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<SOH> SUMMARY OF THE INVENTION <EOH>According to one aspect of the invention, a mold assembly is provided for manufacturing a trim component of an automotive vehicle. The mold assembly comprises a first mold half having a contoured mold surface and an outer peripheral edge and a second mold half having a contoured mold surface and an outer peripheral edge. The mold halves are movable between an open position providing access to the respective mold surfaces and a closed position with the outer peripheral edge of the first mold half aligned with and abutting the outer peripheral edge of the second mold surface. A cutting ridge is formed around the outer peripheral edge of one of the mold halves for engaging the other of the mold halves in the closed position whereby upon the injection of a urethane material onto at least one of the mold halves, the cutting ridge perforates any oversprayed material extending outside of the mold surfaces when the mold halves are moved to the closed position. According to another aspect of the invention, a method is provided for manufacturing a trim component for an automotive vehicle with a mold assembly having a first mold half having a first mold surface and a cutting ridge surrounding the first mold surface and a second mold half having a second mold surface and a projection surrounding the second mold surface, wherein the mold halves are moveable relative to each other between an open position having the cutting ridge disengaged from the projection and a closed position having the cutting ridge engage the projection. The method comprises the steps of applying an in-mold coat to each of the mold halves when the mold halves are in the open position; applying a skin coat to each in-mold coat when the mold halves are in the open position, whereby the skin coat in the first mold half bonds with the respective in-mold coat to form a first structural skin coat in the second mold half bonds with the respective in-mold coat to form a second structural skin; moving the mold halves to the closed position whereby the cutting ridge abuts the projection to cut any overspray of in-mold coat and skin coat extending outside of the first and second mold surfaces; injecting a foam into the mold halves after applying the skin coat to expand and cure between the first and second structural skins forming the trim component; moving the mold halves to the open position after forming the trim component; and removing the trim component from the mold assembly after moving the mold halves to the open position.

Device for combating targets

An ammunition unit, for combating targets (10) with or without using shaped charge effect, that incorporates an openable or removable and replaceable hull or outer casing (2). The explosive charge in the ammunition unit comprises a charge section (3) with shaped charge function arranged to be able to assume either of two freely selectable positions in the ammunition unit, the first of which enables the charge to exert its shaped charge function and the second of which disables the shaped charge function and enables a different effect to be triggered.

1. A device for combating targets (10, 12) with or without using shaped charge effect wherein an ammunition unit (1), for example in the form of a round, shell, projectile, etc., is designed with an openable or removable and replaceable hull or outer casing (2) and whereby the ammunition unit charge comprises an explosive charge section (3) with shaped charge function such that the said charge section is arranged to be indexible between two freely selectable positions, in the first of which the shaped charge function is enabled and in the second of which the shaped charge function is disabled and the charge thus exerts a different function such as a pressure generating and/or fragmentation effect function. 2. A device as claimed in claim 1 wherein the explosive charge section (3) is arranged to be indexible from the first mode/position to the second, or vice versa, by indexing/reversing the main charge 180° in the ammunition unit, such indexing preferably being performed manually. 3. A device as claimed in claim 1 or 2 wherein the initial position of the explosive charge section in the ammunition unit is the position that enables the shaped charge function and the said explosive charge section can be indexed to the second position after opening or removing the hull or outer casing or parts thereof, or can be indexed from second position to initial position in a similar manner. 4. A device as claimed in claim 1, 2 or 3 wherein the explosive charge section (3), herein called the first charge section in the ammunition unit, is interactable with another charge section herein called the second charge section (4). 5. A device as claimed in claim 4 wherein in the first position the conical shaped charge liner (3a, 3b) faces forwards and the rear face (3c) of the first charge section (3) abuts on the front face (4a) of the second charge section (4). 6. A device as claimed in claim 5 wherein the first charge section (3) displays a flat rear face (3c) that in the first position interacts with the corresponding flat front face (4a) of the second charge section (4) while in the second position the first charge section rests against the periphery of the flat front face (4a) of the second charge section (4) to form an empty triangular space (11). 7. A device as claimed in any of the previous claims wherein the hull or casing is openable or removable via a screw joint (9, 9′) arranged so that at least the front section (2a) of the hull or casing (2) is removable to enable the first charge section (3) to be indexed 180°. 8. A device as claimed in any of the previous claims wherein the conical front and rear cavities of the first charge section are arranged so that the distance (a) between the innermost points of the said cavities is relatively small. 9. A device as claimed in any of the previous claims wherein the shaped charge liner (3a, 3b) extends to the lateral surface (3d) of the first charge section (3) thereby forming an extension of the said lateral surface.

Camera-based touch system

A camera-based touch system (50) includes a passive touch surface (60) and at least two cameras (63) associated surface. The at least two cameras (63) have overlapping fields of view (FOV) encompassing the touch surface. The at least two cameras (63) acquire images of the touch surface from different locations and generate image data. A processor (54) receives and processes image data generated by the at least two cameras to determine the location of the pointer relative to the touch surface when the pointer is captured in images acquired by the at least two cameras. Actual pointer contact with the touch surface sand pointer hover above the touch surface can be determined.

1. A camera-based touch system comprising: at least two cameras associated with a passive touch surface and having overlapping fields of view encompassing said touch surface, said at least two cameras acquiring images of said touch surface from different locations and generating image data; and a processor receiving and processing image data generated by said at least two cameras to determine the location of a pointer relative to said touch surface when said pointer is captured in images acquired by said at least two cameras. 2. A touch system according to claim 1 wherein said at least two cameras are digital cameras having fields of view looking generally along the plane of said touch surface. 3. A touch system according to claim 2 wherein the image data generated by each digital camera includes a pointer median line x and a pointer tip location z. 4. A touch system according to claim 3 wherein each of said digital cameras includes a pixel array having selectable pixel rows, pixel intensities of pixels in said selectable pixel rows being used during generation of said image data. 5. A touch system according to claim 4 wherein pixel intensities of pixels in a region of interest within said selectable pixel rows are used during generation of said image data. 6. A touch system according to claim 5 wherein each of said digital cameras packages said image data into packets for transmission to said processor to provide bandwidth economy. 7. A touch system according to claim 6 wherein each of said digital cameras includes a CMOS image sensor and a digital signal processor, said digital signal processor receiving image output from said image sensor and executing a find pointer routine to determine if a pointer is in each image acquired by said digital camera, and if so the median line x of said pointer. 8. A touch system according to claim 7 wherein during said find pointer routine, said digital signal processor builds a vertical intensity histogram including columns of pixel intensities representing differences between an acquired image and a background image, the column of said vertical intensity-histogram having the largest pixel intensity above a threshold level being used to define the center of said region of interest, the width of said region of interest being defined by columns of said vertical intensity histogram on opposite sides of the column defining the center of said region of interest that have pixel intensities greater than said threshold level. 9. A touch system according to claim 8 wherein the digital signal processor of each digital camera analyses the pixels in said region of interest to locate the pixel row where the pointer tip is located and determine said pointer tip location z. 10. A touch system according to claim 9 wherein the digital signal processor of each digital camera creates a mask in said region of interest with white pixels representing said pointer and black pixels representing background to enable said median line x and pointer tip location to be calculated. 11. A touch system according to claim 10 wherein the digital signal processor of each digital camera further executes an update background image routine to update the background image after each image is acquired. 12. A touch system according to claim 11 wherein during said update background image routine, the digital signal processor of each digital camera uses the equation: Bn+1(i,j)=(1-a)Bn(i,j)+aI(i,j) where: Bn+1 is the new background image; Bn is the current background image; I is the current acquired image; i,j are the row and column coordinates of the background image pixels being updated; and a is a number between 0 and 1 that indicates the degree of learning that should be taken from the current acquired image I. 13. A touch system according to claim 12 wherein the digital signal processor of each digital camera further determines the differences between each acquired image and the background image to detect changing light conditions. 14. A touch system according to claim 13 wherein each digital camera transmits light condition information to said processor, said processor using said light condition information to adjust the exposure of each said digital camera. 15. A touch system according to claim 14 wherein the digital signal processor of each digital camera further executes a create packet routine to package said image data and light condition information into said packets. 16. A touch system according to claim 3 wherein for image data received from each digital camera, said processor calculates an angle φcam using the equation: tan ⁢ ⁢ ϕ cam = 2 ⁢ ( x a ) ⁢ tan ⁢ FOV 2 1 - ( 2 ⁢ x a - 1 ) ⁢ tan 2 ⁢ FOV 2 where: x is the number representing the median line or tip of the pointer; and a is the total length enclosed by the field of view (FOV) of the digital camera at a distance from the camera; said processor using the calculated angles to determine the position of the pointer relative to said touch surface using triangulation. 17. A touch system according to claim 16 wherein said calculated angles are adjusted to take into account digital camera offsets prior to determination of said pointer position. 18. A touch system according to claim 17 wherein said digital camera offsets are determined during execution of a digital camera calibration routine. 19. A touch system according to claim 17 including at least three digital cameras, said processor determining the pointer position using triangulation for pairs of digital cameras and averaging the determined pointer positions. 20. A touch system according to claim 19 wherein said processor further executes a touch surface determination routine to calculate the orientation of the touch surface as seen by each digital camera to determine when the pointer is in contact with said touch surface and when said pointer is hovering above said touch surface. 21. A touch system according to claim 20 wherein said processor further calculates the velocity of a pointer as said pointer moves toward said touch surface within the fields of view of said digital cameras. 22. A touch system according to claim 20 wherein said processor tracks said pointer within the fields of view of said digital cameras. 23. A touch system according to claim 21 wherein said processor tracks said pointer using at least one Kalman filter. 24. A touch system according to claim 19 further including a computer coupled to said processor, said computer receiving said pointer location from said processor. 25. A camera-based touch system comprising: a generally rectangular passive touch surface on which contacts are made using a pointer; a digital camera mounted adjacent each corner of said touch surface, said digital cameras having overlapping fields of view encompassing said touch surface, said digital cameras acquiring images of said touch surface and generating image data that includes the median line x and pointer tip location z of a pointer when said pointer is captured in images acquired by said digital cameras; and a processor receiving and processing image data generated by said digital cameras to determine the location of said pointer relative to said touch surface and whether said pointer is in contact with said touch surface. 26. A touch system according to claim 25 wherein each of said digital cameras includes a pixel array with selectable pixel rows, pixel intensities of pixels in said selectable pixel rows being used during generation of said image data. 27. A touch system according to claim 26 wherein pixel intensities of pixels in a region of interest within said selectable pixel rows are used during generation of said image data. 28. A touch system according to claim 27 wherein each of said digital cameras includes a CMOS image sensor and a digital signal processor, said digital signal processor receiving image output from said image sensor and executing a find pointer routine to determine if a pointer is in each image acquired by said digital camera, and if so the median line x of said pointer. 29. A touch system according to claim 28 wherein during said find pointer routine, said digital signal processor of each digital camera builds a vertical intensity histogram including columns of pixel intensities representing differences between an acquired image and a background image, the column of said vertical intensity histogram having the largest pixel intensity above a threshold level being used to define the center of said region of interest, the width of said region of interest being defined by columns of said vertical intensity histogram on opposite sides of the column defining the center of said region of interest that have pixel intensities greater than a threshold level. 30. A touch system according to claim 29 wherein the digital signal processor of each digital camera analyses the pixels in said region of interest to locate the pixel row where the pointer tip is located and determine said pointer tip location z. 31. A touch system according to claim 30 wherein the digital signal processor of each digital camera creates a mask in said region of interest with white pixels representing said pointer and black pixels representing background to enable said median line x and pointer tip location to be calculated. 32. A touch system according to claim 31 wherein the digital signal processor of each digital camera further executes an update background image routine to update the background image after each image is acquired. 33. A touch system according to claim 32 wherein during said update background image routine, the digital signal processor of each digital camera uses the equation: Bn+1(i,j)=(1-a)Bn(i,j)+aI(i,j) where: Bn+1 is the new background image; Bn is the current background image; I is the current acquired image; i,j are the row and column coordinates of the background image pixels being updated; and a is a number between 0 and 1 that indicates the degree of learning that should be taken from the current acquired image I. 34. A touch system according to claim 33 wherein the digital signal processor of each digital camera further determines the differences between each acquired image and the background image to detect changing light conditions. 35. A touch system according to claim 34 wherein each digital camera transmits light condition information to said processor, said processor using said light condition information to adjust the exposure of each said digital camera. 36. A touch system according to claim 3 5 wherein the digital signal processor of each digital camera further executes a create packet routine to package said image data and light condition information into packets for transmission to said processor. 37. A touch system according to claim 26 wherein for image data received from each digital camera, said processor calculates an angle φcam using the equation: tan ⁢ ⁢ ϕ cam = 2 ⁢ ( x a ) ⁢ tan ⁢ FOV 2 1 - ( 2 ⁢ x a - 1 ) ⁢ tan 2 ⁢ FOV 2 where: x is the number representing the median line or tip of the pointer; and a is the total length enclosed by the field of view (FOV) of the digital camera at a distance from the camera; said processor using the calculated angles to determine the position of the pointer relative to said touch surface using triangulation. 38. A touch system according to claim 37 wherein said calculated angles are adjusted to take into account digital camera offsets prior to determination of said pointer position. 39. A touch system according to claim 37 wherein said processor further executes a touch surface determination routine to calculate the orientation of the touch surface as seen by each digital camera to determine when the pointer is in contact with said touch surface and when said pointer is hovering above said touch surface. 40. A touch system according to claim 39 wherein said processor further calculates the velocity of a pointer as said pointer moves toward said touch surface within the fields of view of said digital cameras. 41. A touch system according to claim 40 wherein said processor track said pointer within the fields of view of said digital cameras. 42. A touch system according to claim 41 wherein said processor tracks said pointer using at least one Kalman filter. 43. A touch system according to claim 26 wherein said touch surface is bordered by a frame and wherein each of said digital cameras is mounted on a frame assembly positioned at a corner of said touch surface that is coupled to a frame, each digital camera being oriented so that the field of view thereof looks downward and generally along the plane of said touch surface. 44. A touch system according to claim 26 further including a computer coupled to said processor, said computer receiving pointer location information from said processor and using said pointer location information to update an applications program executed thereby. 45. A touch system according to claim 44 wherein computer display information is presented on said touch surface. 46. A method of detecting the position of a pointer relative to a touch surface comprising the steps of: acquiring images of said touch surface from different locations using cameras having overlapping fields of view and generating image data; and processing said image data to detect the existence of a pointer within said acquired images and to determine the location of said pointer relative to said touch surface. 47. The method of claim 46 wherein during the processing step, the location of said pointer relative to said touch screen is determined using triangulation. 48. The method of claim 47 wherein during said processing step, the images are processed to determine when said pointer is in contact with said touch surface and when said pointer is hovering above said touch surface. 49. The method of claim 48 wherein said processing step further includes the step of tracking the pointer as the pointer approaches the touch surface.

<SOH> BACKGROUND ART <EOH>Touch systems are well known in the art and typically include a touch screen having a touch surface on which contacts are made using a pointer in order to generate user input. Pointer contacts with the touch surface are detected and are used to generate corresponding output depending on areas of the touch surface where the contacts are made. There are basically two general types of touch systems available and they can be broadly classified as “active” touch systems and “passive” touch systems. Active touch systems allow a user to generate user input by contacting the touch surface with a special pointer that usually requires some form of on-board power source, typically batteries. The special pointer emits signals such as infrared light, visible light, ultrasonic frequencies, electromagnetic frequencies, etc. that activate the touch surface. Passive touch systems allow a user to generate user input by contacting the touch surface with a passive pointer and do not require the use of a special pointer in order to activate the touch surface. A passive pointer can be a finger, a cylinder of some material, or any suitable object that can be used to contact some predetermined area of interest on the touch surface. Passive touch systems provide advantages over active touch systems in that any suitable pointing device, including a user's finger, can be used as a pointer to contact the touch surface. As a result, user input can easily be generated. Also, since special active pointers are not necessary in passive touch systems, battery power levels and/or pointer damage, theft, or pointer misplacement are of no concern to users. Passive touch systems have a number of applications relating to computer operation and video display. For example, in one interactive application, as is disclosed in U.S. Pat. No. 5,448,263 to Martin, assigned to the assignee of the present invention, a passive touch system is coupled to a computer and the computer display is presented on the touch surface of the touch screen. The coordinates representing specific locations on the touch surface are mapped to the computer display. When a user contacts the touch surface, the coordinates of the contact position are fed back to the computer and mapped to the computer display thereby allowing the user to operate the computer in a manner similar to using a computer mouse simply by contacting the touch surface. Furthermore, the coordinates fed back to the computer can be recorded in an application and redisplayed at a later time. Recording contact coordinates is typically done when it is desired to record information written or drawn on the touch surface by the user. The resolution of a passive touch screen determines if the touch system is suitable for recording information written or drawn on the touch screen or only useful for selecting areas on the touch screen mapped to regions on the computer or video display in order to manipulate the computer or video display. Resolution is typically measured in dots per inch (DPI). The DPI is related to the size of the touch screen and the sampling ability of the touch system hardware and software used to detect contacts on the touch surface. Low-resolution passive touch screens only have enough DPI to detect contacts on the touch surface within a large group of pixels displayed by the computer or video display. Therefore, these low-resolution passive touch screens are useful only for manipulating the computer or video display. On the other hand, high-resolution passive touch screens have sufficient DPI to detect contacts that are proportional to a small number of pixels or sub-pixels of the computer or video display. However, a requirement for high-resolution touch screens is the ability to detect when the pointer is in contact with the touch surface. This is necessary for writing, drawing, mouse-click operations, etc. Without the ability to detect pointer contact with the touch screen, writing and drawing would be one continuos operation, and mouse clicks would not be possible thereby making computer display manipulation virtually impossible. A secondary requirement is the ability to detect when the pointer is “hovering” above the touch surface. Although not required for writing or drawing, today's computer operating systems are increasingly using hover information to manipulate computer or video displays or pop-up information boxes. Passive touch screens are typically either of the analog resistive type, surface acoustic wave (SAW) type or capacitive type. Unfortunately, these touch screens suffer from a number of problems or shortcomings as will be described. Analog resistive touch screens typically have a high-resolution. Depending on the complexity of the touch system, the resolution of the touch screen can produce 4096×4096 DPI or higher. Analog resistive touch screens are constructed using two flexible sheets that are coated with a resistive material and arranged as a sandwich. The sheets do not come into contact with each other until a contact has been made. The sheets are typically kept separated by insulating microdots or by an insulating air space. The sheets are constructed from ITO, which is mostly transparent. Thus, the touch screen introduces some image distortion but very little parallax. During operation of an analog resistive passive touch screen, a uniform voltage gradient is applied in one direction along a first of the sheets. The second sheet measures the voltage along the first sheet when the two sheets contact one another as a result of a contact made on the touch surface. Since the voltage gradient of the first sheet can be translated to the distance along the first sheet, the measured voltage is proportional to the position of the contact on the touch surface. When a contact coordinate on the first sheet is acquired, the uniform voltage gradient is then applied to the second sheet and the first sheet measures the voltage along the second sheet. The voltage gradient of the second sheet is proportional to the distance along the second sheet. These two contact coordinates represent the X-Y position of the contact on the touch surface in a Cartesian coordinate system. Unfortunately, since mechanical pressure is required to bring both sheets into contact, analog resistive touch screens can only detect contact when there is sufficient pressure to bring the two sheets together. Analog resistive passive touch screens also cannot sense when a pointer is hovering over the touch surface. Therefore, in the case of analog resistive touch screens contact events and positions can only be detected when actual contacts are made with the touch surface. Surface acoustic wave (SAW) touch screens typically provide for medium resolution and are not suitable for recording good quality writing. SAW touch screens employ transducers on the borders of a glass surface to vibrate the glass and produce acoustic waves that ripple over the glass surface. When a contact is made on the glass surface, the acoustic waves reflect back and the contact position is determined from the signature of the reflected acoustic waves. Unfortunately, SAW touch screens exhibit noticeable parallax due to the thickness of the vibrating glass that is placed over the surface of the video or computer display. Also, contact events and positions can only be detected when actual contacts are made with the glass surface. Furthermore, SAW touch screens do not scale beyond a few feet diagonal. Capacitive touch screens provide for low resolution because contacts can only be determined in large areas (approximately ½″×½″). As a result, capacitive touch screens cannot be used for recording writing or drawing but are suitable for selecting areas on the touch screen corresponding to computer generated buttons displayed on the video or computer display. Capacitive touch screens also suffer disadvantages in that they are sensitive to temperature and humidity. Similar to analog resistive touch screens and SAW touch screens, capacitive touch screens can also only detect contact events and positions when actual contacts are made with the touch surface. Scalability of passive touch screens is important since the demand for larger electronic digitizers is increasing. Where digitizers were once small desktop appliances, today they have found there way onto electronic whiteboarding applications. The need to build a passive touch sensitive “wall” has become a requirement for new touch screen applications. Existing passive touch screens of the types discussed above are all limited in the maximum size where they are still functional. As will be appreciated, improvements to passive touch systems are desired. It is therefore an object of the present invention to provide a novel camera-based touch system.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Embodiments of the present invention will now be described more fully with reference to the accompanying drawings in which: FIG. 1 is a schematic diagram of a camera-based touch system in accordance with the present invention; FIG. 2 is an isometric view of a touch screen forming part of the touch system of FIG. 1 ; FIG. 3 is an isometric view of a corner portion of the touch screen of FIG. 2 ; FIG. 4 is a schematic diagram of a digital camera forming part of the touch screen of FIG. 2 ; FIG. 5 is a schematic diagram of a master controller forming part of the touch system of FIG. 1 ; FIG. 6 is a flowchart showing the steps performed during execution of a processFrame routine; FIG. 7 is a flowchart showing the steps performed during execution of a segmentPointer routine; FIG. 8 is a flowchart showing the steps performed during execution of a findPointer routine; FIG. 9 shows an image acquired by a digital camera and a pixel subset of the image that is processed; FIG. 10 shows a region of interest (ROI) within the pixel subset of FIG. 9 ; FIG. 11 shows triangulation geometry used to calculate a pointer contact position on the touch surface of the touch screen illustrated in FIG. 2 ; FIG. 12 shows an image acquired by a digital camera including the pointer tip and its median line; FIG. 13 shows pointer contact and pointer hover for different orientations of the pointer; FIG. 14 is an image of the touch surface of the touch screen as seen by a digital camera; FIGS. 15 and 16 show the results of a Matlab simulation of pointer tracking using a Kalman filter; and FIGS. 17 a to 17 d show the results of another Matlab simulation of pointer tracking using a Kalman filter. detailed-description description="Detailed Description" end="lead"?

