4 N + Y − represents In still another alternative, the cyanide exchange reaction is conducted with apolar solvents such as benzene, xylene or mesitylene and under the influence of microwaves by using i.e. Synthewave 1000™ by Prolabo. The temperature ranges are dependent upon the reaction type. If no catalyst is present, preferred temperatures are in the range of 100-200° C. When the reaction is conducted under the influence of microwaves, the temperature in the reaction mixture may raise to above 300° C. More preferred temperature ranges are between 120-170° C. The most preferred range is 130-150° C. If a catalyst is present, the preferred temperature range is between 0 and 100° C. More preferred are temperature ranges of 40-90° C. Most preferred temperature ranges are between 60-90° C. Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art. Another process for the conversion of a compound of formula (IV), wherein X is Br to the corresponding 5-cyano derivative involves reaction of 5-Br-citalopram of formula (IV) with magnesium to form a Grignard reagent, followed by reaction with a formamide to form an aldehyde. The aldehyde is converted to an oxime or a hydrazone which is converted to a cyano group by dehydration and oxidation, respectively. Alternatively, 5-Br-citalopram of formula (IV), wherein X is bromo, may be reacted with magnesium to form a Grignard reagent, followed by reaction with a compound containing a CN group bound to a leaving group. A detailed description of the above two procedures may be found in WO 01/02383. Compounds of formula (IV), wherein the group X is —CHO, may be converted to escitalopram by methods analogous to those described in WO 99/30548. Compounds of formula (IV), wherein the group X is NHR 1 , wherein R 1 is hydrogen or alkylcarbonyl may be converted by to escitalopram methods analogous to those described in WO 98/19512. Compounds of formula (IV), wherein the group X is —CONR 2 R 3 , wherein R 2 and R 3 are selected from hydrogen optionally substituted alkyl, aralkyl or aryl, may be converted to escitalopram by methods analogous to those described in WO 98/19513 and WO 98/19511. Compounds of formula (IV), wherein the group X is a group of formula (X), may be converted to escitalopram by methods analogous to those described in WO 00/23431. Compounds of formula (IV), wherein X is OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 NO 2 , —CH 2 Cl, —CH 2 Br, —CH 3 and any of the other groups X above, may be converted to escitalopram by methods analogous to those prepared in WO 01/168632. Starting materials of formulas (V) and (VI) may be prepared according to the above mentioned patents and patent applications or by analogous methods. Thus the acid addition salts used according to the invention may be obtained by treatment of intermediates for the synthesis of escitalopram with the acid in a solvent followed by precipitation, isolation and optionally re-crystallisation by known methods and, if desired, micronisation of the crystalline product by wet or dry milling or another convenient process or preparation of particles from a solvent-emulsification process. In the following, the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be construed as limiting. detailed-description description="Detailed Description" end="lead"? |
Benzofuranes and their use in the treatment of atrial fibrillation |
This intention relates to new compounds and their pharmaceutical use, and to the pharmaceutical use of known compounds, which compounds inhibit certain transmembrane potassium currents in the atrium of the heart of a mammal without significantly affecting other ion channels, for the treatment of heart disease particularly atrial fibrillation. The invention also relates to pharmaceutical compositions comprising such compounds. |
1. A compound according to formula I; wherein: R1 is C1-C4 alkyl; R2 is NHCORa, NHCONHRa, or hydrogen; R3 and R4 are independently selected from fluorine, chlorine, C1-C6 alkyl, and CF3; Ra is selected from CF3, C1-3 alkyl, and -(4-Rb)C6H4; Rb is selected from C1-4 alkoxy, hydroxy, fluoro, and nitro; R5 is selected from hydrogen and —CH2—COOH; X is selected from CH2 and C═O; with the proviso that when R5 is hydrogen, X is —CH2—; and pharmaceutically acceptable salts, esters and isomers thereof. 2. A compound according to claim 1 wherein R2 is hydrogen or NHCORa and each of R3 and R4 is independently C1-C4 alkyl. 3. A compound according to claim 2 wherein R3 and R4 are isopropyl. 4. A compound according to claim 1 where R2 is H or NHCORa, and R5 is —CH2—COOH. 5. A compound according to claim 1 wherein R1 is methyl; R2 is hydrogen; R3 and R4 is C1-C4 alkyl; R5 is —CH2—COOH; and X is —CH2—. 