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Method of surface modifiacation and coating, and method and apparatus for producing substrate material using the same |
A method suitable for increasing the hardness, strength, and water resistance of a surface layer such as cedar sheets or cedar plywood is presented. The method does not require a resin component layer such as coating films or resin films provided by the conventional typical coating processes. The method is suitable for modifying surfaces of porous materials such as wooden materials, inorganic materials or ceramic material. Also, the same method can be used for modifying a surface layer portion by impregnating a solution of organic or inorganic matter by using steam and for forming a coating film on the surface. |
1. A method for surface layer modification, comprising the steps of: applying a solution of organic or inorganic matter to the surface of an object to be treated; and bringing steam into contact with the application surface and causing at least the organic or inorganic matter present in the solution to be impregnated at least into the surface layer of the object to be treated. 2. A method for surface layer modification, comprising the steps of applying a solution of organic or inorganic matter to the surface of an object to be treated; bringing steam into contact with the application surface and causing at least the organic or inorganic matter present in the solution to be impregnated at least into the surface layer of the object to be treated; and heating the treatment surface or the entire object to be treated. 3. A method for surface layer modification, comprising the steps of applying a solution of organic or inorganic matter polymerizable by UV radiation or electron beam to the surface of an object to be treated; bringing steam into contact with the application surface and causing the organic or inorganic matter present in the solution to be impregnated at least into the surface layer of the object to be treated; and polymerizing and solidifying the surface layer portion and the impregnated organic or inorganic matter by irradiating the treatment surface with UV radiation or electron beam. 4. The method for surface layer modification according to any one of claims 1 through 3, wherein a recess is provided in the surface of the object to be treated so that the location and depth of impregnation of the solution of organic or inorganic matter into the surface layer can be adjusted. 5. The method for surface layer modification according to any one of claims 1 through 3, wherein, in the impregnation step, the application surface is brought into contact with steam so as not to be wetted with the steam. 6. The method for surface layer modification according to any one of claims 1 through 3, wherein dry steam is used as the steam. 7. The method for surface layer modification according to claim 6, wherein the dry steam temperature is not lower than 120° C. and not higher than 250° C. 8. The method for surface layer modification according to claim 2, wherein, in the heating step, the contact of said steam with the application surface is conducted repeatedly in the same manner as in said impregnation step. 9. The method for surface layer modification according to any one of claims 1 through 3, wherein the steam which is in contact with the application surface is heated and thermally convected by heating means disposed in the vicinity of the application surface. 10. The method for surface layer modification according to any one of claims 1 through 3, wherein the steam is heated and convected by disposing a heating plate opposite the application surface and continuously or intermittently introducing the steam into the gap between the opposing surfaces, while heating the heating plate. 11. The method for surface layer modification according to any one of claims 1 through 3, wherein the steam is heated and convected by disposing a heating plate opposite the application surface and continuously or intermittently introducing the steam from the heating plate itself or from the clearance between a plurality of heating plates into the gap between the application surface and the opposing surface, while heating the heating plate(s). 12. The method for surface layer modification according to any one of claims 1 through 3, wherein in the impregnation step or heating step, the steam and the organic or inorganic matter are activated by using ultrasound oscillation means. 13. The method for surface layer modification according to any one of claims 1 through 3, comprising a step of heating the object to be treated before the application step, after said step, or before and after said process. 14. The method for surface layer modification according to any one of claims 1 through 3, wherein the solution of organic or inorganic matter comprises either a water-soluble coating material or a water-soluble adhesive as the main component. 15. The method for surface layer modification according to any one of claims 1 through 3, wherein the solution of organic or inorganic matter is either a water-soluble coating material or a water-soluble adhesive comprising fine inorganic particles. 16. The method for surface layer modification according to any one of claims 1 through 3, wherein the solution of organic or inorganic matter is either a water-soluble coating material or a water-soluble adhesive mixed with colloidal silica. 