Equipment and method for enhancing combustion and heat transfer in a boiler by using sound

The invention concerns equipment and a method for enhancing the combustion event and heat transfer in a heating boiler. According to the invention, the space above the major combustion zone in the combustion space of the heating boiler is equipped with sound sources, which are used to generate an acoustic field to enhance the combustion event and to achieve more complete combustion.

1. Equipment for enhancing the combustion event and heat transfer in a heating boiler, said equipment comprising sound sources (S) in a space above the major combustion zone in a combustion space (11) of the heating boiler (10), which sound sources (S) generate an acoustic field in order to enhance the combustion event and a more complete combustion, characterised in that the sound sources (S) are placed in such a way that the acoustic pressure patterns generated by the sound sources (S) meet at angles of 20-90° sideways and/or vertically and that the sound sources (S) are fitted into the heating boiler (10) in such a way that the generated acoustic field is rotating. 2. Equipment as defined in claim 1, characterised in that the acoustic field generated by the sound sources (S) is continuous. 3. Equipment as defined in claim 1 or 2, characterised in that the acoustic pressure level generated by the sound sources (S) is no less than 130 dB at the place where the acoustic pressure patterns meet. 4. Equipment as defined in any one of claims 1-3, characterised in that the frequency of the sound generated by the sound sources (S) is in a range of 20-1000 Hz. 5. Equipment as defined in any one of claims 1-4, characterised in that the secondary and/or tertiary air of the heating boiler (10) or a part of that air has been supplied into the boiler through the sound sources (S). 6. Equipment as defined in any one of claims 1-5, characterised in that the sound sources (S) are fitted into the heating boiler (10) in such a way that the generated rotating acoustic field rotates in the direction of the positive acoustic pressure. 7. Equipment as defined in any one of claims 1-6, characterised in that the sound sources (S) are fitted into the heating boiler (10) in such a way that the sound frequency increases towards the top part of the heating boiler (10). 8. Equipment as defined in any one of claims 1-7, characterised in that the sound sources (S) are acoustic horns. 9. Equipment as defined in any one of claims 1-7, characterised in that the sound sources (S) are pneumatically operated continuous sirens. 10. Equipment as defined in any one of claims 1-7, characterised in that the sound sources (S) are sound sources (SP) based on a pulse burner. 11. Equipment as defined in claim 10, characterised in that the fuel of the pulse burner (SP) functioning as sound source essentially includes a gaseous inflammable matter and an oxidiser. 12. Equipment as defined in claim 10 or 11, characterised in that the pulse burner (SP) functioning as sound source includes an antechamber (SP1), into which air under pressure is arranged to be supplied, a set of valves (V) opened and closed by pressure and separating the space between the antechamber (SP1) and the combustion chamber (SP2), and into which combustion chamber (SP2) supply of fuel is arranged, and a sound horn (SP3). 13. Equipment as defined in claim 12, characterised in that a continuous supply of air under pressure is arranged into the antechamber (SP1) of the pulse burner (SP) through an assembly (L1). 14. Equipment as defined in claim 12 or 13, characterised in that the supply of fuel into the combustion chamber (SP2) of the pulse burner (SP) is arranged through an assembly (L2). 15. Equipment as defined in any one of claims 12-14, characterised in that the pressure of the combustion chamber (SP2) of the pulse burner (SP) discharges into the combustion space (11) of the heating boiler (10). 16. Method for enhancing the combustion event and heat transfer in a heating boiler, in which method an acoustic field is generated with sound sources (S) in a space above the major combustion zone in a combustion space (11) of the heating boiler (10), characterised in that a rotating acoustic field is generated by sound sources (S), which are located on various sides and/or at different elevations of the heating boiler (10) in such a way that the acoustic pressure patterns generated by the sound sources (S) meet at angles 20-90° sideways and/or vertically. 17. Method as defined in claim 16, characterised in that sound sources (SP) based on a pulse burner are used as sound sources (S).

Early diagnosis of conformational diseases

A method for the diagnosis or detection of conformational diseases by assaying for a marker (the pathogenic conformer) of such diseases in a sample is described, which method comprises a cyclic amplification system to increase the levels of the pathogenic conformer which causes such diseases. In particular, such transmissible conformational diseases may be prion encephalopathies. Assays, diagnostic kits and apparatus based on such methods are also disclosed.

1. A method for the diagnosis or detection of a conformational disease which is characterized by a conformational transition of an underlying protein between a non-pathogenic and a pathogenic conformer, by assaying a marker of said disease within a sample, which method comprises: (i) contacting said sample with an amount of the non-pathogenic conformer; (ii) disaggregating any aggregates eventually formed during step (i); and (iii) determining the presence and/or amount of said pathogenic conformer within the sample, the pathogenic conformer being a marker for the presence of said disease. 2. The method of claim 1, wherein step (i) comprises step (ia) incubating said sample/non-pathogenic conformer. 3. The method of claim 2, wherein steps (ia) and (ii) form a cycle which is repeated at least twice before carrying out step (iii). 4. The method of claim 3, wherein the cycle is repeated from 5 to 40 times before carrying out step (iii). 5. The method of any one of the preceding claims, wherein step (i) is carried out under physiological conditions. 6. The method of any one of the preceding claims wherein the amount of the non-pathogenic conformer in step (i) is an excess amount. 7. The method of any one of the preceding claims, wherein the conformational disease is a transmissible conformational disease. 8. The method of any one of the preceding claims, wherein the sample to be analysed is subjected to a pre-treatment for selectively concentrating the pathogenic conformer in the sample. 9. The method of claim 8, wherein the pathogenic conformer is PrPSc and the pre-treatment is the extraction from the sample of a fraction which is insoluble in mild detergents. 10. An assay for a marker of a conformational disease which is characterized by a conformation transition of an underlying protein between a non-pathogenic and a pathogenic conformer, within a sample, which assay comprises the following steps: (i) contacting said sample with an amount of the non-pathogenic conformer; (ii) disaggregating any aggregates eventually formed during step (i); and (iii) determining the presence and/or amount of said pathogenic conformer within the sample, the pathogenic conformer being a marker for the presence of said disease. 11. The assay of claim 10, wherein step (i) comprises step (ia) incubating said sample/non-pathogenic conformer. 12. The assay according to claim 11, wherein steps (ia) and (ii) form a cycle which is repeated at least twice before carrying out step (iii). 13. A diagnostic kit for use in the assay of any one of claims 10 to 12 which comprises a known amount of the non-pathogenic conformer, a multi-well microtitre plate and a multi-well sonicator. 14. A method for identifying a compound which modulates the conformational transition of an underlying protein between a non-pathogenic and a pathogenic conformer, comprising: (i) contacting an amount of the non-pathogenic conformer with an amount of the pathogenic conformer (a) in the presence of said compound and (b) in the absence of said compound; (ii) disaggregating any aggregates eventually formed during step (i); and (iii) determining the amount of the pathogenic conformer (a) in the presence of said compound and (b) in the absence of said compound. 15. The method of any one of claims 1 to 9 or 14 or the assay of any one of claims 10 to 12, wherein the pathogenic conformer is PrPSc, the non-pathogenic conformer is PrPC and the underlying protein is the Prion Protein. 16. A method for detecting the presence of a pathogenic form of prion protein within a sample, comprising: (i) contacting the sample with an amount of non-pathogenic prion protein; (ia) incubating the sample/non-pathogenic prion protein; (ii) disaggregating any aggregates formed during step (ia); repeating steps (ia)-(ii) two or more times; and then (iii) determining the presence and/or amount of pathogenic prion protein within the sample. 17. A method for diagnosing CJD within a patient, comprising: taking a sample from the patient; (i) contacting the sample with an amount of PrPC protein; (ia) incubating the sample/PrPC protein; (ii) disaggregating any aggregates formed during step (ia); repeating steps (ia)-(ii) two or more times; and then (iii) determining the presence and/or amount of PrPSc within the sample. 18. A method for detecting the presence of a pathogenic form of β-amyloid protein within a sample, comprising: (i) contacting the sample with an amount of non-pathogenic β-amyloid protein; (ia) incubating the sample/non-pathogenic β-amyloid protein; (ii) disaggregating any aggregates formed during step (ia); repeating steps (ia)-(ii) two or more times; and then (iii) determining the presence and/or amount of pathogenic β-amyloid protein within the sample. 19. A method for diagnosing Alzheimer's disease in a patient, comprising: taking a sample from the patient; (i) contacting the sample with an amount of non-pathogenic β-amyloid protein; (ia) incubating the sample/non-pathogenic β-amyloid protein; (ii) disaggregating any aggregates formed during step (ia); repeating steps (ia)-(ii) two or more times; and then (iii) determining the presence and/or amount of pathogenic β-amyloid protein within the sample. 20. Apparatus for use in the method of any one of claims 1 to 9 or 14 or the assay of any one of claims 10 to 12, comprising a microtitre plate, multi-well sonicator and an amount of a non-pathogenic conformer.

<SOH> BACKGROUND OF THE INVENTION <EOH>Conformational diseases are a group of disorders apparently unrelated to each other, but sharing a striking similarity in clinical presentations that reflect their shared molecular mechanisms of initiation and self-association, with consequent tissue deposition and damage. The structural interest is due to the fact that these varied diseases each arise from an aberrant conformational transition in an underling protein, characteristically leading to protein aggregation and tissue deposition. Medically, the presentation of these conformational diseases reflects this molecular mechanism, with typically a slow and insidious onset when the transition is occurring in a normal protein, but a more sudden onset when it occurs in an unstable variant of the protein. Two examples of special significance of such conformational diseases are the Transmissible Spongiform Encephalopathies and Alzheimer dementia, a disease that threatens to overwhelm health care systems in the developed world (for a review see Carrell et al., 1997). Transmissible spongiform encephalopathies (TSE) also known as prion diseases are a group of neurodegenerative diseases that affect humans and animals. Creutzfeldt-Jakob disease (CJD), kuru, Gerstmann-Straussler-Scheiker disease (GSS) and fatal familial insomnia (FFI) in humans as well as scrapie and bovine spongiform encephalopathy (BSE) in animals are some of the TSE diseases (Prusiner, 1991). Although these diseases are relatively rare in humans, the risk for the transmissibility of BSE to humans through the chain food has taken the attention of the public health authorities and the scientific community (Cousens et al., 1997, Bruce et al., 1997). These diseases are characterized by an extremely long incubation period, followed by a brief and invariably fatal clinical disease (Roos et al., 1973). To date no therapy is available. The key characteristic of the disease is the formation of an abnormally shaped protein named PrP Sc , which is a post-translationally modified version of a normal protein, termed PrP C (Cohen and Prusiner, 1998). Chemical differences have not been detected to distinguish between PrP isoforms (Stahl et al., 1993) and the conversion seems to involve a conformational change whereby the α-helical content of the normal protein diminishes and the amount of β-sheet increases (Pan et al., 1993). The structural changes are followed by alterations in the biochemical properties: PrP C is soluble in non-denaturing detergents, PrP Sc is insoluble; PrP C is readily digested by proteases, while PrP Sc is partially resistant, resulting in the formation of a N-terminally truncated fragment known as “PrPres” (Baldwin et al., 1995; Cohen and Prusiner, 1998), “PrP 27-30” (27-30 kDa) or “PK-resistant” (proteinase K resistant) form. At present there is not an accurate diagnosis for TSE (WHO Report, 1998, Budka et al., 1995, Weber et al., 1997). Attempts to develop a diagnostic test for prion diseases are hampered by the apparent lack of an immune response to PrP Sc . The clinical diagnosis of CJD is based upon the combination of subacute progressive dementia (less than 2 years), myoclonus, and multifocal neurological dysfunction, associated with a characteristic periodic electroencephalogram (EEG) (WHO Report, 1998, Weber et al., 1997). However, variant CJD (vCJD), most of the iatrogenic forms of CJD and up to 40% of the sporadic cases do not have the EEG abnormalities (Steinhoff et al., 1996). On average the accuracy of clinical diagnosis is around 60% for CJD and highly variable for other prion-related diseases. The clinical diagnosis is more accurate only at the late-stage of the disease when clear symptoms have developed (Weber et al., 1997). Genetic analysis is useful for the diagnosis of inherited prion diseases, but these represent only 15% of the cases. Neuroimaging is useful only to exclude other conditions of rapidly progressive dementia due to structural lesions of the brain (Weber et al., 1997). The findings obtained by imaging of the brain by computed tomography (CT) and magnetic resonance imaging (MRI) depend mainly on the stage of the disease. CT is much less sensitive and in early phase no atrophy is detected in 80% of the cases (Galvez and Cartier, 1983). MRI hyperintense signals have been detected in the basal ganglia besides atrophy (Onofrji et al., 1993). Like the changes observed by CT, these alterations are by no means specific. Recent data have identified several neuronal, astrocytic and glial proteins that are elevated in CJD (Jimi et al., 1992). The protein S-100, neuron specific isoenzyme and ubiquitin are significantly increased in the cerebrospinal fluid (CSF) in the early phase of disease with decreasing concentrations over the course of the illness (Jimi et al., 1992). A marker of neuronal death, the 14-3-3 protein, has been proposed as a specific and sensitive test for sporadic CJD (Hsich et al., 1996). However, it is not useful for the diagnosis of vCJD, and much less specific in the genetic forms. As the 14-3-3 protein may be present in the CSF of patients with other conditions, the test is not recommended by WHO as a general screening for CJD and is reserved to confirm the clinical diagnosis (WHO Report, 1998). By combining clinical data with the biochemical markers a higher success in the diagnosis is achieved. However, according to the operational diagnosis currently in use in the European Surveillance of CJD, definitive diagnosis is established only by neuropathological examination and detection of PrP Sc either by immunohistochemistry, histoblot or western blot (Weber et al., 1997, Budka et al., 1995). Formation of PrP Sc is not only the most likely cause of the disease, but it is also the best known marker. Detection of PrP Sc in tissues and cells correlates widely with the disease and with the presence of TSE infectivity, and treatments that inactivate or eliminate TSE infectivity also eliminate PrP Sc (Prusiner, 1991). The identification of PrP Sc in human or animal tissues is considered key for TSE diagnosis (WHO Report, 1998). One important limitation to this approach is the sensitivity, since the amounts of PrP Sc are high (enough for detection with conventional methods) only in the CNS at the late stages of the disease. However, it has been demonstrated that at earlier stages of the disease there is a generalized distribution of PrP Sc (in low amounts), especially in the lymphoreticular system (Aguzzi, 1997). Indeed, the presence of PrP Sc has been reported in palatine tonsillar tissue and appendix obtained from patients with vCJD (Hill et al., 1997). Although it is not known how early in the disease course tonsillar or appendix biopsy could be used in vCJD diagnosis, it has been shown that in sheep genetically susceptible to scrapie, PrP Sc could be detected in tonsillar tissue presymptomatically and early in the incubation period. However, PrP Sc has not been detected in these tissues so far in any cases of sporadic CJD or GSS (Kawashima et al., 1997). The normal protein is expressed in white blood cells and platelets and therefore it is possible that some blood cells may contain PrP Sc in affected individuals (Aguzzi, 1997). This raises the possibility of a blood test for CJD, but this would require an assay with a much greater degree of sensitivity than those currently available. Prion replication is hypothesized to occur when PrP Sc in the infecting inoculum interacts specifically with host PrP C , catalyzing its conversion to the pathogenic form of the protein (Cohen et al., 1994). This process takes from many months to years to reach a concentration of PrP Sc enough to trigger the clinical symptoms. The infective unit of PrP Sc seems to be a β-sheet rich oligomeric structure, which converts the normal protein by integrating it into the growing aggregate ( FIG. 1 ). The conversion has been mimicked in vitro by mixing purified PrP C with a 50-fold molar excess of previously denatured PrP Sc (Kocisko et al., 1994). The in vitro conversion systems described so far have low efficiency, since they require an excess of PrP Sc and therefore are not useful for diagnostic purposes because they cannot monitor undetectable amounts of the marker. The reason for the low efficiency is that the number of PrP Sc oligomers (converting units) remains fixed throughout the course of the assay. The converting units grow sequentially by the ends and as a result they become larger, but do not increase in number ( FIG. 1 ).

Dna sequences coding for a polyol carrier and use thereof, in particular for preparing transgenic plants

The invention concerns the use of a DNA sequence coding for a polyol carrier, in plants and fungi, such as polyols having a main chain containing 5 to 8 carbon atoms, in particular 5 to 7 carbon atoms, more preferably 6 carbon atoms, the polyols being advantageously selected among mannitol, sorbitol, dulcitol, galactitol, inositol, myo-inositol, ribitol and xylitol, and being preferably mannitol, for preparing transgenic plants.