6. 2-methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran (E1); or 2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzoyl)benzofuran (E2); or 2-methyl-3-(3,5-diisopropyl-4-hydroxybenzyl)benzofuran (E3); or 2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzyl)benzofuran (E4); or and pharmaceutically acceptable salts, esters and isomers thereof. 7. (Cancelled). 8. A pharmaceutical composition comprising a compound according to claim 1, together with a pharmaceutically acceptable carrier. 9. A method of treating atrial fibrillation or atrial flutter comprising providing to a patient in need thereof a pharmaceutically effective amount of a compound according to claim 1. 10-15. (Cancelled). 16. A pharmaceutical composition for the treatment of atrial fibrillation or atrial flutter comprising at least one compound that inhibits certain transmembrane potassium currents, which are more active in the diseased atrium of a mammalian heart than in a normal atrium, without affecting other ion channels. 17. The composition according to claim 16, wherein the said inhibition derives from inhibition of one or several of the three ligand-gated potassium currents IK(Ado), IK(ACh) and IK(ATP). 18. The pharmaceutical composition according to claim 16 wherein the said inhibition caused by the compound is not due to the T3 antagonistic effect. 19. The pharmaceutical composition according to claim 16 wherein the compound is a compound according to formula II wherein: R6 is C1-C4 alkyl; R7 is NHCOR5, NHCONHR5, or hydrogen; R8 and R9 are independently selected from iodine and bromine; R10 is selected from CF3, C1-3 alkyl, and 4-R6C6H4; R11 is selected from C1-4 alkoxy, hydroxy, fluoro, and nitro; R12 is selected from hydrogen and —CH2—COOH; X is selected from CH2 and C═O; or pharmaceutically acceptable salts, esters and isomers thereof. 20. The pharmaceutical composition according to claim 19, wherein the compound is 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran (E5); 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran (E6); or pharmaceutically acceptable salts and esters thereof and isomers thereof. 21. A method of treating atrial fibrillation or atrial flutter comprising providing to a patient in need thereof a pharmaceutically effective amount of at least one compound that inhibits certain transmembrane potassium currents, that are more active in the diseased atrium of a mammalian heart than in a normal atrium, without affecting other ion channels. 22. The method according to claim 21, wherein the said inhibition derives from inhibition of one or several of the three ligand-gated potassium currents IK(Ado), IK(ACh) and IK(ATP). 23. The method according to claim 21 wherein said inhibition caused by the compound is not due to the T3 antagonistic effect. 24. The method according to claim 21 wherein the compound is a compound according to formula II as defined in claim 14. wherein: R6 is C1-C4 alkyl; R7 is NHCOR5, NHCONHR5, or hydrogen; R8 and R9 are independently selected from iodine and bromine; R10 is selected from CF3, C1-3 alkyl, and 4-R6C6H4; R11 is selected from C1-4 alkoxy, hydroxy, fluoro, and nitro; R12 is selected from hydrogen and —CH2—COOH; X is selected from CH2 and C═O; or pharmaceutically acceptable salts, esters and isomers thereof. 25. The method according to claim 21 wherein the compound is 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran (ES); 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran E6); or pharmaceutically acceptable salts and esters thereof and isomers thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Cell membranes have a basic lipid bilayer structure that is impermeable to ions. Special proteins (hereafter referred to as ion-channels) have evolved that provide pathways for ions to cross cell membranes and so make the membrane permeable to ions, such as potassium (hereafter K), as sodium (hereafter Na) or calcium (hereafter Ca). Opening and closing of ion-channels make the membrane permeable or impermeable to different ions and thereby they regulate many properties and functions of the cell membrane. Ion-channels enable cells to set up membrane potentials, and allow currents to flow that change these membrane potentials, thereby underlying electrical signaling by the cell membrane. A transmembrane current (hereafter I) is the ion-flow through an open ion-channel. Ion-channels are targets for many antiarrhythmic drugs, which are used to treat abnormal electrical activity