17. The method for surface layer modification according to any one of claims 1 through 2, wherein the solution of organic or inorganic matter comprises either colloidal silica liquid or liquid paraffin as the main component. 18. A modification apparatus used in the surface layer modification method according to claim 2, comprising: heating means disposed opposite an application surface; and steam generation means for heating and convecting steam by continuously or intermittently introducing the steam into the gap between the heating means and the application surface. 19. A modification apparatus used in the surface layer modification method according to claim3, comprising: heating means disposed opposite the application surface; steam generation means for heating and convecting steam by continuously or intermittently introducing the steam into the gap between the heating means and the application surface; and irradiation means for irradiating the treatment surface with UV radiation or electron bear. 20. A modified product comprising a modified surface layer, which is obtained by applying a solution of organic or inorganic matter that comprises at least one of colloidal silica liquid, liquid paraffin, a water-soluble coating material or a water-soluble adhesive as the main component to the surface of a object to be treated having a surface layer of a wooden material, an inorganic material, or a ceramic material, impregnating the solution into said surface layer of the object to be treated and drying and solidifying the solution by steam which is brought into contact with the application surface, thereby eliminating the film of said solution on the surface of said object to be treated and increasing the hardness of the surface layer. 21. The modified product according to claim 19, wherein the solution of organic or inorganic matter contains fine inorganic particles. 22. The modified product according to claim 19, wherein the solution of organic or inorganic matter comprises at least one of water-soluble coating materials or water-soluble adhesives polymerizable by UV radiation or electron beam. 23. A modified product that is converted into resin by containing liquid paraffin steam-impregnated into a thin sheet material or paper. 24. A coating method for a coating material, comprising the steps of: applying a coating material to a coating object; and forming steam atmosphere between a surface to be coated and a heating plate disposed in the vicinity of said surface and solidifying the applied coating material. 25. A coating method for a coating material, comprising the steps of: applying a coating material to a coating object; controlling the coating object to a prescribed temperature; and forming steam atmosphere between a surface to be coated and a heating plate disposed in the vicinity of said surface and solidifying the applied coating material. 26. A coating method comprising the steps of: applying an adhesive to a coating object; controlling the coating object to a prescribed temperature; and forming steam atmosphere between a surface to be coated and a heating plate disposed in the vicinity of said surface and fixing the applied adhesive. 27. An impregnation and coating method for a coating material, comprising the steps of: applying a coating material to a coating object; controlling the coating object to a prescribed temperature; forming steam atmosphere between a surface to be coated and a heating plate disposed in the vicinity of said surface and impregnating the applied coating material into the surface layer of the surface to be coated of the coating object that is being heated; and forming steam atmosphere between said heating plate and the surface to be coated and solidifying said coating material that remained on or was applied to the surface to be coated of the coating object that is being neither cooled nor heated, after said impregnation process. 28. An impregnation and coating method, comprising the steps of: applying an adhesive to a coating object; controlling the coating object to a prescribed temperature; forming steam atmosphere between a surface to be coated a heating plate disposed in the vicinity of said surface and impregnating the applied adhesive into the surface layer of the surface to be coated of the coating object that is being heated; and forming steam atmosphere between said heating plate and said surface to be coated and fixing said adhesive that remained on or was applied to the surface to be coated of the coating object that is being neither cooled nor heated, after said impregnation process. 29. The impregnation and coating method according to claim 27 or claim 28, wherein in the impregnation step, the quantity of the coating material or adhesive impregnated into the surface layer of the application surface is controlled by controlling at least one of the coating object temperature, coating material temperature, and steam temperature. 30. The impregnation and coating method according to claim 27 or claim 28, wherein in the temperature control of the coating object, the heating temperature of the coating object during impregnation is 50° C. or higher, and the temperature of the coating object during solidification or fixing of the coating material is 40° C. or less. 31. The coating method according to any one of claims 24 through 28, wherein the steam temperature is 120° C. or higher. 