1. Use of a DNA sequence coding for a linear polyol carrier, in plants and fungi, such as polyols having main chain containing 5 to 8 carbon atoms, in particular 5 to 7 carbon atoms, in particular 6 carbon atoms, these polyols being advantageously chosen from mannitol, sorbitol, dulcitol, galactitol, inositol, myo-inositol, ribitol and xylitol, and being in particular mannitol, for the preparation of transgenic plants. 2. Use according to claim 1, in which the DNA sequence is chosen from one of the following sequences: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10. 3. Protein characterized in that it comprises or is constituted by: sequence SEQ ID NO: 2, or any sequence derived from SEQ ID NO: 2, in particular by substitution, suppression or addition of one or more amino acids, having the property of transporting linear polyols in plants and fungi, such as polyols having a main chain containing 5 to 8 carbon atoms, in particular 5 to 7 carbon atoms, in particular 6 carbon atoms, these polyols being advantageously chosen from mannitol, sorbitol, dulcitol, galactitol, inositol, ribitol and xylitol, and being in particular mannitol, any homologous sequence of SEQ ID NO: 2, preferably having a homology of at least approximately 50% with sequence SEQ ID NO: 2 and possessing the property of transporting, in plants and fungi, polyols as defined above, or any fragment of one of the sequences defined above, on the condition that it possesses the property of transporting, in plants and fungi, polyols as defined above, in particular any fragment being constituted by at least approximately 10 amino acids adjacent in the sequence SEQ ID NO: 2. 4. Nucleotide sequence coding for a protein as defined in claim 3. 5. DNA sequence which comprises or is constituted by: nucleotide sequence SEQ ID NO: 1, or any nucleotide sequence derived, by degeneration of the genetic code, from the sequence SEQ ID NO: 1 coding for a protein represented by SEQ ID NO: 2, or any nucleotide sequence derived, in particular by substitution, suppression or addition of one or more nucleotides, from the sequence SEQ ID NO: 1 coding for a protein derived from SEQ ID NO: 2, as defined in claim 3, or any homologous nucleotide sequence of SEQ ID NO: 1, preferably having a homology of at least approximately 35% with the sequence SEQ ID NO: 1 coding for a homologous protein of SEQ ID NO: 2, as defined in claim 3, or any fragment of the nucleotide sequence SEQ ID NO: 1 or of the nucleotide sequences defined above, said fragment being preferably constituted of at least approximately 30 nucleotides adjacent in said sequence, or any complementary nucleotide sequence of the above-mentioned sequences or fragments, or any nucleotide sequence capable of hybridizing in stringent conditions with the complementary sequence of one of the abovementioned sequences fragments. 6. Recombinant vector, in particular plasmid, cosmid, phage or virus DNA, containing a nucleotide sequence according to any one of claims 4 or 5. 7. Recombinant vector according to claim 6, containing the elements necessary for the expression in a host cell of polypeptides coded by the nucleic acids according to one of claims 4 or 5, inserted into said vector. 8. Host cell, chosen in particular from bacteria, viruses, yeasts, fingi, plants or mammal cells, said host cell being transformed, in particular using a recombinant vector according to any one of claims 6 or 7. 9. Antisense oligonucleotides or antisense messenger RNA derivatives of the nucleotide sequences according to one of claims 4 or 5. 10. Plant cells containing in their genome a nucleotide sequence according to one of claims 4 or 5. 11. Transgenic plants, parts of plants, plant seeds or plant propagation material containing cells according to claim 10. 12. Transgenic plant according to claim 11, which, in its native state, does not contain or express the gene of the mannitol carrier, into the genome of which is introduced a nucleotide sequence according to one of claims 4 or 5. 13. Transgenic plant according to claim 11, which, in its native state, contains or expresses the gene of the mannitol carrier, into the genome of which is introduced a nucleotide sequence according to one of claims 4 or 5. 14. Process of screening genetically modified plants with at least one nucleotide sequence of interest which comprises the following stages: the transformation of plant cells with a vector containing an insertion sequence, said insertion sequence comprising the nucleotide sequence of interest and a nucleotide sequence coding for a polyol carrier as defined in one of claims 1, 2, 4 and 5, the culture of the cells thus transformed on a medium containing said polyol as the only source of carbon, to obtain transgenic plants or fragments of transgenic plants containing said insertion sequence. 15. Process for obtaining transgenic plants resistant to pathogens, which comprises the following stages: the transformation of plant cells with a nucleotide sequence coding for a polyol carrier as defined in one of claims 1, 2, 4 and 5, the culture of the cells thus transformed to obtain transgenic plants or fragments of transgenic plants. 16. Process for obtaining transgenic plants resistant to saline stress, which comprises the following stages: the transformation of plant cells with a nucleotide sequence coding for a polyol carrier as defined in one of claims 1, 2, 4 and 5, the culture of the cells thus transformed to obtain transgenic plants or fragments of transgenic plants.

Reducing the level of bacteria and viruses in aquaculture

A method of reducing the level of bacteria and viruses in a volume of water during aquaculture comprises: (a) providing the volume of water to be stocked with farmed aquatic organisms or eggs thereof; (b) prior to the stocking, introducing into the water an aqueous solution of glutaraldehyde in an amount such as to provide in the water from 0.1 to 2 ppm of glutaraldehyde; (c) stocking the water with the farmed aquatic organisms or eggs thereof at a time when the concentration of glutaraldehyde is 0.1 to 2 ppm. (d) allowing the farmed aquatic organisms or eggs thereof to grow; and (e) optionally during a period of the growth, introducing into the water at least one further portion of an aqueous solution of glutaraldehyde in an amount such as to maintain the concentration of the glutaraldehyde at 0.1 to 2 ppm.

1. A method of reducing the level of bacteria and viruses in a volume of water during aquaculture, which method comprises: (a) providing the volume of water to be stocked with farmed aquatic organisms or eggs thereof; (b) prior to the stocking, introducing into the water an aqueous solution of glutaraldehyde in an amount such as to provide in the water from 0.1 to 2 ppm of glutaraldehyde; (c) stocking the water with the farmed aquatic organisms or eggs thereof at a time when the concentration of glutaraldehyde is 0.1 to 2 ppm. (d) allowing the farmed aquatic organisms or eggs thereof to grow; and (e) optionally during a period of the growth, introducing into the water at least one further portion of an aqueous solution of glutaraldehyde in an amount such as to maintain the concentration of the glutaraldehyde at 0.1 to 2 ppm. 2. A method according to claim 1, wherein the concentration of glutaraldehyde in each of steps (b), (c) and (e) is within the range 0.5 to 1.5 ppm. 3. A method according to claim 1 or claim 2, applied to bacteria of the species Vibrio. 4. A method according to claim 3, wherein the bacteria of the species Vibrio are selected from Vibrio parahaemolyticus and Vibrio harveyi. 5. A method according to claim 1 or claim 2, applied to viruses selected from White Spot Syndrome Baculovirus (WSBV) complex, Yellow Head Virus and Taura Syndrome Virus. 6. A method according to claim 5, wherein the viruses are WSBV complexes selected from HABV; RV-JP; and SEMBV. 7. A method according to any preceding claim, wherein the farmed aquatic organisms or eggs thereof are crustacea or eggs thereof. 8. A method according to claim 7, wherein the crustacea or eggs thereof are shrimps, prawns or eggs thereof. 9. A method according to claim 7 or claim 8, wherein the crustacea are selected from Litopenaeus vannamei, Litopenaeus setiferus, Litopenaeus stylirostris, Litopenaeus aztecus, Litopenaeus chinensis, Litopenaeus duorarum, Penaeus monodon and Penaeus vannamei. 10. A method according to any preceding claim, which includes the step (e), given and defined in claim 1. 11. A method according to claim 10, wherein at least two portions of the glutaraldehyde are introduced into the water, with an interval of from 5 to 10 days between respective additions thereof. 12. A method according to any preceding claim, which includes, in addition to step (e), a further final period of growth during which no further glutaraldehyde is added. 13. A method according to claim 12, wherein the said further final period is at least thirty days. 14. A method according to any preceding claim, which is carried out using a sealed aerated pond. 15. A method according to any preceding claim, which is carried out in a marine environment.

Adhesive material based on block copolymers having a p(a)-p(b)-p(a) structure

A pressure sensitive adhesive comprised of P(A)-P(B)-P(A) block copolymers, wherein P(A) has a glass transition temperature of 0° C. or below, P(B) has a glass transition temperature of 20° C. or above, and P(A) and P(B) are immiscible.

1. A pressure sensitive adhesive comprised of P(A)-P(B)-P(A) block copolymers, each block copolymer having one middle (co)polymer block P(B) and two end (co)polymer blocks P(A), wherein P(A) represents a (co)polymer block of a component A which is comprised of at least one monomer A1, the (co)polymer block P(A) having a glass transition temperature of 0° C. or below, P(B) represents a (co)polymer block of a component B which is comprised on at least one monomer B1, the (co)polymer block P(B) having a glass transition temperature of 20° C. or above, the (co)polymer block P(B) is insoluble in the (co)polymer block P(A) and the (co)polymer blocks P(A) and P(B) are immiscible. 2. The pressure sensitive adhesive of claim 1, wherein component A is composed of at least two monomers A1 and A2. 3. The pressure sensitive adhesive of claim 1, wherein the monomer A2 has at least one functional group which behaves inertly in a free-radical polymerization reaction and which serves to raise the cohesion of the block copolymer by bonds between the individual block copolymers, the functional group of at least one copolymerized monomer A2 of one block copolymer macromolecule entering into interaction with at least one further block copolymer macromolecule. 4. The pressure sensitive adhesive as claimed in claim 1, wherein the (co)polymer P(A) has a glass transition temperature of between −80° C. and 0° C., or the (co)polymer block P(B) has a glass transition temperature of between 25° C. and 180° C., or both. 5. The pressure sensitive adhesive of claim 1, wherein component A comprises at least one monomer A1 of the formula where R1=H or CH3 and R2 is selected from the group consisting of branched or unbranched, saturated alkyl groups having 4 to 14 carbon atoms. 6. The pressure sensitive adhesive of claim 1, wherein component A comprises at least one monomer A2 of the following formula where R3=H or CH3 and —OR4 represents or contains the functional group for increasing the cohesion. 7. The pressure sensitive adhesive of claim 1, wherein the cohesion-increasing functional group is selected from the group consisting of hydroxyl, carboxyl, epoxy, acid amide, isocyanato amino, a group containing a photoinitiator for UV crosslinking, and an unsaturated group. 8. The pressure sensitive adhesive of claim 1, wherein component B comprises at least one monomer B1 which results in (co)polymer blocks P(B) which are capable of forming a two-phase domain structure with the (co)polymer blocks P(A). 9. The pressure sensitive adhesive of claim 1, having an average molecular weight of between 25,000 and 750,000 g/mol. 10. The pressure sensitive adhesive of claim 1, wherein (co)polymer blocks P(B) represent between 10 and 60% by weight of the entire block copolymer. 11. The pressure sensitive adhesive of claim 1, wherein the weight ration of A2 to A1 is between 0.1 and 20. 12. The pressure sensitive adhesive of claim 1, further comprising up to 50% by weight of additives selected from the group consisting of resins, crosslinkers, aging inhibitors, light stabilizers, ozone protectants, fatty acids, plasticizers, nucleators, blowing agents, accelerators, fillers, and combinations thereof. 13. An adhesive tape provided with the pressure sensitive adhesive of claim 1 on one or both sides. 14. The pressure sensitive adhesive of claim 3, wherein said interaction is a cross-linking reaction. 15. The pressure sensitive adhesive of claim 9, wherein said average molecular weight is between 100,000 and 500,000 g/mol. 16. The pressure sensitive adhesive of claim 10, wherein said (co)polymer blocks P(B) represents between 15 and 40% by weight of the entire block. 17. The pressure sensitive adhesive of claim 11, wherein said weight ratio is between 0.5 and 10. 18. The pressure sensitive adhesive of claim 12, wherein said amount is from 20 to 40% by weight. 19. The adhesive tape of claim 13, wherein said adhesive tape is formed by applying said pressure sensitive adhesive as a melt to one or both sides of a backing.

Iso-truss structure

An iso-truss structure (10) includes at least two helical components (30, 32) and at least one reverse helical component (34) attached thereto with opposing angular orientations. Each helical and reverse helical component preferably includes at least four elongate, straight segments (22) rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about a common axis (14) forming a first square cross section. The structure may further include at least two rotated helical components (80, 92) and at least one rotated reverse helical component (98) which are rotated with respect to the helical and reverse helical components forming a second square cross section, rotated with respect to the first. The structure may be straight, curved, flexible, or form angles.

1. A structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 2. A structural member in accordance with claim 1, wherein all of the helical components have continuous strands of fiber; and wherein the helical components are attached to one another at intersecting locations by over-lapping the fibers of the helical components. 3. A structural member in accordance with claim 1, wherein the helical components define a hollow interior substantially void of material. 4. A structural member in accordance with claim 1, wherein the helical components define openings there between. 5. A structural member in accordance with claim 1, wherein helical components define an imaginary tubular member of square cross section. 6. A structural member in accordance with claim 1, further comprising: a) at least two, spaced apart, rotated helical components, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, each having: 1) a common rotated longitudinal axis, 2) a common angular orientation about the rotated longitudinal axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the rotated axis; and b) at least one rotated reverse helical component, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, having: 1) a common rotated longitudinal axis with the at least two rotated helical components, 2) an opposing angular orientation with respect to the two rotated helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 7. A structural member in accordance with claim 6, wherein the longitudinal axis and the rotated longitudinal axis are concentric, and the segments of the helical components form an imaginary tubular member having a cross section of an eight-pointed star. 8. A structural member in accordance with claim 6, wherein the longitudinal axis and the rotated longitudinal axis are concentric, and the segments form an imaginary tubular member having a cross section of two squares having a common longitudinal axis, but with one square rotated with respect to the other. 9. A structural member in accordance with claim 1, further comprising: an end plate, attached at an end of the helical components, to attach the helical components to another object. 10. A structural member in accordance with claim 9, wherein the helical components have continuous strands of fiber; and wherein the end plate is attached by winding the continuous strands of fiber around the end plate. 11. A structural member in accordance with claim 9, wherein the end plate includes a perimeter, a plurality of indentations formed about the perimeter to receive strands of fiber, and a plurality of holes to attach the end plate to another object. 12. A structural member in accordance with claim 1, wherein the helical components and segments form a repeating pattern of triangles and tetrahedrons; and further comprising: a connector, attached to the helical components and segments, to attach other objects to the helical components and segments, the connector being elongated and having a substantially triangular, cross sectional shape, the connector extending through at least two of the triangles formed by the helical components and segments. 13. A structural member in accordance with claim 1, wherein the axes are vertically oriented, a lower end is attached to a support surface, and an upper end is located above the lower end; and further including another object attached to the upper end selected from the group consisting of: a sign placard with indicia; a horizontal utility member configured to hold utility lines; a light source. 14. A structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; c) at least two, spaced apart, rotated helical components, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, each having: 1) a common rotated longitudinal axis, 2) a common angular orientation about the rotated longitudinal axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the rotated axis; and d) at least one rotated reverse helical component, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, having: 1) a common rotated longitudinal axis with the at least two rotated helical components, 2) an opposing angular orientation with respect to the two rotated helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 15. A structural member in accordance with claim 14, wherein the longitudinal axis and the rotated longitudinal axis are concentric, and the segments of the helical components form an imaginary tubular member having a cross section of an eight-pointed star. 16. A structural member in accordance with claim 14, wherein the longitudinal axis and the rotated longitudinal axis are concentric, and the segments form an imaginary tubular member having a cross section of two squares having a common longitudinal axis, but with one square rotated with respect to the other. 17. A structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and c) the at least one reverse helical component forming an angle with respect to the at least two helical components greater than 60 degrees. 18. A structural member in accordance with claim 17, wherein the at least one reverse helical component forms an angle with respect to the at least two helical components greater than approximately 75 degrees. 19. A structural member in accordance with claim 17, wherein each helical component includes at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 20. A flexible structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least three elongate, straight segments connected end to end in a helical configuration; and c) the helical members being laterally flexible, and are bendable between: 1) a first, straight position in which the axes are substantially straight; and 2) a second, arcuate position in which the axes are substantially arcuate. 21. A structural member in accordance with claim 20, wherein the helical members store energy in the second, arcuate position. 22. A structural member in accordance with claim 20, wherein the helical members are rotationally rigid about the longitudinal axes. 23. An arcuate structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common arcuate axis, 2) a common angular orientation about the axis, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common arcuate axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration. 24. A structural member in accordance with claim 23, wherein the arcuate axes are circular. 25. A structural member in accordance with claim 23, wherein each helical component includes at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 26. A structural member in accordance with claim 23, wherein the arcuate axes include a first curvature, and a different second curvature. 27. A tapering structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and c) the segments of each helical component sequentially reducing in length along the axes such that the structural member tapers. 28. A structural member in accordance with claim 27, wherein each helical component includes at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 29. A preform member, comprising: a) at least two, spaced apart, helical components each having: at least three segments connected end to end in a helical configuration; and b) at least one reverse helical component, attached to the at least two helical components, having: at least three segments connected end to end in a helical configuration; and c) the helical components including fiber and being flexible and collapsible until impregnated with a resin matrix. 30. A preform member in accordance with claim 29, wherein the helical components include a plurality of strands of fiber bound together. 31. A bicycle frame, comprising: a) a handlebar location configured to attach to a handlebar and front fork; b) a seat location configured to attach to a seat; c) a peddle location configured to be attached to a peddle assembly; d) a rear wheel location configured to be attached to a rear wheel; e) a plurality of members, each extending to and between at least one of the handlebar, seat, peddle, and rear wheel locations; and f) at least one of the members including: 1) at least two, spaced apart, helical components each having: i) a common longitudinal axis, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and 2) at least one reverse helical component, attached to the at least two helical components, having: i) a common longitudinal axis with the at least two helical components, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis in an opposing angular orientation. 32. A bicycle frame in accordance with claim 31, wherein each helical component includes at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 33. A method for forming a structural member, comprising the steps of: a) providing a mandrel; b) wrapping a fiber around the mandrel in order to create at least two helical components, each component having at least four elongated, straight segments, the at least two helical components having a common longitudinal axis, a common angular orientation about the axis, and forming a single, substantially complete rotation about the axis; c) wrapping a fiber around the mandrel in order to create at least one reverse helical component having at least four elongate, straight segments having a common longitudinal axis with the at least two helical components, but in an opposing angular orientation, and forming a single, substantially complete rotation about the axis; d) adding a matrix to the fiber; and e) curing the matrix. 34. A method in accordance with claim 33, wherein the step of providing a mandrel further includes: providing a mandrel having an elongated core, and a plurality of heads disposed longitudinally and radially about the core, each head configured to receive and hold fiber for at least two, opposing helical components, and including four angled indentations, two angled indentations for each helical component. 35. A method in accordance with claim 33, further comprising the step of: wrapping a fiber along a length of the mandrel in order to create at least one longitudinal component parallel with the longitudinal axes; and wherein the step of providing a mandrel further includes: providing a mandrel having an elongated core, and a plurality of heads disposed longitudinally and radially about the core, each head configured to receive and hold fiber for at least two, opposing helical components and at least one longitudinal component, and including at least six indentations, including two angled indentations for each helical component and two indentations for the longitudinal component. 36. A method in accordance with claim 33, wherein the step of providing a mandrel further includes providing a collapsible mandrel having: a) an elongated, hollow tube including a plurality of holes, b) an elongated core, removably disposed within the tube, c) a plurality of inserts, removably disposed between the core and the tube, having a plurality of holes, d) a plurality of pins, removably disposed in the holes of the tube and inserts, and e) a plurality of heads disposed on the pins; and further including the steps of: a) removing the core from the tube after curing; b) removing the inserts from the core; c) displacing the pins through the holes into the tube; d) removing the tube; and e) removing the heads. 37. A utility pole, comprising: a) an elongated member, vertically oriented, having a longitudinal axis and upper and lower ends, and being formed of: 1) at least two, spaced apart, helical components each having: i) a common angular orientation about the longitudinal axis, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and 2) at least one reverse helical component, attached to the at least two helical components, having: i) an opposing angular orientation with respect to the two helical components, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; b) an end plate, attached to the lower end of the elongated member, configured to attach the lower end of the elongated member to a support surface; and c) an arm, attached to the elongated member near the upper end and extending generally horizontally, configured to hold a utility line. 38. A utility pole in accordance with claim 37, wherein the elongated member further includes: a) at least two, spaced apart, rotated helical components, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, each having: 1) a common rotated longitudinal axis, 2) a common angular orientation about the rotated longitudinal axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the rotated axis; and b) at least one rotated reverse helical component, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, having: 1) a common rotated longitudinal axis with the at least two rotated helical components, 2) an opposing angular orientation with respect to the two rotated helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 39. A utility pole in accordance with claim 37, wherein the segments of each helical component sequentially reduce in length along the axes such that the structural member tapers. 40. A sign post, comprising: a) an elongated member, vertically oriented, having a longitudinal axis and upper and lower ends, and being formed of: 1) at least two, spaced apart, helical components each having: i) a common angular orientation about the longitudinal axis, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and 2) at least one reverse helical component, attached to the at least two helical components, having: i) an opposing angular orientation with respect to the two helical components, and ii) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; b) an end plate, attached to the lower end of the elongated member, configured to attach the lower end of the elongated member to a support surface; and c) a sign, coupled to the elongated member, including indicia. 41. A sign post in accordance with claim 40, wherein the elongated member further includes: a) at least two, spaced apart, rotated helical components, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, each having: 1) a common rotated longitudinal axis, 2) a common angular orientation about the rotated longitudinal axis, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the rotated axis; and b) at least one rotated reverse helical component, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, having: 1) a common rotated longitudinal axis with the at least two rotated helical components, 2) an opposing angular orientation with respect to the two rotated helical components, and 3) at least four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 42. A sign post in accordance with claim 40, further comprising: a) an arcuate member having a first end attached to the upper end of the elongated member, and also including: 1) at least two, spaced apart, helical components each having: i) a common arcuate axis, ii) a common angular orientation about the axis, and iii) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and 2) at least one reverse helical component, attached to the at least two helical components, having: i) a common arcuate axis with the at least two helical components, ii) an opposing angular orientation with respect to the two helical components, and iii) at least three elongate, straight segments rigidly connected end to end in a helical configuration; and b) the sign is coupled to the arcuate member. 43. A structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 44. A structural member in accordance with claim 43, further comprising: a) at least two, spaced apart, rotated helical components, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, each having: 1) a common rotated longitudinal axis, 2) a common angular orientation about the rotated longitudinal axis, and 3) four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the rotated axis; and b) at least one rotated reverse helical component, attached to and rotated with respect to the at least two helical components and at least one reverse helical component, having: 1) a common rotated longitudinal axis with the at least two rotated helical components, 2) an opposing angular orientation with respect to the two rotated helical components, and 3) four elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis. 45. A structural member, comprising: a) at least two, spaced apart, helical components each having: 1) a common longitudinal axis, 2) a common angular orientation about the axis, and 3) five elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis; and b) at least one reverse helical component, attached to the at least two helical components, having: 1) a common longitudinal axis with the at least two helical components, 2) an opposing angular orientation with respect to the two helical components, and 3) five elongate, straight segments rigidly connected end to end in a helical configuration forming a single, substantially complete rotation about the axis.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. The Field of the Invention The present invention relates generally to a three-dimensional structural member which is strong and light-weight. More particularly, the present invention relates to a structural member having a plurality of helical components wrapped about an axis, each having straight segments connected end-to-end in a helical configuration. 2. The Background Art The pursuit of structurally efficient structures in the civil, mechanical, aerospace and sports arenas is an ongoing quest. An efficient truss structure is one that has a high strength to weight ratio and/or a high stiffness to weight ratio. An efficient truss structure can also be described as one that is relatively inexpensive, easy to fabricate and assemble, and does not waste material. Trusses are typically stationary, fully constrained structures designed to support loads. They consist of straight members connected at joints at the end of each member. The members are two-force members with forces directed along the member. Two-force members can only produce axial forces such as tension and compression forces in the member. Trusses are often used in the construction of bridges and buildings. Trusses are designed to carry loads which act in the plane of the truss. Therefore, trusses are often treated, and analyzed, as two-dimensional structures. The simplest two-dimensional truss consists of three members joined at their ends to form a triangle. By consecutively adding two members to the simple structure and a new joint, larger structures may be obtained. The simplest three-dimensional truss consists of six members joined at their ends to form a tetrahedron. By consecutively adding three members to the tetrahedron and a new joint, larger structures may be obtained. This three dimensional structure is known as a space truss. Frames, as opposed to trusses, are also typically stationary, fully constrained structures, but have at least one multi-force member with a force that is not directed along the member. Machines are structures containing moving parts and are designed to transmit and modify forces. Machines, like frames, contain at least one multi-force member. A multi-force member can produce not only tension and compression forces, but shear and bending as well. Traditional structural designs have been limited to one or two-dimensional analyses resisting a single load type. For example, I-beams are optimized to resist bending and tubes are optimized to resist torsion. Limiting the design analysis to two dimensions simplifies the design process but neglects combined loading. Three-dimensional analysis is difficult because of the difficulty in conceptualizing and calculating three-dimensional loads and structures. In reality, many structures must be able to resist multiple loadings. Computers are now being utilized to model more complex structures.