in the heart. From a therapeutic perspective, blocking of K-channels prolongs the action potential duration (APD) and lengthens the refractory period, and is a classical antiarrhythmic mechanism generating a Q-T prolongation on the surface ECG (Singh B and Nademanee K, Am Heart J, 1985, 109:421-30). Several different kinds of ion-channels, including Na— Ca— and K— ion channels, are active in the mammalian heart giving rise to different ion-currents (e.g. INa, ICa and IK). Most K-channels are either voltage activated such as the Delayed Rectifier K-channel (resulting in the current IK), the Transient Outward K-channel (resulting in the current Ito) or ligand operated such as the ATP-sensitive K-channel which is opened during metabolic impairment (when intracellular levels of ATP are reduced) which generates the current IK(ATP). Another ligand-activated K-channel is the Muscarinic K-channel which is activated when acetylcholine binds to the muscarinic receptor M2 (resulting in the current IK(ACh) or when adenosine binds to the adenosine receptor A1 in the current IK(Ado). Antiarrhythmic drugs are grouped according to their essential inhibitory effects on certain ion-currents; class I drugs predominantly inhibit sodium currents and class III drugs predominantly inhibit potassium currents. However, antiarrhythmic drugs that are used today are not selective in their ion-channel blocking and every drug used today interacts with several currents. K-channel blocking in the heart may be one of the most efficient antiarrhythmic mechanisms identified so far. The problem is that any drug that prolongs repolarization has an intrinsically associated risk of inducing torsade de points arrhythmia in the ventricle. However, since the K-channels responsible for repolarization actually differ between the atrium and the ventricle, it is possible to identify K-channels that will be active against supraventricular arrhythmias but that will not prolong the QT-interval and thus will not be proarrhythinic. Blocking of the particular ligand-activated K-currents IK(Ado) and/or IK(ACh) has been shown to occur with anti-arrhythmic agents. It has also been postulated that this mechanism may be of importance in explaining the efficacy of anti-arrhythmic drugs for the treatment of atrial fibrillation (Mori K, et al. Circulation 1995 Jun. 1;91(11):2834-43; Ohmoto-Sekine Y, et al. Br J Pharmacol 1999 February;126(3):751-61; Watanabe Y, et al. J Pharmacol Exp Ther 1996 November;279(2):617-24). The ligand-gated currents IK(Ado), IK(ACh) and Il((ATP) probably only have minor roles in shaping repolarization under normal conditions but, when activated by extracellular acetylcholine, by extracellular adenosine or reduction of intracellular ATP concentrations respectively, these currents are increased and thus can substantially shorten the action potential duration (APD) (Belardinelli L, et al. FASEB J 1995; 9(5):359-365; Belardinelli L and Isenberg G. Am J Physiol 1983; 244(5):H734-H737; Findlay I and Faivre J F. FEBS Lett 1991; 279(1):95-97). The therapeutic effect of anti arrhythmic agents is to prolong APD and thereby make the atrial myocardium more refractive to abnormal electrical activity. It is expected that the ligand-gated channels IK(Ado) and IM(ATP) are-more active in atrial tachyarrhythmias (i.e. atrial fibrillation (AF) and atrial flutter) than in normal sinus-rhythm, whereas IK(ACh), activation is dependent on vagal activity (presynaptic release of ACh). Atrial consumption of ATP is increased in atrial tachyarrhythmias leading to increased levels of adenosine (a metabolite of ATP) activating IK(Ado) and leading to reduced intracellular ATP concentration, hence, activating IK(ATP) (Asheroft S J and Ashcroft F M. Cell Signal 1990; 2(3):197-214). Atrial fibrillation is today seldom treated with antiarrhythmic agents to normalize the abnormal electric activity. The primary reason for the reluctance to treat AF-patients with drugs that effectively normalize atrial electric activity is that available anti-arrhythmic drugs also block other ion-channels, in addition to the ligand-gated channels IK(Ado), IK(ACh) and IK(ATP), in the heart. Therefore, treatment of AF-patients with currently-available anti-arrhythmic drugs is associated with a substantial risk to induce lethal proarrhythmic effects (as Torsade-de Points in the ventricle); It is of importance to consider that the antiarrhythmic agents referenced in Table 1 are not exclusively active on the ligand-gated currents IK(Ado), IK(ACh) and IK(ATP), but also block other transmembrane currents (references in Table 