32. The coating method according to any one of claims 24 through 28, wherein the steam temperature is 140° C. or higher. 33. The coating method according to any one of claims 24 through 28, wherein the steam pressure prior to releasing between the heating plate and the surface to be coated is 2 MPa or higher. 34. The coating method according to any one of claims 24 through 28, wherein the steam pressure prior to releasing between the heating plate and the surface to be coated is 4 MPa or higher. 35. The coating method according to any one of claims 24 through 28, wherein the temperature of the heating plate is 200° C. or higher. 36. The coating method according to any one of claims 24 through 28, wherein the temperature of the heating plate is 300° C. or higher. 37. The coating method according to any one of claims 24 through 28, wherein the distance between the heating plate and the surface to be coated is 5 to 20 mm. 38. The coating method according to any one of claims 24 through 28, wherein the coating material or adhesive is a water-soluble coating material or a water-dispersible coating material component comprising any one from alkyd resins, melamine resins, urea resins, phenolic resins, acrylic resins, and epoxy resins as the main component. 39. The coating method according to claim 38, wherein the coating material or adhesive is a dispersion of a resin component and fine inorganic particles in an aqueous medium. 40. The method for coating a water-soluble coating material, according to claim 39, wherein the water-soluble coating material comprises 20 wt. % or less of the resin component and 5% or less of the fine inorganic particle component. 41. The coating method for a water-soluble coating material, according to claim 39, wherein the water-soluble coating material comprises 15 to 18% resin component and 2 to 5% fine inorganic particle component. 42. The coating method according to claim 39, wherein the fine inorganic particles are SiO2 with a mean particle size of 50 nm or less. 43. The coating method according to claim 27 or claim 28, wherein the fine inorganic particles contained in the coating material or adhesive applied during the impregnation step are SiO2 with a mean particle size of 20 nm or less, and the fine inorganic particles contained in the coating material or adhesive applied during the coating step are SiO2 with a mean particle size of more than 20 nm and not more than 50 nm. 44. A coating apparatus comprising: a carrying or holding unit for a coating object, comprising heating or cooling means for adjusting the temperature of the coating object to a prescribed temperature; a coating unit for coating the coating material or adhesive on a prescribed surface of the coating object; a heating plate unit in which a heating plate is arranged in the vicinity of the surface to be coated and which maintains the heating plate at a prescribed temperature; and a steam generating unit for forming steam atmosphere in the gap between the surface to be coated and the heating plate by releasing steam maintained at a high temperature and a high pressure into said gap. 45. A method for the manufacture of a substrate material, comprising the steps of: impregnating a solution of organic or inorganic matter into a surface layer of a substrate material; and forming a convex or concave shape in the surface layer of the substrate material by roll molding or press molding before and after the impregnation step. 46. A method for the manufacture of a substrate material, comprising the steps of: impregnating a solution of organic or inorganic matter polymerizable by UV radiation or electron beam into a surface layer of a substrate material; forming a convex or concave shape in the surface layer of the substrate material by roll molding or press molding before and after the impregnation step; and polymerizing and solidifying the surface layer portion and the impregnated organic or inorganic matter by irradiating the treatment surface with UV radiation or electron beam. 47. The method for the manufacture of a substrate material, according to claim 45 or claim 46, wherein the convex or concave shape has a rounded groove shape. 48. The method for the manufacture of a substrate material, according to claim 45 or claim 46, wherein the substrate material is a single sheet of a wooden material or an inorganic material, a laminated sheet comprising a wooden material or an inorganic material, or said single sheet or laminated sheet having a decorative material on the surface. 49. The method for the manufacture of a substrate material, according to claim 45 or claim 46, wherein the step of impregnating the solution of organic or inorganic matter is conducted by a steam impregnation process comprising the steps of bringing steam into contact with the substrate material after applying the solution of organic or inorganic matter, impregnating the solution of organic or inorganic matter at least into the surface layer of said material, and heating the treatment surface or the entire material. 50. The method for the manufacture of a substrate material, according to claim 45 or claim 46, wherein the solution of organic or inorganic matter is any of water-soluble coating materials or adhesives, or water-soluble coating materials or adhesives containing fine inorganic particles (including colloidal silica). 