<SOH> SUMMARY OF THE INVENTION <EOH>It has been recognized that it would be advantageous to develop a structural member with enhanced performance characteristics, such as strength reduced weight, etc. The invention provides a three-dimensional structure or structural member, including: 1) at least two, spaced apart, helical components, and 2) at least one reverse helical component attached to the two helical components. The helical and reverse helical components have a common longitudinal axis, but opposing angular orientations about the axis. In addition, each helical and reverse helical component advantageously includes at least four elongate, straight segments rigidly connected end-to-end in a helical configuration forming a single, substantially complete rotation about the axis. Thus, the helical and reverse helical components form a first square-shaped cross section. In one aspect, the structure includes four helical components and four reverse helical components. In addition, the iso-truss structure can include 1) rotated helical components, and 2) rotated reverse helical components, similar to, but rotated with respect to, the helical and reverse helical components above. Thus, the rotated helical and rotated reverse helical components form a second square-shaped cross section, rotated with respect to the first. In one aspect, the structure includes four rotated helical components and four rotated reverse helical components, for a total of sixteen helical components. The various helical components intersect at external nodes and internal nodes. In one aspect, the components form eight internal and eight external nodes. Longitudinal or axial components may extend parallel to the axis and intersect the internal and/or external nodes. In one aspect, the structure includes eight external nodes. It has been found that such an eight node structure has unexpected structural or performance characteristics. In accordance with one aspect of the present invention, the structure can further include an end plate attached at an end of the helical components to attach the helical components to another object. In one aspect, the helical components may be formed of continuous strands of fiber, which may be wound around the end plate. The end plate can include a perimeter with a plurality of indentations to receive the strands of fiber. In accordance with another aspect of the present invention, the structure can further include a connector member attached to the helical components and segments to attach other objects to the helical components and segments. The connector member can include a triangular cross-sectional shape extending through triangular openings formed by the components. In accordance with another aspect of the present invention, the helical and reverse helical components may form an angle therebetween greater than approximately 60 degrees. It has been found that such angles have unexpected structural or performance characteristics. In accordance with another aspect of the present invention, the helical and reverse helical members can be axially and/or laterally flexible, but torsionally stiff. The structure may bend between a first, straight position in which the axes are substantially straight; and a second, arcuate position in which the axes are substantially arcuate. In addition, the structure may compress and/or expand longitudinally. In either case, the structure may store energy, and thus be utilized as a spring member. In accordance with another aspect of the present invention, the structure may be arcuate, and the components may be formed about an arcuate axis. Thus, the arcuate structure may form more complex shapes than a singular, linear structure, and may be better suited for certain applications. In accordance with another aspect of the present invention, the structure may taper. The segments of each helical component may sequentially reduce in length along the axes such that the structural member tapers. Thus, the tapering structure may form more complex shapes than a singular, linear structure, and may be better suited for certain applications. In accordance with another aspect of the present invention, the iso-truss structure may be utilized to hold signs, utility lines, or lights. The iso-truss structure further may be utilized for bicycle frames, aircraft and marine structures, etc. A method for forming an iso-truss structure in accordance with the present invention can include wrapping a fiber around a mandrel in order to create the two helical components and the reverse helical component. A matrix or resin can be added to the fiber and cured. The mandrel may be removed from the structure. The mandrel may include a plurality of heads disposed thereon to receive and hold fiber. The mandrel may be a collapsible or dissolvable mandrel. Additional features and advantages of the invention will be set forth in the detailed description which follows, taken in conjunction with the accompanying drawings, which together illustrate by way of example, the features of the invention.

Dishwashing compositions comprising floating particles

A machine dishwashing detergent composition is disclosed. The composition includes delayed-release solid particles comprising at least one ingredient that is intended to perform its function during the rinse cycle of an automatic dishwashing cycle wherein the particles float in water and have no more than one dimension bigger than 1 cm.

1. Machine dishwashing detergent composition comprising delayed-release solid particles which particles have a composition comprising at least one ingredient that is intended to perform its function during the rinse cycle characterised in that said particles float in water and have no more than one dimension bigger than 1 cm. 2. Composition according to claim 1 characterised in that the floating particles have not more than one dimension bigger than 0,5 cm preferably having no more than one dimension bigger than 0,2 cm. 3. Composition according to claims 1 or 2 characterised in that the surface of the particles is made sticky to metallic or plastic surfaces. 4. Composition according to any of preceding claims characterised in that the particle has a bulk density lower than 1 g/cm3. 5. Composition according to any of preceding claims characterised in that the solid particles remain substantially undissolved in an amount of at least 30% at the end of the last washing cycle when the particles are dosed to a MIELE dishwasher together with 30 g. of standard ICE B dishwashing detergent and the dishwasher is run at its 55° C. mild program. 6. Composition according to any of preceding claims characterised in that the particle is substantially water-insoluble at low temperatures (<55° C.) and it is soluble or at least dispersible at the higher temperatures of the rinse cycle. 7. Composition according to any of preceding claims characterised in that the particle is substantially insoluble at relatively high ionic strength and/or high pH and it is solubilised upon decrease of pH or ionic strength. 8. Composition according to claims 1 to 6 characterised in that the particle comprises a rinse additive. 9. Composition according to claims 1 to 6 characterised in that the particle comprises a fragrance. 10. Composition according to the invention substantially as hereinbefore described with reference to any one of Examples 1 and 2.

Apparatus and method for producing porous polymer particles

An apparatus and method for producing porous polymer particles is disclosed. The apparatus includes a rotating atomizer wheel (39) onto which a uniform thin layer of a polymer may be applied via a distributor (40), followed by the movement of the polymer to the periphery of the wheel due to centrifugal force and the subsequent release of free flying particles at the periphery of the wheel. The apparatus further includes a catch tray (14) to collect the porous polymer particles produced and an enclosure defining a partition between an interior environment and an exterior environment of the apparatus. The enclosure includes an aperture allowing a gaseous exchange between the interior and exterior environments.

1. An atomizer machine for the production of porous polymer particles, comprising: a) an atomizer wheel having an edge, wherein said wheel is rotatable about an axis; b) a distributor for depositing polymer in fluid state to said wheel; c) a catch tray disposed under the atomizer wheel to collect the polymer particles formed as a result of ejection of the polymer from the edge as the atomizer wheel rotates; d) an enclosure, enclosing said atomizer wheel, said distributor and said catch tray, said enclosure defining a partition between an interior environment of said atomizer machine and an exterior environment of said atomizer machine; e) an aperture on said enclosure allowing a gaseous exchange between the interior environment of said atomizer machine and the exterior environment of said atomizer machine. 2. An atomizer machine as defined in claim 1, wherein said aperture is of variable size. 3. An atomizer machine as defined in claim 2, wherein said enclosure includes a peripheral wall surrounding said atomizer wheel, said distributor and said catch tray and a roof portion covering said peripheral wall. 4. An atomizer machine as defined in claim 3 wherein said peripheral wall is generally circular. 5. An atomizer machine as defined in claim 4, wherein said aperture extends circumferentially along said peripheral wall. 6. An atomizer machine as defined in claim 4, wherein said peripheral wall includes an upper portion and a lower portion, said aperture being defined between said upper portion and between said lower portion. 7. An atomizer machine as defined in claim 6, further comprising an actuator to displace said upper portion and said lower portion with relation to one another to vary the size of said aperture. 8. An atomizer machine as defined in claim 7, wherein said actuator is operative to displace said upper portion along said axis to vary the size of said aperture. 9. An atomizer machine as defined in claim 2, including a temperature control unit to regulate a temperature in said interior environment. 10. An atomizer machine as defined in claim 2, including a humidity control unit to regulate a level of humidity in said interior environment. 11. An atomizer machine as defined in claim 9, further comprising a monitor capable of indicating a level of temperature in said interior environment. 12. An atomizer machine as defined in claim 10, further comprising a monitor capable of indicating a level of humidity in said interior environment. 13. An atomizer machine according to claim 9 wherein the temperature control unit comprises at least one of: a unit for controlling a size of said aperture, a unit for controlling a level of temperature of the distributor and wheel, a unit for controlling a level of temperature and a flow rate of water in the catch tray, at least one valve providing at least one respective vapor stream at a periphery of said atomizer wheel, over the wheel and in the enclosure, and at least one steam trap for de-misting air in said interior environment and preventing water droplets from falling on said atomizer wheel. 14. An atomizer machine according to claim 10 wherein said humidity control unit comprises at least one of: a unit for controlling a size of said aperture, a unit for controlling a level of temperature of the distributor and wheel, a unit for controlling a level of temperature and a flow rate of water in the catch tray, at least one valve providing at least one respective vapor stream at a periphery of said atomizer wheel periphery, over the wheel and in the enclosure, and at least one steam trap for de-misting the air in the interior environment and preventing water droplets from falling on said atomizer wheel. 15. An atomizer machine as defined in claim 13, further comprising a monitor capable of indicating a level of temperature in said interior environment. 16. An atomizer machine as defined in claim 14, further comprising a monitor capable of indicating a level of humidity in said interior environment. 17. An atomizer machine according to claim 1 further comprising a trajectory control means to control a trajectory of the particles from a periphery of said atomizer wheel to said catch tray. 18. An atomizer machine according to claim 17 wherein the trajectory control means comprises a unit for controlling a size of said aperture, disposing steam valves at the periphery of said atomizer wheel, over said atomizer wheel and directly into said enclosure, and controlling airflow patterns at the periphery of said atomizer wheel. 19. An atomizer machine according to claim 1 further comprising a reactor for producing the polymer and at least one temperature controlled conduit for feeding the polymer to the distributor. 20. An atomizer machine according to claim 19 wherein the at least one conduit consists of a double jacket tube defining an inner passage for feeding the polymer to the distributor and an outer envelope surrounding the inner passage, through which outer envelope a temperature liquid is flowed to control a level of temperature of the polymer. 21. An atomizer machine according to claim 1, wherein said distributor rotates in the same direction as said atomizer wheel. 22. An atomizer machine according to claim 1 wherein the distributor comprises a plurality of holes. 23. An atomizer machine according to claim 22 wherein the plurality of holes are disposed in a circle. 24. An atomizer machine according to claim 22 wherein the distributor has 24 holes. 25. An atomizer machine according to claim 1 wherein said atomizer wheel has a flat surface. 26. An atomizer machine according to claim 1, further comprising a shaft for receiving said atomizer wheel, said shaft being conical and tapered so as to reduce vibrations during rotation of said atomizer wheel. 27. An atomizer machine according to claim 1, further comprising a shaft for receiving said atomizer wheel, said shaft having a threaded section for securing said atomizer wheel to said shaft. 28. An atomizer machine according to claim 1, further comprising a sorting bin for receiving and sorting the particles from said catch tray. 29. An atomizer machine according to claim 1, wherein said atomizer wheel has a perimeter, and wherein said atomizer wheel has at said perimeter radially projecting teeth. 30. An atomizer machine according to claim 1, further comprising at least one baffle disposed within the enclosure for regulating air flow within said internal environment. 31. The atomizer machine according to claim 30 wherein the at least one baffle is a plurality of baffles. 32. The atomizer machine according to claim 31 wherein the plurality of baffles comprises 4 baffles. 33. A method for producing polymer particles, said method comprising: a) providing an atomizer wheel, distributor and a catch tray enclosed by an enclosure defining a partition between an interior and an exterior environment and having an aperture for allowing gaseous exchange between said interior and said exterior environment; and b) allowing gaseous exchange through said aperture thereby to regulate at least one condition of temperature, humidity or air flow within said interior environment. 34. The method of claim 33 further comprising varying a size of said aperture to vary a rate of gaseous exchange.

<SOH> BACKGROUND <EOH>The capacity of certain porous support particles to cause selective retardation based on either size or shape is well known. Such particles are used in chromatographic separation techniques, for example gel filtration, to separate biological macromolecules, e.g. proteins, DNA, RNA polysaccharides and the like. The sieving particles are characterized by the presence of a microporous structure that exerts a selective action on the migrating solute macromolecules, restricting passage of larger particles more than that of the smaller particles. Thus, the utility of sieving lies in the capacity of the particles to distinguish between molecules of different sizes and shapes. Affinity chromatography is a chromatographic method used for the isolation of proteins and other biological compounds. This technique is performed using an affinity ligand attached to a support particle and the resulting adsorbent packed into a chromatography column. The target protein is captured from solution by selective binding to the immobilized ligand. The bound protein may be washed to remove unwanted contaminants and subsequently eluted in a highly purified form. Good separation using chromatography techniques depends on the size of particles, the size distribution of particles and the porosity of the particles. The beads, once packed into a column, should be of a high strength in order to support the liquid flow rates observed during purification and column regeneration. The effect of polymer concentration and other preparation parameters on agarose particle porosity and strength are presented in S. Hjertén and K. O. Eriksson, Analytical Biochemistry, 137, 313-317 (1984), herein incorporated by reference. Additional fundamental information is presented in Studies on Structure and Properties of Agarose, A. S. Medin, pH.D. Thesis, Uppsala, 1995, herein incorporated by reference. The description of chemical additives that help to improve the agarose particle porosity are found in M. Letherby and D. A. Young, J. Chem. Soc., Faraday Trans. 1, 77, 1953-1966 (1981) and in M. Tako and S. Nakamura, Carbohydrate Research, 180, 277-284 (1988), both herein incorporated by reference. Many particle formation methods and apparatus have been developed using centrifugal action to divide a liquid or into droplets or particles. Rotary atomizer machines in general are discussed in the text Spray Drying Handbook, K. Masters, Fifth edition, Longman Scientific & Technical, Longman Group UK Limited, herein incorporated by reference. Other relevant references related to atomization are Atomization and Sprays, A. Lefebvre, Hemisphere Publications, 1989 and Liquid Atomization, L. Bayvel and Z. Orzechowski, Taylor and Francis, 1993, both herein incorporated by reference. A fundamental theory used in the present invention is known as “spray congealing”, based on spray drying principles with the exception that solidification is the objective instead of drying. Traditional emulsion based methods for agarose bead preparation are described in, for example, Studies on Structure and Properties of Agarose, A. S. Medin, pH.D. Thesis, Uppsala, 1995 and in “The Preparation of Agarose Spheres for Chromatography of Molecules and Particles”, Biochimica et Biophysica Acta, 79, 393-398 (1964). The particle size distribution produced by known apparatus and methods require further sorting steps or procedures in order to select particles of uniform size required for chromatography. The additional sorting steps introduce further costs that could be avoided if the factors determining size distribution of the particles and operating variables are closely controlled. Without additional sorting steps, the products manufactured by conventional rotary atomization or emulsion techniques cannot be used in applications where the size distribution of the particles must be very narrow. For example, when using particles in blood purification applications, small particles must be avoided as small particles could be caught by the carrier fluid and would result in contamination of the purified material. Of course a narrow particle size distribution improves performances of particles in many applications, including chromatographic applications. Operating variables that influence droplet size produced from atomizer wheels and hence particle size include speed of rotation, wheel diameter, wheel design, feed rate, viscosity of feed and air, density of feed and air and surface tension of feed. The atmosphere within which a particle passes is important in order to avoid reduction of pore size. In particular, humidity and temperature control avoids particle desiccation during polymerization and gelling stages. Particle desiccation reduces pore size. It is desirable to have a machine and process to produce particles using centrifugal action in such a manner as that the particles have a narrow particle size distribution with both high porosity and flow. Lengthy consideration of prior art devices and processes has identified a number of factors that may be responsible for the wider size distribution of particles. Such factors include interruptions on the wheel surface that may impede radial acceleration of the particle solution and adhesion to the surface of the wheel; lack of adequate temperature control on the atomizer wheel that may result in changes in feed viscosity and particle structure; and uncontrolled airflow patterns at the perimeter of the atomizer wheel that may result in particle twinning due to collisions between particles prior to gelation and in undesired drying of the particles due to a modification in their path down from the wheel to the collecting liquid.