2). The class III-agent amiodarone has been shown to be effective for treatment of AF (Roy D, et al., N Engl J Med 2000 Mar. 30;342(13):913-20) and indeed aniodarone does block ligand-gated currents IK(Ado) and IK(ACh) (Watanabe Y, et al. supra). However, in spite of the proven efficacy of amiodarone to treat AF, the side effect profile of the drug is complex; there are features such as pulmonary toxicity, ocular and skin changes, and other forms of organ toxicity that clearly limit its widespread clinical utility (Pollak, T. M. Am. J. Cardiol., 1999, 84, 37R-45R; Wiersinga, W. M. Chapter 10, Amiodarone and the Thyroid, In Handbook of Experimental Pharmacology, Weetman A. P., Grossman, A., Eds.; Springer-Verlag.: Berlin, Heidelberg, 1997, Vol 128). Amiodarone has a complex pharmacokinetic profile and the elimination of the drug is extremely slow (Wiersingha, supra). In spite of its proven efficacy for treatment of AF, amiodarone is not frequently used as a treatment due to all side effects associated with its use. A novel anti-arrhytmic drug which shares the inhibitory effect on the ligand activated currents IK(Ado)/IK(ACh) with amiodarone but displays lower organ toxicity than that drug would provide an improved treatment for AF. Indeed, data from toxicological studies performed with compounds of the, present invention or used in the present invention suggest a reduced toxicity as compared to amiodarone. The extreme pharmacokinetic behavior amiodarone complicates dosing of that drug and thus it would be of great clinical benefit to have a drug which shares the inhibitory effects on the; ligand activated currents IK(Ado)/IK(ACh)/IK(ATP) with amiodarone but that displays mainstream pharmacokinetics. Data from blood pharmacokinetics, tissue distribution and mass balance studies on compounds used in the present invention indicates that the clinical use of these compounds will be less complicated than that of amiodarone. An ideal drug for treatment of atrial fibrillation should also selectively inhibit the atrial currents that are increased under the pathological conditions characterizing the disease and lack effects on other currents. This is the case with the compounds of the present invention since the IK(Ado)/ATP current is predominantly active in the fibrillating atrium and the IK(ACh) is the current responsible for the induction of vagal-triggered atrial fibrillation. In comparison with other antiaarhythmic drugs (see table 2) the compounds of the present invention are essentially free from interactions with other ion-currents and can therefore be regarded as selective inhibitors of the K-currents (IK(Ado), IK(ACh) and IK(ATP)) that have an increased activity in supraventricular cardiac arrhytmias (i.e. atrial fibrillation) but without the ability to block the ion-currents that mediate electrical activity in the cardiac ventricles and in the normal atrium. Both the compounds that are the subject of the present invention and amiodarone have been shown to antagonize triiodthyronine (T3)-signalling action in cells (manuscript in preparation) and therefore it should be noted that the inhibitory effects seen with such compounds on IK(Ado), IK(ACh) and IK(ATP)) are not due to T3-antagonism. There are two findings that support this statement; a) T3 does not have acute effects on IK(Ado) or IK(ACh) and b) potent T3-antagonists (100× more potent than the compounds that are the subject of the present invention on T3-receptor mediated signaling) do not display similar acute effects on IK(Ado) or IK(ACh). detailed-description description="Detailed Description" end="lead"? |
Attitude indicator for an aircraft |
This attitude indicator comprises a display device (11) with screen (110), producing on a screen background (4, 5), a three-dimensional aircraft silhouette (3), mobile according to the three axes of rotation and viewed from the rear, according to attitude angles which correspond to the attitude angle measurements received by onboard instruments and which are referenced with respect to an aircraft datum having a roll axis perpendicular to the surface of the screen and pitch and yaw axes in the plane of the screen, one, the pitch axis, being horizontal and the other, the yaw axis, vertical. It has the advantage of affording the crew a concrete view of the attitude of the aircraft enabling piloting to be rendered more natural and more intuitive, and hence safety to be improved. |