<SOH> SUMMARY OF THE INVENTION <EOH>Applicants have recognized that control of humidity and temperature within specific parameters in the immediate area of the atomizer wheel will yield particles of a narrower size distribution than previously possible with both good porosity and rigidity. Specifically, It has been discovered that the air flow rate, temperature and humidity may be controlled in the immediate area of the atomizer wheel with sufficient accuracy to produce particles of a narrow size distribution. Control of temperature and humidity is achieved by the combination of temperature and humidity control means and an enclosure comprising an aperture, thus partially enclosing the atomizer machine. The apparatus and method of the present invention produce particles having improved properties including very good bead shape and a narrower size distribution than possible with conventional production apparatus and methods. The apparatus and method are particularly well suited for the production of agarose beads for use in chromatography. According to a first broad aspect, the invention provides an atomizer machine for the production of porous polymer particles, comprising: a) an atomizer wheel having an edge, wherein the wheel is rotatable about an axis; b) a distributor for depositing polymer in fluid state to the wheel; c) a catch tray disposed under the atomizer wheel to collect the polymer particles formed as a result of ejection of the polymer from the edge as the atomizer wheel rotates; d) an enclosure, enclosing the atomizer wheel, the distributor and the catch tray, the enclosure defining a partition between an interior environment of the atomizer machine and an exterior environment of the atomizer machine; e) an aperture on the enclosure allowing a gaseous exchange between the interior environment of the atomizer machine and the exterior environment of the atomizer machine. In an embodiment, the above-mentioned aperture is of variable size. In an embodiment, the above-mentioned enclosure includes a peripheral wall surrounding the atomizer wheel, the distributor and the catch tray and a roof portion covering the peripheral wall. In an embodiment, the above-mentioned peripheral wall is generally circular. In an embodiment, the above-mentioned aperture extends circumferentially along the peripheral wall. In an embodiment, the above-mentioned peripheral wall includes an upper portion and a lower portion, the aperture being defined between the upper portion and between the lower portion. In an embodiment, the above-mentioned atomizer machine further comprises an actuator to displace the upper portion and the lower portion with relation to one another to vary the size of the aperture. In an embodiment, the above-mentioned actuator is operative to displace the upper portion along the axis to vary the size of the aperture. In an embodiment, the above-mentioned atomizer machine includes a temperature control unit to regulate a level of temperature in the interior environment. In an embodiment, the above-mentioned atomizer machine includes a humidity control unit to regulate a level of humidity in the interior environment. In an embodiment, the above-mentioned temperature control unit comprises at least one of: a unit for controlling a size of the aperture, a unit for controlling a level of temperature of the distributor and wheel, a unit for controlling a level of temperature and a flow rate of water in the catch tray, at least one valve providing at least one respective vapor stream at a periphery of the atomizer wheel, over the wheel and in the enclosure, and at least one steam trap for de-misting air in the interior environment and preventing water droplets from falling on the atomizer wheel. In an embodiment, the above-mentioned humidity control unit comprises at least one of: a unit for controlling a size of the aperture, a unit for controlling a level of temperature of the distributor and wheel, a unit for controlling a level of temperature and a flow rate of water in the catch tray, at least one valve providing at least one respective vapor stream at a periphery of the atomizer wheel, over the wheel and in the enclosure, and at least one steam trap for de-misting the air in the interior environment and preventing water droplets from falling on the atomizer wheel. In an embodiment, the above-mentioned atomizer machine further comprises a monitor capable of indicating a level of temperature in the interior environment. In an embodiment, the above-mentioned atomizer machine further comprises a monitor capable of indicating a level of humidity in the interior environment. In an embodiment, the above-mentioned atomizer machine further comprises a trajectory control means to control a trajectory of the particles from a periphery of the atomizer wheel to the catch tray. In an embodiment, the above-mentioned trajectory control means comprises a unit for controlling a size of the aperture, disposing steam valves at the periphery of the atomizer wheel, over the atomizer wheel and directly into the enclosure, and controlling airflow patterns at the periphery of the atomizer wheel. In an embodiment, the above-mentioned atomizer machine further comprises a reactor for producing the polymer and at least one temperature controlled conduit for feeding the polymer to the distributor. In an embodiment, the above-mentioned at least one conduit consists of a double jacket tube defining an inner passage for feeding the polymer to the distributor and an outer envelope surrounding the inner passage, through which outer envelope a temperature liquid is flowed to control a level of temperature of the polymer. In an embodiment, the above-mentioned distributor rotates in the same direction as the atomizer wheel. In an embodiment, the above-mentioned distributor comprises a plurality of holes. In an embodiment, the above-mentioned plurality of holes are disposed in a circle. In an embodiment, the above-mentioned distributor has 24 holes. In an embodiment, the above-mentioned atomizer wheel has a flat surface. In an embodiment, the above-mentioned atomizer machine further comprises a shaft for receiving the atomizer wheel, the shaft being conical and tapered so as to reduce vibrations during rotation of the atomizer wheel. In an embodiment, the above-mentioned atomizer machine further comprises a shaft for receiving the atomizer wheel, the shaft having a threaded section for securing the atomizer wheel to the shaft. In an embodiment, the above-mentioned atomizer machine further comprises a sorting bin for receiving and sorting the particles from the catch tray. In an embodiment, the above-mentioned atomizer wheel has a perimeter, the perimeter having radially projecting teeth. In an embodiment, the above-mentioned atomizer machine further comprises at least one baffle disposed within the enclosure for regulating air flow within the internal environment. In an embodiment, the above-mentioned at least one baffle is a plurality of baffles. In an embodiment, the above-mentioned plurality of baffles is 4 baffles. According to a second broad aspect, the invention provides a method for producing polymer particles, the method comprising: a) providing an atomizer wheel, distributor and a catch tray enclosed by an enclosure defining a partition between an interior and an exterior environment and having an aperture for allowing gaseous exchange between the interior and the exterior environment; and b) allowing gaseous exchange through the aperture thereby to regulate at least one condition of temperature, humidity or air flow within the interior environment. In an embodiment, the above-mentioned method further comprises varying a size of the aperture to vary a rate of gaseous exchange. In a further embodiment, the above mentioned enclosure comprises a dome. The dome partially enclosing the atomizer machine at once creates an open-system and creates a zone surrounding the machine. The open system is necessary to obtain an air flow current from within the zone to the exterior of the zone. The air flow current contributes to the control of temperature and humidity by preventing build-up of heat within the immediate vicinity of the wheel as a result of rapid rotation of the wheel. The creation of a zone surrounding the machine is necessary to define an area within which a desired temperature and humidity profile may be maintained. It has been found that accurate control of the factors that determine the temperature and humidity surrounding the machine is not possible in absence of a structure that defines a zone within which the temperature and humidity control means operate to maintain the desired temperature and humidity profile. Advantageously, the dome is adjustable, thus providing adjustment of the aperture size, to compensate for variations in the factors that affect the temperature and humidity in the immediate vicinity of the gel and particles. Temperature, humidity and turbulence of the air surrounding the apparatus and inside the apparatus affect the properties of beads: porosity, flow, average particle size, particle size distribution, bead shape and non-specific binding. In a further embodiment, the invention further provides an atomizer machine for the production of porous polymer particles having a narrow size distribution comprising: a) an atomizer wheel rotating about an axis; b) a distributor for providing a uniform thin layer of a gelatinous polymer on the wheel; c) a shaft connecting the wheel to a rotor; d) a catch tray disposed under the wheel to collect the particles; e) a dome partially enclosing the atomizer wheel and catch tray so as to maintain an open system and defining a zone surrounding the wheel and catch tray; f) a means for temperature and humidity control for creating and maintaining a temperature and humidity gradient within the zone; wherein the gelatinous polymer deposited on the rotating wheel moves to the periphery of the wheel under action of centrifugal force, the film being broken into free flying particles at the edge of the wheel. These and other aspects of the invention shall become apparent to those of ordinary skill in the art upon consideration of the following description of specific embodiments in conjunction with the accompanying drawings.

Engine piston and manufacture

An engine piston is manufactured by assembling an outer shell, comprising a crown and tubular side wall in which a ring groove region and skirt are defined, with a plate-like mounting member and bonding them together by brazing or welding. The mounting member is located within the tubular side wall displaced axially from the crown and is bonded near, but displaced radially from, its centre to the crown and at its periphery to the side wall at the end of the ring groove region. The mounting member carries gudgeon pin boss means facing away from the crown. The outer shell is formed by extrusion or the like that permits minimal wall thickness and the bonded structure is of light weight but great strength and stiffness, particularly in the ring groove region. A combustion bowl formed in the crown facilitates bonding to the mounting member and defines with the mounting member an annular cooling chamber adjacent the ring groove region and crown.

1-72. (canceled) 73. An engine piston comprising a prefabricated outer shell, said shell including a crown centred on a longitudinal piston axis and a tubular side wall extending axially with respect to the periphery of the crown to an open end; and a prefabricated mounting member within the tubular side wall of the shell, said mounting member carrying gudgeon pin bosses and extending transversely to the longitudinal piston axis, said mounting member also having an upper member part interfacing with the crown at a radially extending crown location interface between them serving as a mutual axial location reference and interfacing with the side wall spaced from the crown, defining a transversely extending closure plate-like member closing partly from below a peripheral chamber in the crown, the mounting member being bonded permanently to the crown at a crown bonding interface and bonded permanently to the side wall by at least one axially extending peripheral interface with the side wall. 74. A piston according to claim 73 wherein the bond between the mounting member and the tubular side wall is at substantially the same longitudinal position as the bond between the mounting member and the crown. 75. A piston according to claim 73 wherein the tubular side wall includes, adjacent the crown, a region of axially spaced, circumferentially extending ring grooves and the mounting member is bonded to the side wall at the end of the ring groove region remote from the crown. 76. A piston according to claim 73 wherein the crown has a central region surrounded by a peripheral region, the peripheral region being of integral formation with the tubular side wall, and the central region comprises a combustion bowl having a bowl wall and a bowl floor displaced axially from the crown peripheral region by said bowl wall and the bowl floor being formed by the mounting member bonded to the bowl wall. 77. A piston according to claim 76 wherein the combustion bowl floor and bowl wall are bonded together at a bonding interface between them extending in a substantially axial direction. 78. A piston according to claim 77 wherein the bonding interface is accessible from externally of the combustion bowl. 79. A piston according to claim 76 wherein said radially extending interface between the mounting member and crown serving as a mutual axial location reference is disposed between the mounting member and an end region of the bowl wall. 80. A piston according to claim 76 wherein the mounting member includes at least one fluid channel between the peripheral chamber and shell open end, at least one said channel extending through the mounting member from a said upper part defining the peripheral chamber to below the combustion bowl floor defined by the mounting member. 81. A piston as claimed in claim 76 wherein the gudgeon pin bosses are defined integrally with, and provided solely by, the mounting member on a face of the mounting member facing the open end of the tubular wall member and disposed axially between the open end of the shell and the bond between the mounting member and side wall, said bosses including a bore for the passage of a gudgeon pin extending transversely to the longitudinal piston axis and being spaced apart along the axis of said bore the gudgeon pin bosses. 82. A piston according to claim 73 in which the crown has a central region surrounded by a peripheral region, the peripheral region being of integral formation with the tubular side wall and the central region comprises a combustion bowl having a bowl wall and a bowl floor displaced axially from the crown peripheral region by said bowl wall, the combustion bowl floor being formed integrally with the bowl wall and said mounting member being bonded to the crown at the combustion bowl. 83. A piston according to claim 82 wherein said radially extending interface between the mounting member and crown serving as a mutual axial location reference is defined between the mounting member and the crown at the junction between the combustion bowl wall and bowl floor. 84. A piston according to claim 82 wherein said radially extending interface is defined by an axial extension to the combustion bowl wall. 85. A piston according to claim 82 wherein the mounting member is bonded to the crown at said radially extending crown location interface between the mounting member and crown serving as a mutual axial location reference. 86. A piston as claimed in claim 82 wherein the gudgeon pin bosses are defined integrally with, and provided solely by, the mounting member on a face of the mounting member facing the open end of the tubular wall member and axially between the open end of the shell and the bond between the mounting member and side wall, said bosses including a bore for the passage of a gudgeon pin extending transversely to the longitudinal piston axis and being spaced apart along the axis of said bore the gudgeon pin bosses. 87. A piston as claimed in claim 86 wherein the mounting member comprises an axially thin plate having increased axial thickness at the periphery and to effect the piston bosses. 88. A piston as claimed in claim 86 wherein the mounting member includes a connecting rod aperture extending through the mounting member along the longitudinal piston axis between said gudgeon pin bosses and exposing the central region of the crown to the open end of the tubular side wall. 89. A piston as claimed in claim 88 wherein the mounting member is of substantially uniform cross-section in said direction of the gudgeon pin bore, except for the connecting rod aperture. 90. A piston as claimed in claim 88 wherein the mounting member upper part has an upper surface and includes at least one fluid channel between the peripheral chamber and shell open end, at least one said fluid channel extending in the upper surface of the mounting plate from said peripheral chamber to the connecting rod aperture. 91. A piston as claimed in claim 73 wherein the junction between the periphery of the mounting member and the shoulder means is in line with the open end of the tubular side wall. 92. A piston as claimed in claim 73 wherein the gudgeon pin boss means includes a bore for the passage of a gudgeon pin transversely to the longitudinal piston axis and the side wall includes cooperating apertures in the tubular side wall and the boss means is bonded with the tubular side wall at said apertures. 93. A piston as claimed in claim 73 wherein the tubular side wall has therein shoulder means provided by a change in internal diameter of the wall and facing towards the open end of the side wall, and the periphery of the mounting member is bonded to the side wall at the shoulder means. 94. A piston as claimed in claim 88 wherein the tubular side wall has between the end of the ring groove section and said open end a reduction in thickness defined principally by the shoulder means, the shoulder means comprises a first, smaller thickness of the ring groove region and a second, larger reduction in thickness between the ring groove region and open end. 95. A piston as claimed in claim 73 wherein the outer shell is made from a metal alloy deformable in the solid state. 96. A piston as claimed in claim 95 wherein the material is steel. 97. A piston as claimed in claim 95 wherein the mounting member and outer shell are made from the same material. 98. A piston as claimed in claim 95 wherein the mounting member and outer shell are bonded together by at least one welded joint. 99. A method of making an engine piston comprising forming an outer shell part comprising a crown, centered on a longitudinal axis, and a tubular side wall extending axially with respect to the periphery of the crown to an open end, said crown having at least a peripheral region integral with the side wall; forming a mounting member having an upper member part and opposite thereto gudgeon pin bosses and a periphery dimensioned to fit within and interface with the tubular side wall; disposing the mounting member within the tubular side wall such that the gudgeon pin bosses face the open end, the upper part interfaces with the crown at least a radially extending crown interface defining mutual axial location reference, and the periphery interfaces with the side wall at a wall interface spaced axially from the crown periphery and radially from said radially extending crown interface, defining thereby a transversely extending closure plate closing partly from below a peripheral chamber in the crown; and permanently bonding the mounting member to the shell part at said wall interface and to the crown at a crown bonding interface radially inwardly of said wall interface. 100. The method of claim 99 comprising bonding the mounting member to said crown and wall at interfaces at substantially the same axial position. 101. The method of claim 99 comprising forming in the tubular side wall adjacent the crown a region of axially spaced circumferentially extending ring grooves and bonding the periphery of the mounting member to the side wall at the end of the ring groove region remote from the crown. 102. The method of claim 99 comprising forming the tubular side wall and at least a peripheral region of the crown, bounding a central crown region, as an integral shell body and by forming at least part of the central crown region as a combustion bowl having a bowl wall and a bowl floor displaced axially of the crown peripheral region by said bowl wall, and by bonding the mounting member to the crown at the combustion bowl. 103. The method of claim 102 comprising defining said radially extending crown location interface between the mounting member and crown, serving as a mutual axial location reference between the mounting member and the crown, at the junction between the combustion bowl wall and bowl floor. 104. The method according to claim 103 comprising defining said radially extending interface by an axial extension to the combustion bowl wall. 105. The method according to claim 102 comprising bonding the mounting member to the crown at the radially extending crown location interface between the mounting member and crown serving as a mutual axial location reference. 106. The method of claim 99 comprising forming the tubular side wall and at least a peripheral region of the crown, bounding a central crown region, as an integral shell body and by forming at least part of the central crown region as a combustion bowl having a bowl wall and defining a bowl floor displaced axially of the crown peripheral region by said bowl wall by the mounting member. 107. The method of claim 106 comprising defining said radially extending crown location interface, serving as a mutual axial location reference, between the mounting member and the combustion bowl wall. 108. The method of claim 106 comprising bonding the mounting member to the crown by way of a said crown bonding interface between the combustion bowl floor defined by the mounting member and the combustion bowl wall defined by the crown. 109. The method of claim 108 comprising defining said crown bonding interface extending in a substantially axial direction accessible from outside of the combustion bowl and bonding the combustion bowl floor to the combustion bowl wall by access through the combustion bowl. 110. The method of claim 109 comprising bonding the combustion bowl floor to the combustion bowl wall metallurgically by applying heat from a source externally of the piston by access through the combustion bowl. 111. The method of claim 110 comprising bonding the interface by welding. 112. The method of claim 99 comprising defining the wall interface accessible from externally of the piston and bonding metallurgically by applying heat from a source externally of the piston. 113. The method of claim 112 comprising bonding the interface by welding. 114. The method of claim 99 comprising bonding the mounting member to the side wall substantially about the whole of its periphery. 115. The method of claim 99 comprising casting the mounting member. 116. The method of claim 99 comprising extruding the mounting member. 117. The method of claim 99 comprising forming the outer shell part by flow forming about a rotating mandrel shaped to define the interior of the tubular side wall. 118. The method of claim 99 comprising forming the outer shell part by back extrusion about a mandrel shaped to define the interior of the tubular side wall. 119. The method of claim 118 comprising forming at least one valve pocket in the crown during extrusion. 120. The method of claim 99 comprising forming the body shell and mounting member from the same material. 121. The method of claim 99 comprising forming the outer shell part from steel. 122. A method of making an engine piston having a crown, centered on a longitudinal axis, and a tubular side wall, extending axially with respect to the periphery of the crown to an open end and defining a region for a belt of ring grooves and a skirt, the method being characterized by rotating a unitary body of metal and by flow forming thereof defining at least a peripheral portion of piston crown and the side wall extending therefrom. 123. A method of making an engine piston having a crown, centered on a longitudinal axis, and a tubular side wall, extending axially with respect to the periphery of the crown to an open end and defining a region for a belt of ring grooves and a skirt, the method being characterized by back extruding a unitary body of metal to define at least a peripheral portion of piston crown and the side wall extending therefrom.

Glazing for vehicles

The invention relates to laminated glazing for vehicles having a limited energy transmittance. According to the invention, the glazing has a light transmittance of at least 70%, an energy transmittance TE that is at most equal to 51% and, for thicknesses requested by manufacturers, thicknesses for which Texe, wherein e is the total thickness of the sheets of glass in millimetres, is at most equal to 200. The inventive glazing provides a balanced solution that satisfies demands in terms of cost and sun-protection properties for vehicles, particularly motor vehicles.

1. Laminated glazing for vehicles comprising two sheets of coloured glass, of which the light transmission (TL) for the thicknesses required by manufacturers is at least equal to 70%, the energy transmittance (TE) is at most equal to 51% and the term TExe, wherein TE is expressed as a percentage and e is the total thickness of the two glass sheets expressed in millimetres, is at most equal to 200. 2. Laminated glazing according to claim 1, wherein the energy transmittance is at most equal to 48%. 3. (Canceled) 4. (Canceled) 5. 6. (Canceled) 7. (Canceled) 8. (Canceled) 9. (Canceled) 10. (Canceled) 11. (Canceled) 12. Laminated glazing according to claim 1, and further including at least one of the following (A) through (D): A. wherein the total thickness of the two glass sheets is in the range of between 3.5 and 5.5 mm; B. wherein the two glass sheets have the same glass composition; C. wherein the glass sheets have the same thickness; D. wherein the glass sheets the following soda-lime composition: SiO2 60-75% Na2O 10-20% CaO 0-16% K2O 0-10% MgO 0-10% Al2O3 0-5% BaO 0-2% with K2O + Na2O 10-20% CaO + MgO + BaO 10-20% and comprising the following main colouring agents: Fe2O3 (total iron expressed as) 0.5-1% FeO 0.14-0.25% Co 0-0.0040% Cr2O3 0-0.0500% Vr2O5 0-0.0200% Se 0-0.0050%. 13. Laminated glazing according to claim 12, and including at least two of the features (A) through (D). 14. Laminated glazing according to claim 12, and including all of the features (A) through (D). 15. Laminated glazing according to claim 1, wherein the total thickness of the two glass sheets is in the range of between 3.8 and 5.2 mm. 16. Laminated glazing according to claim 1, for which the term TExe is at most equal to 195. 17. Laminated glazing according to claim 1, wherein the soda-lime composition of the glass sheets comprises the following colouring agents: Fe2O3 (total iron expressed as) 0.5-0.6% FeO 0.16-0.20% Co 0-0.0020% Cr2O3 0.0020-0.0045%. 18. Laminated glazing according to claim 1, wherein the soda-lime composition of the glass sheets comprises the following colouring agents: Fe2O3 (total iron expressed as) 0.7-1% FeO 0.18-0.24% V2O5 0-0.0200%.

Naadp analogues for modulating t-cell activity

A method for modulating T cell activity by modulating the intracellular concentration and/or activity of NAADP+, compounds capable of modulating the effect of NAADP+ on T cell Ca2+ levels, and methods for identifying the same, are described.