1. An aircraft attitude indicator receiving, from equipment aboard the aircraft, information on the aircraft flight conditions including measurements of the roll, pitch and yaw attitude angles of said aircraft with respect to a ground datum, comprising; a display device producing on a screen, an image representing on a screen background, a three-dimensional aircraft silhouette, the screen background being split into two zones: a lower zone symbolizing the ground and an upper zone symbolizing the sky which are separated by a horizontal boundary line symbolizing the horizon line, and the aircraft silhouette being mobile according to the three axes of rotation and viewed from the rear, according to attitude angles which correspond to the attitude angle measurements received and which are referenced with respect to an aircraft datum having a roll axis perpendicular to the surface of the screen and pitch and yaw axes in the plane of the screen, one, the pitch axis, being horizontal and the other, the yaw axis, vertical, wherein the horizon line displayed moves heightwise over the screen as a function of the height of the aircraft with respect to the ground, as measured by the equipment aboard the aircraft. 2. The attitude indicator as claimed in claim 1, wherein said display device produces, on a screen background, an aircraft 3D silhouette exhibiting a difference of hue between its belly and its back so as to differentiate the nose-up attitudes from the nose-down attitudes. 3. The attitude indicator as claimed in claim 1, wherein said display device produces, on a screen background, an aircraft 3D silhouette resembling the type of aircraft that is intended to be equipped therewith. 4. The attitude indicator as claimed in claim 1, wherein said display device produces a screen background split into two zones: one of which symbolizes the sky and is blue in color. 5. The attitude indicator as claimed in claim 1, wherein said display device produces a screen background split into two zones: one of which symbolizes the earth and is brown in color. 6. The attitude indicator as claimed in claim 1, wherein said display device produces a screen background split into two zones: one of which symbolizes the earth and is green in color. 7. The attitude indicator as claimed in claim 1, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette comprising parts changing aspect as a function of the momentary state of the corresponding part of the aircraft. 8. The attitude indicator as claimed in claim 7, wherein said parts changing aspect comprise movable elements depicting movable aerodynamic planes of the aircraft equipped with the attitude indicator, placed in positions corresponding to position indications provided by equipment aboard the aircraft. 9. The attitude indicator as claimed in claim 8, wherein said parts changing aspect comprise movable elements depicting the flaps of the aircraft equipped with the attitude indicator, placed in positions corresponding to flap position indications provided by equipment aboard the aircraft. 10. The attitude indicator as claimed in claim 9, wherein the movable depicting the flaps of the aircraft equipped with the attitude indicator are bar scales exhibiting as many bars as flap notches extended. 11. The attitude indicator as claimed in claim 8, wherein the movable elements depicting the airbrakes of the aircraft equipped with the attitude indicator, placed in positions corresponding to airbrake/spoiler position indications provided by equipment aboard the aircraft. 12. The attitude indicator as claimed in claim 11, wherein the movable elements depicting the airbrakes/spoiler of the aircraft equipped with the attitude indicator are bar scales exhibiting as many bars as airbrake notches extended. 13. The attitude indicator as claimed in claim 7, wherein said parts changing aspect comprise movable elements depicting the landing gear of the aircraft equipped with the attitude indicator, placed in positions corresponding to landing gear position indications provided by equipment aboard the aircraft. 14. The attitude indicator as claimed in claim 1, wherein said parts changing aspect comprise movable elements depicting the landing gear of the aircraft equipped with the attitude indicator, placed in positions corresponding to landing gear position indications provided by equipment aboard the aircraft. 15. The attitude indicator as claimed in claim 1, wherein said display device produces on a screen background in addition to an aircraft 3D silhouette, alignment symbols, corresponding to attitude presets for the aircraft. 