1. A method for modulating T cell activity, which comprises the step of modulating the intracellular concentration of NAADP+ or a bioisostere thereof. 2. A method according to claim 1, which comprises the step of stimulating a rise in intracellular Ca2+ levels by raising the intracellular concentration of NAADP+, or a bioisostere thereof, to an activating concentration. 3. A method according to claim 1, which comprises the step of inhibiting TCR/CD3-associated Ca2+ signalling by raising the intracellular concentration of NAADP+, or a bioisostere thereof, to an inactivating concentration. 4. A compound capable of antagonising the NAADP+-mediated rise in intracellular Ca2+ levels in a T cell, said rise being in response to stimulation of the T cell receptor/CD3 complex, for use in modulating T cell activity. 5. A compound capable of inducing the NAADP+-mediated inhibition of TCR/CD3-associated Ca2+ signalling, for use in modulating T cell activity 6. A compound according to claim 5, which is capable of raising the intracellular concentration of NAADP+, or a bioisostere thereof, to an inactivating concentration 7. A compound according to any of claims 4 to 6, for use in inducing T cell anergy. 8. A compound according to any of claims 4 to 6, for use in blocking T cell proliferation. 9. A compound capable of agonising the NAADP+-mediated rise in intracellular Ca2+ levels in a T cell, said rise being in response to stimulation of the T cell receptor/CD3 complex, for use in modulating T cell activity. 10. A compound capable of preventing the NAADP+-mediated inhibition of TCR/CD3-associated Ca2+ signalling, for use in modulating T cell activity 11. A compound according to claim 9 or 10, for stimulating T cell proliferation and/or differentiation. 12. A compound according to any one of claims 4-11 wherein said compound is a NAADP analogue. 13. A compound according to claim 12 wherein the NAADP analogue has the formula (I): wherein P is a substituent group independently selected from NH2, OH, SH; each of W1, W2 or W3 is independently selected from either a CH or a heteroatom, such as N, P, S or O, preferably N; X is a substituent group independently selected from OH, SH, NH2, or a halo group (preferably Br); each of R1, R2 or R3 is independently selected from H or each of Y1, Y2 or Y3 is independently selected from OH, H, NH2, halo (preferably F), wherein R4 is a hydrocarbyl; each of Z1 or Z2 is independently selected from O, S, CH2 or a halo derivative thereof, preferably CF2; and L is a linker group, suitably the linker group may have the formula (II): or may be selected from one ore more the group comprising: a phosphate, a polyphosphate, a phosphorothioate, a polyethylene glycol, an alkyl, an alkylaryl, a peptide and a polyamine; or isomeric forms of the compound of Formula (I). 14. A compound according to claim 12 or claim 13 wherein said NAADP analogue is 8-bromo-nicotinic acid adenine dinucleotide phosphate. 15. Use of a compound as defined in any one of claims 4 to 14 in the manufacture of a medicament for use in modulating the immune response of a mammal. 16. Use of a compound as defined in any one of claims 4 to 8 in the manufacture of a medicament for use in treating an autoimmune disease or graft rejection. 17. Use according to claim 16 wherein the autoimmune disease is selected from thyroiditis, insulitis, multiple sclerosis, iridocyclitis, uveitis, orchitis, hepatitis, Addison's disease, myasthenia gravis, rhematoid arthritis and lupus erythematosus. 18. Use of a compound as defined in any one of claims 4 to 17 in the manufacture of a medicament for use in treating or preventing an immune disorder in a human or animal. 19. A method of treating or preventing a disease in a human or animal patient which method comprises administering to the patient an effective amount of a compound as defined in any one of claims 4 to 14. 20. A method for identifying a substance capable of antagonising the NAADP+-mediated rise in intracellular Ca2+ levels in a T cell, which method comprises: (i) contacting a T cell, which has been stimulated via its T cell receptor, with a candidate substance under conditions that would permit a rise in intracellular Ca2+ levels in the absence of the substance; and (ii) determining whether the substance inhibits a rise in intracellular Ca2+ levels. 21. A method for identifying a substance capable of inducing the NAADP+-mediated inhibition of TCR/CD3-associated Ca2+ signalling, which method comprises: (i) contacting a T cell with a candidate substance; (ii) stimulating the T cells via TCR/CD3; and (ii) determining whether the substance inhibits TCR/CD3-associated Ca2+ signalling. 22. A method for identifying a substance capable of agonising the NAADP+-mediated rise in intracellular Ca2+ levels in a T cell, which method comprises: (i) contacting a T cell with a candidate substance; and (ii) determining whether the substance elicits or enhances a rise in intracellular NAADP+ and/or Ca2+ levels. 23. A substance identified by the method of claim 20, 21 or 22. 24. A process comprising the steps of: (a) performing the method according to claim 20, 21 or 22; (b) preparing a quantity of one or more substances identified by the method. 25. A compound capable of modulating the intracellular concentration and/or the binding affinity of NAADP+ wherein the compound is a NAADP analogue. 26. A compound capable of modulating the intracellular concentration and/or the binding affinity of NAADP+ wherein the compound has the formula (I): wherein P is a substituent group independently selected from NH2, OH, SH; each of W1, W2 or W3 is independently selected from either a CH or a heteroatom, such as N, P, S or O, preferably N; X is a substituent group independently selected from OH, SH, NH2, or a halo group (preferably Br); each of R1, R2 or R3 is independently selected from H or each of Y1, Y2 or Y3 is independently selected from OH, H, NH2, halo (preferably F), SH, OR4, or wherein R4 is a hydrocarbyl; each of Z1 or Z2 is independently selected from O, S, CH2 or a halo derivative thereof, preferably CF2; and L is a linker group, suitably the linker group may have the formula (II): or may be selected from one ore more the group comprising: a phosphate, a polyphosphate, a phosphorothioate, a polyethylene glycol, an alkyl, an alkylaryl, a peptide and a polyamine; or isomeric forms of the compound of Formula (I). 27. A compound capable of modulating the intracellular concentration and/or the binding affinity of NAADP+ wherein the compound is 8-bromo-nicotinic acid adenine dinucleotide phosphate. 28. Use of a NAADP analogue in the manufacture of a medicament for use in modulating the immune response of a mammal. 29. Use of a compound having formula (I): wherein P is a substituent group independently selected from NH2, OH, SH; each of W1, W2 or W3 is independently selected from either a CH or a heteroatom, such as N, P, S or O, preferably N; X is a substituent group independently selected from OH, SH, NH2, or a halo group (preferably Br); each of R1, R2 or R3 is independently selected from H or each of Y1, Y2 or Y3 is independently selected from OH, H, NH2, halo (preferably F), SH, OR4, or wherein R4 is a hydrocarbyl; each of Z1 or Z2 is independently selected from O, S, CH2 or a halo derivative thereof, preferably CF2; and L is a linker group, suitably the linker group may have the formula (II): or may be selected from one ore more the group comprising: a phosphate, a polyphosphate, a phosphorothioate, a polyethylene glycol, an alkyl, an alkylaryl, a peptide and a polyamine; or isomeric forms of the compound of Formula (I) in the manufacture of a medicament for use in modulating the immune response of a mammal. 30. Use of 8-bromo-nicotinic acid adenine dinucleotide phosphate in the manufacture of a medicament for use in modulating the immune response of a mammal. 31. Use of a NAADP analogue in the manufacture of a medicament for use in treating an autoimmune disease or graft rejection. 32. Use of a compound having formula (I): wherein P is a substituent group independently selected from NH2, OH, SH; each of W1, W2 or W3 is independently selected from either a CH or a heteroatom, such as N, P, S or O, preferably N; X is a substituent group independently selected from OH, SH, NH2, or a halo group (preferably Br); each of R1, R2 or R3 is independently selected from H or each of Y1, Y2 or Y3 is independently selected from OH, H, NH2, halo (preferably F), SH, OR4, or wherein R4 is a hydrocarbyl; each of Z1 or Z2 is independently selected from O, S, CH2 or a halo derivative thereof, preferably CF2; and L is a linker group, suitably the linker group may have the formula (II): or may be selected from one ore more the group comprising: a phosphate, a polyphosphate, a phosphorothioate, a polyethylene glycol, an alkyl, an alkylaryl, a peptide and a polyamine; or isomeric forms of the compound of Formula (I) in the manufacture of a medicament for use in treating an autoimmune disease or graft rejection. 33. Use of 8-bromo-nicotinic acid adenine dinucleotide phosphate in the manufacture of a medicament for use in treating an autoimmune disease or graft rejection. 34. A method of treating or preventing a disease in a human or animal patient which method comprises administering to the patient an effective amount of a NAADP analogue. 35. A method of treating or preventing a disease in a human or animal patient which method comprises administering to the patient an effective amount of a compound having formula (I): wherein P is a substituent group independently selected from NH2, OH, SH; each of W1, W2 or W3 is independently selected from either a CH or a heteroatom, such as N, P, S or O, preferably N; X is a substituent group independently selected from OH, SH, NH2, or a halo group (preferably Br); each of R1, R2 or R3 is independently selected from H or each of Y1, Y2 or Y3 is independently selected from OH, H, NH2, halo (preferably F), SH, OR4, or wherein R4 is a hydrocarbyl; each of Z1 or Z2 is independently selected from O, S, CH2 or a halo derivative thereof, preferably CF2; and L is a linker group, suitably the linker group may have the formula (II): or may be selected from one ore more the group comprising: a phosphate, a polyphosphate, a phosphorothioate, a polyethylene glycol, an alkyl, an alkylaryl, a peptide and a polyamine; or isomeric forms of the compound of Formula (I). 36. A method of treating or preventing a disease in a human or animal patient which method comprises administering to the patient an effective amount of 8-bromo-nicotinic acid adenine dinucleotide phosphate.

<SOH> BACKGROUND TO THE INVENTION <EOH>Adaptive or specific immune responses are normally stimulated when an individual is exposed to a foreign antigen. Specific immunity is mediated by lymphocytes, e.g. B and T lymphocytes. During an immune response, recognition of an antigen leads to activation of lymphocytes that specifically recognise that particular antigen. The lymphocytes proliferate and differentiate into specialised effector cells. The immune response culminates in the development of mechanisms that ultimately eliminate the antigen. Adaptive immune responses are critical components of host defence during protection against foreign antigens, such as infectious organisms or toxins. However, specific immune responses are also sometimes elicited by antigens not associated with infectious agents, and this may cause serious disease. For example, one of the most remarkable properties of specific immunity is the ability to distinguish between self antigens and foreign antigens. Thus, the lymphocytes in each individual are able to recognise and respond to numerous foreign antigens but are normally unresponsive to potentially antigenic substances present in the individual itself Unresponsiveness to self antigens is an acquired process that has to be learned by the individual's lymphocytes and has to be maintained throughout life. Abnormalities in the induction or maintenance of self-tolerance lead to immune responses against self antigens, and debilitating diseases that are commonly called autoimmune diseases. The spectrum of autoimmune disorders ranges from organ specific diseases (such as thyroiditis, insulitis, multiple sclerosis, iridocyclitis, uveitis, orchitis, hepatitis, Addison's disease, myasthenia gravis) to systemic illnesses such as rheumatoid arthritis or lupus erythematosus. Another example in which specific immunity against antigens that are not associated with infections causes severe medical problems are rejections of transplanted allografts. In fact, adaptive immune responses to grafted tissues are the major impediment to successful transplantation in most cases. It is not known what causes the breakdown of tolerance and the initiation of an autoimmune response. However, the mechanisms of tissue destruction in autoimmune diseases and in allograft rejection are essentially the same as those operating in protective immunity. It is generally believed that both autoimmune reactions and allograft rejections are initiated and perpetuated by a response involving T cells. Thus, in the absence of a specific therapy for any of the autoimmune diseases or for allograft rejection, many therapeutic strategies currently employed aim at down modulating the activity of the immune system, in particular by reducing or preventing the activation of T cells. Recently, monoclonal antibodies to T cell surface antigens, that inhibit T cell activation, or substances that interfere with intracellular T cell activation pathways, such as Cyclosporin A or FK506, have been introduced for the treatment of both allograft rejection and several autoimmune diseases. However, current approaches for the treatment of undesirable T cell activation have been associated with a number of side effects related to general immunosuppression and therefore cannot be considered to be optimal therapy. Stimulation of T-lymphocytes via the T cell receptor/CD3 complex (TCR/CD3) is a critical step in T cell activation and subsequent clonal expansion. Previous studies have shown that activation of the TCR/CD3-complex involves the elevation of the free cytosolic Ca 2+ concentration ([Ca 2+ ] i ) by at least two mechanisms, a rapid elevation caused by Ca 2+ release from intracellular stores mediated by inositol (1,4,5) trisphosphate (Ins(1,4,5)P 3 ), and a prolonged elevation that is completely dependent on the influx of extracellular calcium (reviewed in Guse, 1998). Ca 2+ -release is activated by the calcium mobilizing second messengers Ins(1,4,5)P 3 (Jayaraman et al, 1995) and cADPR (Guse et al., 1999). Recent work indicates that Ins(1,4,5)P 3 primarily acts during the initial phase of Ca 2+ -signaling in T cells, whereas cADPR is essentially involved in the sustained phase of Ca 2+ -signaling. The exact mechanism of Ca 2+ signalling in T cells is still unclear, but it is of fundamental importance for proliferation and clonal expansion, and thus for a functional immune response. An improved understanding of the signalling pathways involved in T cell activation may be of assistance in developing strategies to stimulate a desirable adaptive immune response or to suppress inappropriate T cell activity.

<SOH> SUMMARY OF THE INVENTION <EOH>The present inventors have shown that NAADP+ specifically and dose-dependently stimulates Ca 2+ signalling in human T cells. At an activating concentration, NAADP+ either evokes repetitive and longlasting Ca 2+ oscillations or a single Ca 2+ -spike of high amplitude. The present inventors have also shown that NAADP+ can be self-inactivating. An inactivating concentration of NAADP+ inhibits subsequent stimulation of Ca 2+ signaling via the T cell receptor/CD3. For example, inactivation of the NAADP + /Ca 2+ -release system almost completely abolishes subsequent Ins(1,4,5)P 3 - or cADPR-mediated Ca 2+ -signaling. This shows that a functional NAADP+/Ca 2+ release system is essential for T-lymphocyte Ca 2+ signaling. These findings have important implications for the design of compounds capable of modulating T cell activity, since regulation of this NAADP+/Ca 2+ signalling pathway may provide an important means of stimulating T cells (and adaptive immune responses) and controlling T cell responses in a variety of T cell mediated immune disorders. Accordingly the present invention provides a method for modulating T cell activity, which comprises the step of modulating the intracellular concentration of NAADP+ or a bioisostere thereof. In one embodiment, the method involves stimulating a rise in intracellular Ca 2+ levels by raising the intracellular concentration of NAADP+ to an activating concentration. The present inventors have found that an intracellular concentration of 10 nM NAADP+ evokes repetitive and longlasting Ca 2+ oscillations of low amplitude, while 50 and 100 nM produces a rapid and high initial Ca 2+ peak followed by trains of smaller Ca 2+ oscillations. Higher concentrations of NAADP+(1 and 10 μM) gradually reduce the initial Ca 2+ peak. Thus an “activating concentration” of NAADP+ may be between 5 nM and 1 μM, preferably between 5 and 100 nM. In another embodiment, the method involves inhibiting TCR/CD3-associated Ca 2+ signaling by raising the intracellular concentration of NAADP+ to an inactivating concentration. The present inventors have shown that an intracellular concentration of 100 μM NAADP+ causes complete self-inactivation of Ca 2+ -signals. Thus an “inactivating concentration” of NAADP+ may be greater than 1 μM, preferably greater than 10 M, most preferably 100 μM or greater. The elucidation of a novel NAADP+-mediated T cell activation pathway also enables the identification of substances that modulate T cell activation via this pathway. The present invention thus also provides a compound capable of (a) antagonising the NAADP+-mediated rise in intracellular Ca 2+ levels caused by TCR/CD3 stimulation; (b) agonising the NAADP+-mediated rise in intracellular Ca 2+ levels caused by TCR/CD3 stimulation; (c) inducing the NAADP+-mediated inhibition of TCR/CD3-associated Ca 2+ signaling; or (d) preventing the NAADP+-mediated inhibition of TCR/CD3-associated Ca 2+ signaling Compounds of the invention which inhibit T cell proliferation and/or differentiation, or induce T cell anergy may be used in treating diseases characterised by an excessive or inappropriate T cell response, such as autoimmune diseases, allergies and allograft rejection. Candidate autoimmune diseases include thyroiditis, insulitis, multiple sclerosis, iridocyclitis, uveitis, orchitis, hepatitis, Addison's disease, myasthenia gravis, rheumatoid arthritis and lupus erythematosus. Compounds of the invention which induce or enhance T cell proliferation and/or differentiation or prevent the induction of T cell anergy may be used generally to boost or induce T cell immune responses. Virtually all adaptive immune responses require the activation of T cells and their differentiation into cytokine-producing cells. Thus these compounds may be used generally to prevent and treat conditions such as infectious diseases (such as viral or bacterial infections), cancers and, in particular, immunodeficiencies characterised by impaired T cell function (such as AIDS). The present invention further provides a method for identifying a substance capable of antagonising the NAADP+-mediated rise in intracellular Ca 2+ levels in a T cell, which method comprises: (i) contacting a T cell, which has been stimulated via its T cell receptor, with a candidate substance under conditions that would permit a sustained rise in intracellular Ca 2+ levels in the absence of the substance; and (ii) determining whether the substance inhibits a sustained rise in intracellular Ca 2+ levels. In one embodiment, the substance inhibits NAADP+ synthesis, for example reduces or abolishes NAADP+ synthesis. In another embodiment, the substance modulates, for example inhibits, binding of endogenous NAADP+ to its receptor binding site. The present invention further provides a method for identifying a substance capable of inducing the NAADP+-mediated inhibition of TCR/CD3-associated Ca 2+ signalling, which method comprises: (i) contacting a T cell with a candidate substance; (ii) stimulating the T cells via TCR/CD3; and (ii) determining whether the substance inhibits TCR/CD3-associated Ca 2+ signalling. In one embodiment, the substance causes the intracellular concentration of NAADP+ (or a bioisostere thereof) to rise to an inactivating concentration. The present invention further provides a method for identifying a substance capable of agonising the NAADP+-mediated rise in intracellular Ca 2+ levels in a T cell, which method comprises: (i) contacting a T cell with a candidate substance; and (ii) determining whether the substance elicits or enhances a rise in intracellular NAADP+ and/or Ca 2+ levels. In one embodiment, the substance induces or enhances NAADP+ synthesis. In another embodiment, the substance modulates, for example enhances, binding of endogenous NAADP+ to its receptor binding site. A compound identified by the methods of the invention may be used in modulating the immune response of a mammal. Thus, for example, in another aspect of the present invention, a compound identified by a method of the invention is provided for use in treating (i) an autoimmune disease, such as thyroiditis, insulitis, multiple sclerosis, iridocyclitis, uveitis, orchitis, hepatitis, Addison's disease, myasthenia gravis, rhematoid arthritis and lupus erythematosus or (ii) allograft rejection. The present invention also provides a pharmaceutical composition (which term also includes a veterinary formulation) comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent, excipient or carrier. The invention further provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a human or animal medicament.

Method for producing concrete or mortar using a vegetal aggregate

A method for producing concrete or mortar based on an exclusively vegetal aggregate, a mineral binding agent, and mixing water is described. Instead of the vegetal aggregate being premineralized in a separate step of the operation, 4 to 14 kg of a non-hydratizable, finely ground mineralizator is added for each cubic meter of vegetable aggregate when the concrete or mortar is being mixed. Raw calcium carbonate is a preferred mineralizator.

1. Method for producing concrete or mortar based on an exclusively vegetal aggregate, a mineral binding agent, and mixing water, the vegetal aggregate having a specific weight of 80 to 160 kg/m3, as measured at a residual moisture of approximately 15%, characterized in that 4 to 14 kg of a non-hydratizable, finely ground mineralizator is added for each cubic meter of the vegetal aggregate when the concrete or mortar is being mixed. 2. Method as defined in claim 1, characterized in that the mineralizator is a finely ground stone dust. 3. Method as defined in claim 1 or claim 2, characterized in that at least 80%-mass of the mineralizator that is added has a grain size of less than 0.09 mm. 4. Method as defined in one of the claims 1 to 3, characterized in that the mineralizator essentially includes raw calcium carbonate. 5. Method as defined in one of the claims 1 to 4, characterized in that the mineral binding agent includes Portland cement, in particular PZ 42.5 Grade Portland cement. 6. Method as defined in one of the claims 1 to 5, characterized in that the mineral binding agent is a mixture of Portland cement and white lime. 7. Method as defined in one of the claims 1 to 6, characterized in that between 180 and 400 kg of mineral binding agent is added for each cubic meter of the vegetal aggregate. 8. Method as defined in one of the claims 1 to 7, characterized in that the mixing ratio of mineralizator to mixing water amounts to 25 kg to 50 kg of mineralizator to 1,000 kg of water. 9. Method as defined in one of the claims 1 to 8, characterized in that the vegetal aggregate is composed for the most part of fibrous particles with diameters ranging from 0 mm to 5.0 mm. 10. Method as defined in claim 9, characterized in that a light concrete or a light wash floor is produced, the vegetal aggregate being composed for the most part of fibrous particles with the lengths ranging from 5 mm to 40 mm. 11. Method as defined in claim 9, characterized in that a light plaster or thermal insulation plaster is produced, the vegetal aggregate being composed for the most part of fibrous particles with lengths of less than 5 mm. 12. Method as defined in claim 1 to claim 11, characterized in that coniferous wood, hemp and/or reeds are used during the production of the vegetal aggregate. 13. Method as defined in one of the claims 1 to 12, characterized in that plants of the Miscanthus family are used for the production of the vegetal aggregate. 14. Method as defined in claim 14, characterized in that the plant Miscanthus Gigantheus is used for production of the vegetal aggregate. 15. Method as defined in one of the claims 1 to 14, characterized in that the method is used for producing light concrete, light mortar, light wash floor, as well as light plaster and thermal insulation plaster.

Peptidomimetic protease inhibitors

The present invention relates to peptidomimetic compounds useful as protease inhibitors, particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective processes to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.

1. A compound of formula I wherein: R0 is a bond or difluoromethylene; R1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R2 and R9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R3, R5 and R7 are each independently; optionally substituted (1,1- or 1,2-)cycloalkylene; or optionally substituted (1,1- or 1,2-)heterocyclylene; or methylene or ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent; or R4, R6, R8 and R10 are each independently is hydrogen or optionally substituted aliphatic group; is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R9-L-(N(R8)—R7—C(O)—)nN(R6)—R5—C(O)—N moiety and to which the —C(O)—N(R4)—R3—C(O)C(O)NR2R1 moiety is attached; L is —C(O)—, —OC(O)—, —NR10C(O)—, —S(O)2—, or —NR10S(O)2—; and n is 0 or 1, or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided when is substituted then L is —OC(O)— and R9is optionally substituted aliphatic; or at least one of R3, R5 and R7 is ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group and wherein the ethylene is further optionally substituted with an aliphatic group substituent; or R4 is optionally substituted aliphatic. 2. A compound of claim 1 wherein R0 is a bond. 3. A compound of claim 2 wherein: optionally substituted aliphatic groups are alkyl, alkenyl or alkynyl, optionally substituted with one or more aliphatic group substituent; optionally substituted cyclic groups are cycloalkyl, cycloalkenly, heterocyclyl or heterocyclenyl groups optionally substituted with one or more ring group substituents; optionally substituted aromatic groups are aryl or heteroaryl gropus optionally substituted with one or more ring group substituents; optionally substituted (1,1- or 1,2) cycloalkylene groups are (1,1- or 1,2) cycloalkylene groups optionally substituted with one or more ring group substituents; optionally substituted (1,1- or 1,2) heterocyclylene groups are (1,1- or 1,2) heterocyclylene groups optionally substituted with one or more ring group substituents; as substituted monocyclic azaheterocyclyl is a monocyclic azaheterocyclyl group substituted directly or through a linker group by at least one substituent selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl or its thio analogue, heteroaryl or its thioxo analogue, aroyloxy, heteroaroyloxy, aryloxycarbonyl, heteroaryloxycarbonyl, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aryldiazo, heteroaryldiazo, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2— wherein at least one of Y1 and Y2 is aryl or heteroaryl, wherein said linker group is selected from the group consisting of —C(O)—, —OC(O)—, lower alkyl, lower alkoxy, lower alkenyl, —O—, —S—, —C(O)C(O)—, —S(O)—, —S(O)2—, —NR80—, where R80 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl; optionally substituted multicyclic azaheterocyclyl is a multicyclic azaheterocyclyl group optionally substituted by one or more ring group substituents; optionally substituted multicyclic azaheterocyenyll is a multicyclic azaheterocyclenyll group optionally substituted by one or more ring group substituents; wherein: aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; ring group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), acid biostere, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl, or when a ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H2C═), oxo (O═) and thioxo (S═); aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms; cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms; cycloalkenyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms which contain at least one carbon-carbon double bond; cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl; heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atomsin which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon; heterocyclenyl means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond; and heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon. 4. A compound of claim 1 wherein R0 is difluoromethylene. 5. A compound of claim 3 wherein R1 is hydrogen or optionally substituted lower aliphatic group. 6. A compound of claims 5 wherein R1 is hydrogen or lower alkyl. 7. A compound of claim 6 wherein R1 is hydrogen. 8. A compound of claim 3 wherein R2 is optionally substituted lower aliphatic group or optionally substituted monocyclic group. 9. A compound of claim 8 wherein R2 is optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted monocyclic cycloalkyl. 10. A compound of claim 9 wherein R2 is carboxymethyl, 1-carboxy-2-phenylethyl, cyclopropyl, cyclobutyl, 1-cyclohexylethyl, 1-phenylethyl, but-2-yl, 1-pyrid4-ylethyl, propen-3-yl or 3-methylbut-2-yl. 11. A compound of claim 3 wherein R3 is optionally substituted lower aliphatic group methylene. 12. A compound of claim 11 wherein R3is optionally halo substituted lower (alkyl or alkenyl)methylene. 13. A compound of claim 12 wherein R3 is propylmethylene, 2,2-difluoroethylmethylene, 2,2,2-trifluoromethylene or propen-3-ylmethylene; 14. A compound of claim 13 wherein R3 is propylmethylene or 2,2-difluoroethylmethylene. 15. A compound of claim 14 wherein R3 is propylmethylene. 16. A compound of claim 3 wherein R4 is hydrogen or optionally substituted lower aliphatic group. 17. A compound of claim 16 wherein R4 is hydrogen. 18. A compound of claim 3 wherein R5 is optionally substituted lower aliphatic group methylene. 19. A compound of claim 18 wherein R5 is optionally (phenyl, carboxy, carboxamido or alkoxycarbonyl) substituted lower (alkyl or alkenyl) methylene. 20. A compound of claim 19 wherein R5 is methylmethylene, isopropylmethylene, t-butylmethylene, but-2-ylmethylene, butylmethylene, benzylmethylene, 3-methylbutylmethylene, 2-methylpropylmethylene, carboxymethylmethylene, carboxamidomethylmethylene, benzyloxycarbonylmethylmethylene, benzyloxycarbonylpropylmethylene or phenylpropen-3-ylmethylene. 21. A compound of claim 20 wherein R5is isopropylmethylene or t-butylmethylene. 22. A compound of claim 3 wherein R6 is hydrogen or optionally substituted lower aliphatic group. 23. A compound of claim 22 wherein R6 is hydrogen or lower alkyl. 24. A compound of claim 23 wherein R6 is hydrogen. 25. A compound of claim 3 wherein R7 is optionally substituted lower aliphatic group methylene, optionally substituted lower cyclic group methylene or optionally substituted monocyclic (aryl or heteroaryl) methylene. 26. A compound of claim 25 wherein R7is optionally substituted lower alkylmethylene, optionally substituted lower cycloalkylmethylene or optional substituted phenylmethylene. 27. A compound of claim 26 wherein R7 is methylmethylene, isopropylmethylene, n-propylmethylene, phenylmethylene, cyclohexylmethylene, cyclopentylmethylene, t-butylmethylene, s-butylmethylene, cyclohexylmethylmethylene, or phenylmethylmethylene. 28. A compound of claom 27 wherein R7is isopropylmethylene, cyclohexylmethylene, cyclopentylmethylene, t-butylmethylene or s-butylmethylene. 29. A compound of claim 3 wherein each of R3, R5, and R7is mono substituted methylene. 30. A compound of claim 29 wherein R3is mono substituted methylene and has an (S) configuration on the carbon attached to the —C(O)—R0—C(O)—NR1R2 moiety. 31. A compound of claim 30 wherein R8 is hydrogen or optionally substituted lower aliphatic group. 32. A compound of claim 31 wherein R8is hydrogen or lower alkyl. 33. A compound of claim 32 wherein R8 is hydrogen. 34. A compound of claim 3 wherein R9 is optionally substituted lower aliphatic group or optionally substituted monocyclic aromatic group. 35. A compound of claim 34 wherein R9is optionally substituted lower alkyl or optionally substituted monocyclic heteroaryl. 36. A compound of claim 34 wherein R9is optionally (carboxy, (loweralkyl)SO2NH—, (lower alkyl)HNCO—, hydroxy, phenyl, heteroaryl, or (lower alkyl)OC(O)NH—)-substituted lower alkyl, or optionally substituted monocyclic heteroaryl. 37. A compound of claim 3 wherein R9 is lower alkyl substituted by (mono- or di-)MeOC(O)NH—. 38. A compound of claim 3 wherein R9 is (carboxy, (lower alkyl)HNCO— or tetrazolyl)substituted lower alkyl. 39. A compound of claim 3 wherein R9 is 3-carboxypropyl, 2-tetrazol-5ylpropyl, 3-(N-methylcarboxamido)propyl or 3-carboxy-2,2-dimethylpropyl. 40. A compound of claim 3 wherein R9 is 3-carboxypropyl, 2-tetrazol-5ylpropyl or 3-(N-methylcarboxamido)propyl. 41. A compound of claim 3 wherein R9 is optionally subtituted lower alkyl. 42. A compound of claim 3 wherein R9 is 1-hydroxy-2-phenylethyl, isopropyl or 1-butyl. 43. A compound of claim 3 wherein R9 is isopropyl or t-butyl. 44. A compound of claim 3 wherein R9 is selected from the group consisting of 45. A compound of claim 3 wherein R9 is pyrazinyl. 46. A compound of claim 3 wherein R10 is hydrogen or optionally substituted lower aliphatic group. 47. A compound of claim 46 wherein R10 is hydrogen or lower alkyl. 48. A compound of claim 47 wherein R10 is hydrogen. 49. A compound of claim 3 wherein as a substituted monocyclic azaheterocyclyl is substituted pyrrolidinyl. 50. A compound of claim 3 wherein as a substituted monocyclic azaheterocyclyl is optionally substituted or optionally substituted wherein Ar is R2 that comprises an aromatic moiety. 51. A compound of claim 3 wherein as a substituted monocyclic azaheterocyclyl is optionally substituted 52. A compound of claim 3 wherein 53. A compound of claim 3 wherein as an optionally substituted multicyclic azaheterocyclyl is optionally substituted 54. A compound of claim 3 wherein as an optionally substituted multicyclic azaheterocyclyl is optionally substituted 55. A compound of claim 3 wherein as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted 56. A compound of claim 3 wherein as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted 57. A compound of claim 3 wherein as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted 58. A compound of claim 3 wherein the —C(O)—N(R4)—R3—C(O)R0 C(O)NR2R1 moiety attached to is attached a carbon α to the nitrogen atom. 59. A compound of claim 58 wherein L is —C(O)— or —OC(O)—. 60. A compound of claim 59 wherein n is 0. 61. A compound of claim 59 wherein n is 1. 62. A compound as claimed in claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug. 63. A pharmaceutical compositions comprising a pharmaceutically acceptable amount of the compound of claim 3 and a pharmaceutically acceptable carrier. 64. A method for inhibiting HCV protease comprising contacting the protease with a compound claim 3. 65. A method for treating a patient suffering from an HCV infection or physiological conditions related to the infection comprising administering to the patient a pharmaceutically effective amount of a compound of claim 3. 66. A method for treating a patient suffering from an HCV infection or physiological conditions related to the infection comprising administering to the patient a pharmaceutically effective amount of a compound of claim 3 in combination with a pharmaceutically effective amount of another anti-HCV therapeutic. 67. The method of claim 66 wherein the anti-HCV therapeutic is interferon or derivatized interferon. 68. A pharmaceutical composition, comprising a hepatitis C virus serine protease inhibitor, an interferon having anti-hepatitis C virus activity, and a pharmaceutically acceptable carrier. 69. The pharmaceutical composition of claim 68, further comprising a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 70. A pharmaceutical composition, comprising a hepatitis C virus serine protease inhibitor, a compound having anti-hepatitis C virus activity, and a pharmaceutically acceptable carrier, wherein said compound is other than an interferon. 71. The pharmaceutical composition of claim 69, wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof. 72. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a hepatitis C virus serine protease inhibitor compound of claim 3; an interferon selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and a compound having anti-hepatitis C virus activity selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine and wherein said serine protease inhibitor, said interferon and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount and a combination thereof. 73. A method of treating or preventing a hepatitis C virus infection in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a combination of a hepatitis C virus serine protease inhibitor and an interferon having anti-hepatitis C virus activity. 74. The method of claim 73, wherein said pharmaceutically effective amount of said combination further comprises a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 75. A method of treating or preventing a hepatitis C virus infection in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a combination of a hepatitis C virus serine protease inhibitor and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 76. The method of claim 74, wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof. 77. A method of treating or preventing a hepatitis C infection in a patient in need thereof comprising a hepatitis C virus serine protease inhibitor compound claim 3; an interferon selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and a compound having anti-hepatitis C virus activity selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine and wherein said serine protease inhibitor, said interferon and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount and a combination thereof. 83. A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor and at least another of said containers contains an interferon having anti-hepatitis C virus activity. 84. A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor and at least another of said containers contains a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 85. A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor, at least another of said containers contains an interferon having anti-hepatitis C virus activity, and at least another of said containers contains a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 86. The kit or pharmaceutical pack of claim 85, wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof. 87. A kit or pharmaceutical pack comprising a plurality of separate containers wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor compound of claims 3; at least another of said containers contains an interferon selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and at least another of said containers contains a compound having anti-hepatitis C virus activity selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine and wherein said serine protease inhibitor, said interferon and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount and a combination thereof. 88. A method of inhibiting hepatitis C virus replication in a cell, comprising contacting said cell, a hepatitis C virus serine protease inhibitor, and an interferon having anti-hepatitis C virus activity. 89. The method of claim 88, further comprising contacting said cell and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 90. A method of inhibiting hepatitis C virus replication in a cell, comprising contacting said cell, a hepatitis C virus serine protease inhibitor, and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon. 91. The method of claim 88, wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof. 92. A method of inhibiting heptatitis C virus replication in a cell comprising contacting said cell with a hepatitis C virus serine protease inhibitor compound of claim 3; an interferon selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and a compound having anti-hepatitis C virus activity selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine and wherein said serine protease inhibitor, said interferon and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount and a combination thereof. 93. A compound of formula 24 wherein: is optionally substituted cycloalkyl or optionally substituted fused arylcycloalkyl; R11 is —CO2R13; R12 is an iminic glycinimide derivative adduct; and R13 is acid protecting group or optionally substituted aliphatic group. 94. A compound of claim 93 wherein: optionally substituted cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms optionally substituted with one or more ring group substituents; optionally substituted fused arylcycloalkyl means a fused arylcycloalkyl optionally substituted with one or more ring group substituents; optionally substituted aliphatic group are alkyl, alkenyl, or alkynyl optionally substituted with an aliphatic group substituent; an iminic glycinimide derivative adduct is a compound selected from the group consisting of wherein: R16 is an acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; R17 is optionally substituted aryl, optionally substituted aliphatic group, R18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl; wherein; ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclycarbonyl or its thioxoinalue alroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H2C═), oxo (O═) and thioxo (S═); and aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; and aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms. 95. A compound according to claim 94 where R11 is —CO2R13. 96. A compound according to claim 95 where R13 is an optionally substituted aliphatic group. 97. A compound according to claim 96 where R13 is an alkyl group. 98. A compound according to claim 97 where R13 is lower alkyl. 99. A compound according to claim 98 where R13 is methyl. 100. A compound according to claim 99 where R12 is wherein: R15 is optionally substituted aliphatic group; R16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; R17 is optionally substituted aryl, optionally substituted aliphatic group, R18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl; R17 and R18 taken together with the carbon to which R17 and R18 are attached {circle over (S)} is a solid phase. 101. A compound according to claim 100 where R14 is —CO2R16. 102. A compound according to claim 101 where R16 is optionally substituted aliphatic. 103. A compound according to claim 102 where R16 is alkyl. 104. A compound according to claim 103 where R16 is lower alkyl. 105. A compound according to claims 104 where R16 is t-Bu. 106. A compound according to claims 105 where R17 is optionally substituted aryl. 107. A compound according to claim 106 where R17 is phenyl. 108. A compound according to claim 107 where R18 is optionally substituted aryl. 109. A compound according to claim 108 where R18 is phenyl. 110. A compound of formula 25 wherein: R15 is optionally substituted aliphatic group; and R16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group. 111. A compound according to claim 110 wherein: optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents; optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents; wherein; ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue; aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H2C═), oxo (O═) and thioxo (S═); and aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl. 112. A compound according to claim 111 where R14 is —CO2R16. 113. A compound according to claim 112 where R16 is optionally substituted aliphatic. 114. A compound according to claim 113 where R16 is alkyl. 115. A compound according to claim 114 where R16 is lower alkyl. 116. A compound according to claim 115 where R16 is t-Bu. 117. A compound of formula 26 wherein: po is amide protecting group; R15 is optionally substituted aliphatic group; and R16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group. 118. A compound according to claim 117 wherein: optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents; optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents; wherein; ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H2C═), oxo (O═) and thioxo (S═); and aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl. 119. A compound according to claim 118 where R14 is —CO2R16. 120. A compound according to claim 119 where R16 is optionally substituted aliphatic. 121. A compound according to claim 120 where R16 is alkyl. 122. A compound according to claim 121 where R16 is loweralkyl. 123. A compound according to claim 122 where R16 is t-Bu. 124. A compound according to claim 123 where p0 is selected from the group consisting of BOC, CBz, and —CO2alkyl. 125. A compound according to claim 124 where p0 is BOC. 126. A compound of formula 27 wherein: po is amide protecting group; R15 is optionally substituted aliphatic group; and R16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group. 127. A compound according to claim 126 wherein: optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents; optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents; wherein; ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue ,heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H2C═), oxo (O═) and thioxo (S═); and aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroaryl sulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl. 128. A compound according to claim 127 where R14 is —CO2R16. 129. A compound according to claim 128 where R16 is optionally substituted aliphatic. 130. A compound according to claim 129 where R16 is alkyl. 131. A compound according to claim 130 where R16 is lower alkyl. 132. A compound according to claim 131 where R16 is t-Bu. 133. A compound according to claim 132 where p0 is selected from the group consisting of BOC, CBz, and —CO2alkyl. 134. A compound according to claim 133 where p0 is BOC. 135. A process for preparing a chiral bicycloprolinate compound of formula 28 comprising the steps of: (a) cleaving and cyclizing a compound of formula 24 wherein: is optionally substituted cycloalkyl or optionally substituted fused arylcycloalkyl; R11 is —CO2R3; R12 is an iminic glycinimide derivative adduct; R13 is acid protecting group or optionally substituted aliphatic group; under cleaving and cyclizing conditions to form a compound of formula 25 wherein: R15 is optionally substituted aliphatic group; R16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; and (b) protecting the nitrogen of the lactam moiety in the compound of formula 25 with an amide protecting group to form a compound of formula 26 wherein: p0 is amide protecting group; R14 is as described herein; and (c) reducing the compound of formula 26 under reducing conditions to form a compound of formula 27 wherein: po and R14 are as described herein; and (d) deprotecting the compound of formula 27 under deprotecting conditions to form a compound of formula 28 wherein: R14 is as described herein. 136. A compound according to claim 135 wherein: optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents; optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents; optionally substituted cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms optionally substituted with one or more ring group substituents; optionally substituted fused arylcycloalkyl means a fused arylcycloalkyl optionally substituted with one or more ring group substituents; an iminic glycinimide derivative adduct is a compound selected from the group consisting of wherein: R16 is an acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; R17 is optionally substituted aryl, optionally substituted aliphatic group, R18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl; wherein; ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2N—, Y1Y2NC(O)—, Y1Y2 NC(O)O, Y1Y2NC(O)NY1— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H2C═), oxo (O═) and thioxo (S═); and aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl. 137. The process of claim 136 further comprising the step wherein the compound of formula 24 is prepared by effecting a Michael addition with an iminic glycinimide compound on a compound of formula 29 wherein: is optionally substituted cycloalkenyl or optionally substituted fused arylcycloalkenyl; wherein: the compound of formula 29 may be prepared by esterifying a compound of formula 29a wherein: R11a is —CHO, —COR15, —C≡N, or —CONR15R15. 138. The process of claim 137 wherein the process is carried out at a temperature between 0° C. and −78° C. 139. The process of claim 138 wherein the process is carried out at −60°. 140. The process of claim 139 wherein the process is catalyzed by a chiral phase transfer catalyst. 141. The process of claim 139 wherein the process is catalyzed by a nonchiral phase transfer catalyst. 142. The process of claim 141 wherein the protecting group is BOC. 143. The process of claim 142 wherein the iminic glycinimide is (N-diphenylmethylene)-glycine tert-butyl ester. 162. A compound of claim 1 wherein: R0 is a bond; R1 is hydrogen; R2 is lower alkyl optionally substituted with 1 to 3 aliphatic group substituents; or lower cycloalky optionally substituted with 1 to 3 cyclic group substituents; R3 and R5 are each independently methylene optionally substituted with 1 to 3 aliphatic group substitutents; R4, R6, R8 and R10 are hydrogen; R7 is methylene substituted with cycloalkyl, lower alkyl or aryl; or or (1,1- or 1,2-)cycloalkenyl optionally substituted with cycloalkyl, lower alkyl or aryl; R9 is lower alkyl optionally substituted with 1 to 3 aliphatic group substituents; or heteroaryl optionally substituted with 1 to 3 cyclic group substituents; or heterocyclic optionally substituted with 1 to 3 cyclic group substituents; is monocyclic azaheterocyclyl, multicyclic azaheterocyclyl, or multicyclic azaheterocyclenyl optionally substituted with from 1 to 3 cyclic group substituents; and L is —C(O)—, —OC(O)—. 163. A compound of claim 162 wherein: aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH2OH, —C(O)—CH2SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, aryl sulfonyl, heteroaryl sulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H2C═), oxo (O═), thioxo (S═), Y1Y2N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3—, Y1Y2NSO2—, or Y3SO2NY1— wherein R2 is as defined herein, Y1 and Y2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; ring group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), acid biostere, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y1Y2 N—, Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, wherein Y1, Y2 and Y3 are independently hydrogen, alkyl, aryl,or heteroaryl, or for where the substituent is Y1Y2N—, then one of Y1 and Y2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y1 and Y2 is as defined previously, or for where the substituent is Y1Y2NC(O)—, Y1Y2NC(O)O—, Y1Y2NC(O)NY3— or Y1Y2NSO2—, Y1 and Y2 may also be taken together with the N atom through which Y1 and Y2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl, or when a ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H2C═), oxo (O═) and thioxo (S═); aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms; cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms; cycloalkenyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms which contain at least one carbon-carbon double bond; cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl; heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atomsin which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon; and heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon. 166. A compound of claim 163 wherein the optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group of R9 is substituted with at least one heteroaryl substituent. 167. A compound of claim 163 wherein the optionally substituted aromatic group of R9 is optionally substituted heteroaryl. 168. A compound of claim 166 wherein the optionally substituted aliphatic group of R9 is optionally substituted alkylheteroaryl. 169. The process of claim 142 wherein the compound of formula 29 is 1-carboxy-1-cyclopentene methyl ester. 170. A compound of the formula or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug.