16. The attitude indicator as claimed in claim 15, wherein said display device produces an image representing, on a screen background in addition to an aircraft 3D silhouette, an alignment symbol of circular shape, with the diameter of the aircraft 3D silhouette, and into which the pilot must inlay the fuselace or the tail of the aircraft 3D silhouette so as to comply with the corresponding attitude preset. 17. The attitude indicator as claimed in claim 15, wherein said display device produces an image representing, on a screen background, in addition to an aircraft 3D silhouette, an alignment symbol in the shape of an arc of a circle, with the concavity pointing toward the nose of the aircraft 3D silhouette, into which the pilot must bring the nose of the aircraft 3D silhouette so as to comply with the corresponding attitude preset. 18. The attitude indicator as claimed in claim 1, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with leading edges whose aspects differ as a function of the extent of the icing noted by equipment aboard the aircraft. 19. The attitude indicator as claimed in claim 18, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with leading edges having contours enhanced and overlaid as a function of the extent of the deposition of ice noted by equipment aboard the aircraft. 20. The attitude indicator as claimed in claim 19, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with leading edges having contours enhanced and overlaid in red or yellow, as a function of the extent of the deposition of ice noted by equipment aboard the aircraft. 21. The attitude indicator as claimed in claim 1, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines whose aspects differ as a function of their operating states. 22. The attitude indicator as claimed in claim 21, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines struck through with a cross in case of loss of power noted by equipment aboard the aircraft. 23. The attitude indicator as claimed in claim 22, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines struck through with a red or yellow cross (34) in case of loss of power noted by equipment aboard the aircraft. 24. The attitude indicator as claimed in claim 21, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines followed by a plume in case of detection of fire made by equipment aboard the aircraft. 25. The attitude indicator as claimed in claim 24, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines followed by a plume symbolized by a fan of lines in case of detection of fire made by equipment aboard the aircraft. 26. The attitude indicator as claimed in claim 24, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with engines followed by a plume symbolized by a fan of red lines in case of detection of fire made by equipment aboard the aircraft. 27. The attitude indicator as claimed in claim 1, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette and numeral inlays corresponding to values of flight parameters. 28. The attitude indicator as claimed in claim 27, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette and numeral inlays corresponding to the height of the aircraft above the ground as measured by equipment of the aircraft. 29. The attitude indicator as claimed in claim 28, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette with numeral inlays corresponding to the height of the aircraft above the ground as measured by equipment of the aircraft, it vertically enframes these numeral inlays (36) with two elevation arrows showing that a measurement of vertical distance with respect to the ground is involved. 30. The attitude indicator as claimed in claim 15, wherein said display device produces an image representing, on a screen background, in addition to an aircraft 3D silhouette, an alignment symbol corresponding to an attitude preset for the aircraft, it also produces two numeral inlays, one corresponding to the angle of pitch corresponding to the attitude preset and the other to the measured angle of pitch. 31. The attitude indicator as claimed in claim 15, wherein said display device produces an image representing, on a screen background, in addition to an aircraft 3D silhouette, an alignment symbol in the form of two strokes against which the pilot must bring the leading edge of the wings of the aircraft silhouette so as to comply with the corresponding attitude preset. 32. The attitude indicator as claimed in claim 21, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette, with engines colored yellow or amber in case of loss of power noted by equipment aboard the aircraft. 33. The attitude indicator as claimed in claim 21, wherein said display device produces an image representing, on a screen background, an aircraft 3D silhouette, with engines colored red and followed by a plume in case of detection of fire made by equipment aboard the aircraft. 34. The attitude indicator as claimed in claim 1, wherein said display device produces at the image boarder, at least one scale graduated in terms of angle of pitch and a movable marker moving opposite same indicating the graduation value corresponding to the pitch angle measurement provided by the equipment aboard the aircraft. 35. The attitude indicator as claimed in claim 34, wherein said display device produces, at the image lateral borders, two scales graduated in terms of angle of pitch and movable markers moving opposite same indicting the graduation value corresponding to the pitch angle measurement provided by the equipment aboard the aircraft. 36. The attitude indicator as claimed in claim 34, wherein said display device produces, at the image upper border, a scale graduated in terms of angle of roll and a movable marker moving opposite same indicting the graduation value corresponding to the roll angle measurement provided by the equipment aboard the aircraft. |
Phosphate limited inducible promoter and a bacillus expression system |
An evolvable production strain of B. subtilis exhibiting continuous or high level expression during protein evolution is described. An evolved Bacillus subtilis pstS promoter facilitates screening and production of secreted proteins. |
1. An isolated nucleic acid comprising a B. subtilis PstS promoter variant. 2. The isolated nucleic acid of claim 1, wherein said nucleic acid encodes Os-6. 3. At least one B. subtilis host cell comprising the nucleic acid of claim 1. 4. The host cells of claim 3, wherein said nucleic acid is integrated into the chromosome of said host cell. 5. The host cells of claim 3, further comprising a nucleic acid encoding a polypeptide of interest under the transcriptional control of said PstS promoter variant. 6. An expression construct comprising an isolated nucleic acid encoding a B. subtilis PstS promoter and a nucleic acid molecule encoding a polypeptide of interest. 7. A method for controlling the expression kinetics of a protein of interest, said method comprising culturing the host cells of claim 3 under phosphate limiting conditions. 8. A method of producing a protein, comprising: (a) providing a host cell transformed with an expression vector comprising the nucleic acid of claim 1; (b) cultivating said transformed host cell under conditions suitable for said host cell to produce said protein; and (c) recovering said protein. 9. A method of screening mutants cells for protein secretion comprising: (a) providing a host cell transformed with an expression vector comprising the nucleic acid of claim 1; (b) cultivating said transformed host cell under conditions suitable for said host cell to produce said protein in the presence of a hydrolysable substrate; and (c) measuring the extent of hydrolysis of the substrate. 10. A Bacillus host cell comprising the nucleic acid of claim 1, wherein said Bacillus host cell expresses a heterologous sequence under nutrient limited conditions. 11. The Bacillus of claim 10, wherein said expression is prolonged. |
<SOH> BACKGROUND OF THE INVENTION <EOH>One desired property for a Bacillus expression cassette is a strong promoter, induced in stationary phase from a single gene copy. However, it was originally believed that a single gene expression system would not deliver enough messages to saturate the expression machinery of the Bacillus host. Thus, the current Bacillus production protocols have been designed such that amplification is utilized in order to create tandem gene repeats. Two problems typically arise from the use of these repeats. First, genetic manipulation of tandem genes is very difficult. Consequently, protein engineering is performed in lab strains as single copy, then later moved from a lab strain into a production strain and amplified before testing. This causes delays in product development and is plagued by numerous concerns, including the differences between the characteristics of screen and production strains. Second, the amplification process used to make the repeats requires an antibiotic marker, which is not allowed for use in some production strains (e.g., depending upon the product produced by the strains). Thus, there is a need for improved Bacillus expression systems. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides improved methods and compositions for Bacillus expression systems. In preferred embodiments, the present invention provides evolvable production strains of B. subtilis exhibiting continuous or high level expression during protein evolution. In particularly preferred embodiments, the evolved B. subtilis pstS promoter of the present invention facilitates screening and production of secreted proteins. In some particularly preferred embodiments, the evolved promoter of the present invention provides better specific productivity in low phosphate medium than other stationary phase promoters (e.g., aprE), drives long term production of relatively large amounts of protein during fermentation, is not sensitive to comK, finds use as a single gene with no antibiotic marker, and finds use in production as a single or amplified gene. Furthermore, in some embodiments, the use of a sporulation minus strain (e.g., spoIIe) prevents cells from entering the non-productive spore state. In some preferred embodiments, the present invention provides isolated nucleic acid comprising a B. subtilis PstS promoter variant. In some particularly preferred embodiments, the present invention provides an isolated nucleic acid that encodes OS-6. In some alternative embodiments, the present invention provides at least one B. subtilis host cell comprising nucleic acid comprising a B. subtilis PstS promoter variant. In still further embodiments, the present invention provides host cells in which the B. subtilis PstS promoter variant nucleic acid is integrated into the chromosome of the host cell. In yet additional embodiments, the present invention provides host cells that further comprise a nucleic acid encoding a polypeptide of interest under the transcriptional control of the PstS promoter variant. The present invention also provides expression constructs comprising an isolated nucleic acid encoding B. subtilis PstS promoter and a nucleic acid molecule encoding a polypeptide of interest. The present invention further provides methods for controlling the expression kinetics for a protein of interest, wherein preferred methods comprise culturing the cells under phosphate limiting conditions. In other embodiments, the present invention provides methods for producing a protein. In some preferred embodiments, the methods of the present invention comprise providing a host cell transformed with an expression vector comprising nucleic acid encoding at least one PstS promoter variant, cultivating the transformed host cell under conditions suitable for said host cell to produce the protein; and recovering the protein. The present invention also provides methods for screening mutants cells for protein secretion (i.e., secretion of a protein of interest) comprising: providing a host cell transformed with an expression vector comprising PstS promoter; cultivating the transformed host cell under conditions suitable for the host cell to produce the protein in the presence of a hydrolysable substrate; and measuring the extent of hydrolysis of the substrate. The present invention further provides Bacillus host cells capable of expressing a heterologous sequence under nutrient limited conditions. In some preferred embodiments, the expression by Bacillus is prolonged. |
Method for making diamond-coated composite materials |
The invention concerns a method for making a diamond-coated composite material comprising deposition on a substrate of an intermediate layer and deposition on the intermediate layer of a diamond coating. The invention is characterised in that the intermediate layer is an expansible layer capable of producing chemical bonds with the substrate while chemically developing during deposition of the diamond coating. The invention is applicable to a large number of articles and components made of diamond composite. |
1. A process for manufacturing a diamond-coated composite comprising a substrate consisting of a cobalt-alloyed tungsten carbide WC, the proportion of cobalt by weight ranging from 3 to 20%, in which process the following are carried out in succession: deposition on the substrate of an interlayer of titanium heminitride or titanium carbonitride capable of forming chemical bonds with the substrate and with a diamond coating, surface treatment of the interlayer, annealing of the substrate/interlayer assembly and deposition of the diamond coating by CVD techniques. 2. The method as claimed in claim 1, characterized in that the surface treatment of the interlayer is a polishing treatment. 3. Diamond-coated composites obtained by the process as claimed in either of claims 1 and 2. 4. Articles or parts made of a diamond-coated composite as claimed in claim 3. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.