<SOH> BACKGROUND OF THE INVENTION <EOH>Infection by the HCV is a compelling human medical problem and is now recognized as the causative agent for most cases of non-A, non-B hepatitis. The HCV is thought to infect chronically 3% of the world's population [A. Alberti et al., “Natural History of Hepatitis C,” J. Hepatology, 31, (Suppl. 1), 17-24 (1999)]. In the United States alone the infection rate is 1.8% or 3.9 million people [M. J. Alter, “Hepatitis C Virus Infection in the United States,” J. Hepatology, 31, (Suppl. 1), 88-91 (1999)]. Of all patients infected over 70% develop a chronic infection that is believed to be a major cause of cirrhosis and hepatocellular carcinoma. [D. Lavanchy, “Global Surveillance and Control of Hepatitis C,” J. Viral Hepatitis, 6, 35-47 (1999)] The replication of the HCV encompasses genomic encoding a polyprotein of 3010-3033 amino acids [Q.-L. Choo, et al., “Genetic Organization and Diversity of the Hepatitis C Virus”, Proc. Natl. Acad. Sci. USA, 88, 2451-2455 (1991); N. Kato et al., “Molecular Cloning of the Human Hepatitis C Virus Genome Prom Japanese Patients with Non-A, Non-B Hepatitis”, Proc. Natl. Acad. Sci. USA, 87, 9524-9528 (1990); A. Takamizawa et al., “Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers”, J. Virol., 65, 1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions”, J. Virol., 67, 3835-3844 (1993); A. Grakoui et al. “Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites”, J. Virol., 67, 2832-2843 (1993); A. Grakoui et al., Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products”, J. Virol., 67, 1385-1395 (1993); L. Tomei et al., “NS3 is a serine protease required for processing of hepatitis C virus polyprotein”, J. Virol., 67, 4017-4026 (1993)]. In fact, it is the first 181 amino acids of NS3 (residues 1027-1207 of the viral polyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics”, J. Virol., 68, 8147-8157 (1994)]. The HCV NS protein 3 (NS3) contains a serine protease activity that helps in the processing of the majority of the viral enzymes, and thus is considered essential for viral replication and infectivity. The essentiality of the NS3 protease was inferred from the fact that mutations in the yellow fever virus NS3 protease decreases viral infectivity [T. J. Chambers et al., “Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein”, Proc. Natl. Acad. Sci. USA, 87, 8898-8902 (1990)]. More recently, it was demonstrated that mutations at the active site of the HCV NS3 protease could completely abolish the HCV infection in a chimpanzee model [C. M. Rice et al. “Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′-nontranslated region are essential for virus replication in vivo.” J. Virol., 74(4) 2046-51 (2000)]. The HCV NS3 serine protease is also considered essential for viral replication as it and its associated cofactor, NS4A, help in the processing of all of the viral enzymes. This processing appears to be analogous to that carried out by the human immunodeficiency virus (“HIV”) aspartyl protease. In addition, the demonstrated use of HIV protease inhibitors as potent antiviral agents in man demonstrates that interrupting a protease protein processing stage in the viral life cycle does result in therapeutically active agents. Consequently, the protease enzyme is an attractive target for drug discovery. Several potential HCV protease inhibitors have been described. PCT Publications Numbers WO 00/09558, WO 00/09543, WO 99/64442, WO 99/07733, WO 99107734, WO 99/50230, WO98/46630, WO 98/17679 and WO 97/43310, U.S. Pat. No. 5,990,276, M. Llinás-Brunet et al., Bioorg. Med. Chem. Lett., 8, 1713-1718 (1998), W. Han et al., Bioorg. Med. Chem. Lett., 10, 711-713 (2000), R. Dunsdon et al., Bioorg. Med. Chem. Lett., 10, 1571-1579 (2000), M. Llinás-Brunet et al., Bioorg. Med. Chem. Lett., 10, 2267-2270 (2000), and S. LaPlante et al., Bioorg. Med. Chem. Lett., 10, 2271-2274 (2000) each describe potential HCV NS3 protease inhibitors. Unfortunately, there are no serine protease inhibitors available currently as anti-HCV agents. In fact, there are no anti-HCV therapies except interferon-α, interferon-α/ribavirin combination and more recently pegylated inteferon-α. The sustained response rates for the interferon-α therapies and interferon-α/ribavirin however tend to be low (<50%) and the side effects exhibited by the therapies tend to be significant and severe [M. A. Walker, “Hepatitis C Virus: an Overview of Current Approaches and Progress,” DDT, 4, 518-529 (1999); D. Moradpour et al., “Current and Evolving Therapies for Hepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, 1199-1202 (1999); H. L. A. Janssen et al., “Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis,” J. Hepatol., 21, 241-243 (1994); and P. F. Renault et al., “Side effects of alpha interferon”, Seminars in Liver Disease 9, 273-277, (1989)]. Furthermore, the interferon therapies only induce long term remission in only a fraction (˜25%) of cases [O. Weiland, “Interferon Therapy in Chronic Hepatitis C Virus Infection”, FEMS Microbiol. Rev., 14, 279-288(1994)]. The aforesaid problems with the interferon-a therapies has even led to the development and clinical study of pegylated derivatized interferon-α compounds as improved anti-HCV therapeutics. In view of the current situation regarding anti-HCV therapeutics, it is clear that there is a need for more effective and better tolerated therapies. Furthermore, synthesis of complex peptidomimetic compounds has long been hampered by the nonstereoselective nature of most synthetic organic processes. It is well known that the therapeutic activity of enantiomers of peptidomimetic compounds varies widely. It is therefore of great benefit to provide such stereospecific synthetic processes. Previous attempts to synthesize chirally specific bicycloprolinate intermediates, useful in the synthesis of the present therapeutic peptidomimetic protease inhibitors have suffered from being non enatioselective, or diasteroselective, or long encompassing synthetic pathways, or being unsuitable for preparing large quantities of product. Thus, there is also a need for a means of preparing large quantities of bicycloprolinates in a diastereoselective manner and enantiomerically enriched form.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a peptidomimetic compound of formula 1 wherein: R 0 is a bond or difluoromethylene; R 1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R 2 and R 9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R 3 , R 5 and R 7 are each independently (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group)(optionally substituted methylene or optionally substituted ethylene), optionally substituted (1,1- or 1,2-)cycloalkylene or optionally substituted (1,1- or 1,2-)heterocyclylene; R 4 , R 6 , R 8 and R 10 are each independently hydrogen or optionally substituted aliphatic group; is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R 9 -L-N(R 8 )—R 7 —C(O)—) n N(R 6 )—R 5 —C(O)—N moiety and to which the —C(O)—N(R 4 )—R 3 —C(O)C(O)NR 2 R 1 moiety is attached; L is —C(O)—, —OC(O)—, —NR 10 C(O)—, —S(O) 2 —, or —NR 10 S(O) 2 —; and n is 0 or 1, or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided when is substituted then L is —OC(O)— and R 9 is optionally substituted aliphatic, or at least one of R 3 , R 5 and R 7 is (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group)(optionally substituted ethanediyl), or R 4 is optionally substituted aliphatic. This inventions also provides a compound having the structural formula: wherein: R 1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R 2 and R 9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group; R 3 , R 5 and R 7 are each independently (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group)(optionally substituted methanediyl or optionally substituted ethanediyl); R 4 , R 6 , R 8 and R 10 are each independently is hydrogen or optionally substituted aliphatic group; is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R 9 -L-(N(R 8 )—R 7 —C(O)—) n (R 6 )—R 5 —C(O)—N moiety and to which the —C(O)—N(R 4 )—R 3 —C(O)C(O)NR 2 R 1 moiety is attached; L is —C(O)—, —OC(O)—, —NR 10 C(O)—, —S(O) 2 —, or —NR 10 S(O) 2 —; and n is 0 or 1, or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided when is substituted then L is —C(O)— and R 9 is optionally substituted aliphatic, or at least one of R 3 , R 5 and R 7 is (optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group)(optionally substituted ethanediyl), or R 4 is optionally substituted aliphatic. The invention is also directed to a pharmaceutical composition comprising a compound of formula 1, and method for using the compound of formula 1 for inhibiting HCV protease, or treating or preventing an HCV infection in patients or physiological condition related to the infection. The invention is also directed to a stereoselective process for preparing a chiral bicycloprolinate compound that is an intermediate useful in preparing a compound of formula 1. The synthetic process comprises the steps of: (a) cleaving and cyclizing a compound of formula 24 wherein: is optionally substituted cycloalkyl or optionally substituted fused arylcycloalkyl; R 11 is —CO 2 R 13 ; R 12 is an iminic glycinimide adduct; R 13 is acid protecting group or optionally substituted aliphatic group; under cleaving and cyclizing conditions to form a compound of formula 25 wherein: R 15 is optionally substituted aliphatic group; R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; and (b) protecting the nitrogen of the lactam moiety in the compound of formula 25 with an amide protecting group to form a compound of formula 26 wherein: p o is amide protecting group; R 14 is as described herein; and (c) reducing the compound of formula 26 under reducing conditions to form a compound of formula 27 wherein: p o and R 14 are as described herein; and (d) deprotecting the compound of formula 27 under deprotecting conditions to form a compound of formula 28 wherein: R 14 is as described herein. The invention is also directed to the above synthetic process further comprising the step wherein the compound of formula 24 is prepared by effecting a Michael addition with an iminic glycinimide compound on a compound of formula 29 wherein: is optionally substituted cycloalkenyl or optionally substituted fused arylcycloalkenyl; R 11 is —CO 2 R 13 ; wherein: the compound of formula 29 may be prepared by esterifying a compound of formula 29a wherein: is optionally substituted cycloalkenyl or optionally substituted fused arylcycloalkenyl; R 11a is —CHO, —COR 15 , —C≡N , or —CONR 15 R 15 ; and R 15 is as described herein. Notably, one skilled in the art would know that conversion of ketones to esters may be accomplished, for example, by a Bayer-Villiger reaction. Conversion of nitrites and amides to esters may be accomplished, for example, by aqueous hydrolysis followed by further esterification. Conversion of aldehydes to esters may be accomplished, for example, by oxidation of the aldehyde followed by esterification. Another aspect of the invention is a compound of formula 1 wherein the substituents are selected from a combination of preferred or particular embodiments as defined herein. Another aspect of the invention is a compound of formulae 24-29 wherein the substituents are selected from a combination of preferred or particular embodiments as defined herein. Another aspect of the invention are pharmaceutical compositions comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons or compounds that induce the production of interferons that exhibit anti-HCV activity and/or one or more compounds having anti HCV activity, including immunomodulatory compounds such as immunostimulatory cytokines exhibiting HCV antiviral activity, and a pharmaceutically acceptable carrier. Another aspect of the invention are methods of treating or preventing a HCV infection in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a combination of one or more HCV serine protease inhibitors; one or more interferons or compounds that induce the production of an inteferon that exhibit anti-HCV activity; and/or one or more compounds having anti-HCV activity, including immunomodulatory compounds such as immunostimulatory cytokines exhibiting HCV antiviral activity. The invention is also directed to the use of one or more HCV serine protease inhibitors in combination with one or more interferons or compounds that induce the production of an inteferon that exhibit anti-HCV activity and/or one or more compounds having anti-HCV activity, including immunomodulatory compounds such as immunostimulatory cytokines exhibiting HCV antiviral activity, to prepare a medicament for treating or preventing a HCV infection in a patient in need thereof. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient, wherein the kit or pharmaceutical pack comprises a plurality of separate containers, wherein at least one of said containers contains one or more HCV serine protease inhibitors (alone or in combination with a pharmaceutically acceptable carrier or diluent), at least another of said containers contains one or more interferons or compounds that induce the production of an inteferon that exhibit anti-HCV activity, (alone or in combination with a pharmaceutically acceptable carrier or diluent) and, optionally, at least another of said containers contains one or more compounds having anti-HCV activity (alone or in combination with a pharmaceutically acceptable carrier or diluent), including immunomodulatory compounds such as immunostimulatory cytokines exhibiting HCV antiviral activity. The amount of the HCV serine protease inhibitor(s), interferon(s), or anti-HCV compound(s) in any of the foregoing applications can be a pharmaceutically effective amount, a subclinical anti-HCV effective amount, or combinations thereof, so long as the final combination of HCV serine protease inhibitor(s), interferon(s), or compounds that induce the production of an interferon that exhibit anti-HCV activity, and/or anti-HCV compound(s) comprises a pharmaceutically effective amount of compounds that is effective in treating or preventing HCV infection in a patient.

Novel diamines having a casr modulating activity

The invention concerns diamines of general formula (I), wherein: A represents a group A1 or A2 of general formula (II); B represents a group B1 or B2 of general formula (III); X represents a SO2, CH2, C═O or COO; YZ represents a group of formula CH(R25)—CH(R26) or CH(R27)═(R28), and R1 to R28, identical or different, represent independently of one another, a hydrogen or halogen atom or an alkyl, cycloalkyl, CN, NO2, hydroxy, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino diarylalkylamino, trihalogenoalkyl or trihalogenoalkoxy group, provided that in the group A1, at least one of the radicals R1, R2, R3, R4 or R5 represents the hydrogen atom when the other four do not represent the hydrogen atom and in the group B1, at least one of the radicals R13, R14, R15, R16 or R17 represents the hydrogen atom when the other four do not represent the hydrogen atom, and their salts with a pharmaceutically acceptable acid, in the form of racemic mixture or their optically pore isomers. The invention also concerns their preparation, pharmaceutical compositions comprising them and their use as CaSR activity modulator and as medicine particularly designed for the treatment of psychological diseases and disorders involving CaSR activity modulation.

1-20. (canceled) 21. A compound comprising a diamine of general formula (I): wherein: A is A1 or A2 having the following general formula: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that when A is A1 at least one of the radicals R1, R2, R3, R4 or R5 is hydrogen when the other four radicals are not hydrogen, B is B1 or B2 having the following general formula: wherein R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23 and R24, are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that when B is B1, at least one of the radicals R13, R14, R15, R16 or R17 is hydrogen when the other four radicals are not hydrogen, X is SO2, CH2, C═O or COO, is CH(R25)—CH(R26) or CH(R27)═CH(R28), wherein R25, R26, R27 and R28 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy; and salts thereof optionally further comprising a pharmaceutically acceptable acid, wherein the diamine is a racemic mixture of isomers or a purified isomer. 22. The compound of claim 21, wherein A is A1, B is B2 and is CH(R25)—CH(R26), wherein R25 and R26 are both hydrogen. 23. The compound of claim 21, wherein X is SO2. 24. The compound of claim 21, wherein the diamine is selected from the group consisting of the following formulae: and the salts thereof further comprising a pharmaceutically acceptable acid. 25. A method for preparing the compound of claim 21, wherein is CH(R25)—CH(R26) and at least one of the radicals R25 and R26 is not hydrogen, wherein at least one of the radical(s) R25 and R26 is selectively introduced into the molecule to yield the following general formula II: A is A1 or A2 having the following general formula: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that when A is A1 at least one of the radicals R1, R2, R3, R4 or R5 is hydrogen when the other four radicals are not hydrogen, B is B1 or B2 having the following general formula: wherein R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23 and R24, are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that when B is B1, at least one of the radicals R13, R14, R15, R16 or R17 is hydrogen when the other four radicals are not hydrogen, and X is SO2, CH2, C═O or COO. 26. A method for preparing the compound of claim 21, wherein is CH2—CH2 or CH(R27)═CH(R28) and X is CH2, C═O or COO comprising the steps of: a) selectively introducing an arylmethyl, aroyl or aryloxycarbonyl group, said groups being optionally substituted, to generate the compound depicted in formula III: wherein B is B1 or B2 having the following general formula: wherein R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23 and R24, are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that when B is B1, at least one of the radicals R13, R14, R15, R16 or R17 is hydrogen when the other four radicals are not hydrogen, and R27 and R28 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy; and b) deprotecting the compound obtained in step (a). 27. A method for preparing the compound of claim 21, wherein X is SO2 and is CH2—CH2 or CH(R27)═CH(R28), comprising the steps of: a) subjecting the compound of formula III to a deprotection reaction, and b) introducing an optionally substituted arylsulfonyl group into the NH2 functional group of the compound obtained in step (a). 28. The method of claim 25, wherein X is CH2, C═O or COO and the compound of formula II is prepared by the method of claim 26. 29. The method of claim 25 wherein X is SO2, and the compound of formula II is prepared by the method of claim 27. 30. The method of claim 26, wherein the compound of formula III is prepared by the step of nucleophilic opening of an aziridine of general formula IV: wherein is CH2—CH2 or CH(R27)═CH(R28), wherein R27 and R28 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, said nucleophilic opening being performed by a compound having the following general formula V: wherein B is B1 or B2 having the following general formula: wherein R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23 and R24 independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy, provided that in the group B1, at least one of the radicals R13, R14, R15, R16 or R17 represents the hydrogen atom when the other four radicals do not represent hydrogen. 31. The method of claim 30, wherein the compound of formula IV is prepared by reaction between an olefin of general formula VI: wherein is CH2—CH2 or CH(R27)═CH(R28) and a compound having the following formula VII: 32. A pharmaceutical composition comprising at least one compound as claimed in claim 21 and an appropriate pharmaceutical excipient. 33. A method of using the compound of claim 21 as a CaSR activity modulator. 34. A method of using the compound of claim 21 as a CaSR antagonist, wherein X is selected from the group consisting of SO2, C═O and COO group. 35. A method of using the compound of claim 21 as a CaSR agonist, wherein X is CH2. 36. A method of using the compound of claim 21 for the treatment of physiological diseases or disorders linked to disturbances in CaSR activity. 37. A method of using the compound of claim 21, wherein X is SO2, C═O or COO for the treatment of demyelinating diseases associated with the expression of CaSRs in the oligodendrocytes, osteoporosis, Paget's disease, rheumatoid arthritis, tumors associated with humoral hypercalcemia, osteoarthritis, osteosarcomas, fractures, cardiovascular, gastrointestinal, endrocrin or neurodegenerative diseases or cancers where (Ca2+)e ions are abnormally high. 38. A method of using the compound of claim 21, wherein X is CH2 for the treatment of diseases linked to hypercalcemia, primary or secondary hyperparathyroidism, osteoporosis, cardiovascular, gastrointestinal, endocrin or neurodegenerative diseases or certain cancers where the (Ca2+)e ions are abnormally high. 39. A compound comprising an aziridine of general formula IV: wherein is CH(R27) CH(R28), and wherein R27 and R28 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, CN, NO2, hydroxyl, aryl, aralkyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, arylalkylamino, diarylamino, diarylalkylamino, trihaloalkyl and trihaloalkoxy.

Short chain dehydrogenases/reductases(sdr)

The present invention relates to a method for identifying or verifying members of the short chain dehydrogenase (SDR) family, to a method for providing modulators for members of the SDR family and to the preparation of pharmaceutical agents using these modulators.