51. The method for the manufacture of a substrate material, according to claim 45 or claim 46, wherein a metal mold used in roll molding or press molding comprises a rounded protrusion of a circular arc form including no straight lines and the cross-sectional shape thereof in the vertical plane orthogonal to the longitudinal direction of the protrusion is composed of a plurality of circular arcs. 52. A mold for molding a substrate material, which is provided with a protruding portion in the mold surface and used for roll molding or press molding, the mold comprising a rounded protrusion of a circular arc form including no straight lines and the cross-sectional shape thereof in the vertical plane orthogonal to the longitudinal direction of the protrusion is composed of a plurality of circular arcs. 53. The mold for molding a substrate material according to claim 52, wherein the rounded protrusions of the mold are arranged parallel to each other. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Wooden materials, in particular coniferous wooden materials such as fir, abies, larch, cedar, cypress, and sawara cypress, are called soft wood because they are soft and lightweight and are widely used as a variety of source materials for construction in the manufacture of core materials with the required cross-sectional shape. However, the application of sliced single sheets or plywood of soft materials was very limited. Thus, because the sheet surface is soft and can be easily scratched, the soft materials could be used, for example, for construction plywood, whereas their application to flooring or wall materials, which are unavoidably brought into contact, was restricted. Furthermore, presently the tastes have been shifting from the conventional oak pattern to diffuse-pore patterns such as those of beech, cherry, and maple for floors, walls, and door materials, regardless of whether a solid material or a plywood is used. Multiple problems of various types that have to be resolved are encountered when a soft wood is used for a surface layer in any usage mode, that is, as a solid material or a plywood of various types. Thus, scratch resistance and indentation resistance are obviously degraded with respect to those of hard materials, and there is the so-called material deviation such that only few materials can meet the floor warming specifications or can be used only under certain conditions and not under others. Moreover, there is a VOC problem associated with adhesives or coating agents used and also a problem of discoloration under the effect of IR radiation such as solar radiation. In particular, wood materials such as those for floors, walls, and doors are by themselves subjected to machining of grooves or holes, polishing, and press forming to provide them with design features, but measures of various types are necessary to stabilize the moisture content in the wood materials and retain their machinability. Therefore, the wooden materials subjected to machining are also required to have a high surface hardness and water resistance, but optimum aqueous coating materials or aqueous adhesives could not be impregnated into the surface layer of wooden material. On the other hand, not only various substrates such as plywood of a variety of types, MDF, PB, laminated lumber, and inorganic sheets, but also decorative substrates obtained by pasting a design decorative material such as a resin film, a decorative paper, or a veneer on the aforesaid substrates are well known as the construction material. Such substrate materials are usually flat and have poor design properties. For this reason, in order to make the flat design to look more three-dimensional, a design surface material is pasted onto a flat sheet and then cutting is conducted with a cutter or groove processing is carried out with a press. For example, design peak-valleys shapes have been formed by employing a variety of grooving operations, such as forming grooves with V-like cross section by using a flat mold or a roll mold, providing the V-like grooves and then press expanding shoulders, forming U- or V-like grooves with a cutter and then deforming the shoulders thereof into circular arcs, or producing step-like grooves in which the cross-sectional shape of the groove has a step-like form. The problem associated with groove machining with a cutter is that the design of the groove portion is changed significantly when the material is removed. Furthermore, the problem associated with groove machining with a press is that, the pasted design surface material is ruptured and the zone of plastic deformation created by the press returns to the original state with time. Plastic deformation provided to wooden material can easily restore to the original state because the fluctuations of input heat and atmosphere humidity easily change the moisture content ratio in the material itself. For example, such a restoration can be caused by moisture absorption by the material itself, and it is well known that restoration to the original state starts immediately if moisture adheres to the machined zone or if heat is additionally applied. To resolve this problem, permanent strains were provided with a tooling press at a temperature of about 180° C. or higher after molding. However, such a treatment sometimes damaged the design surface material and limited the range of surface decorative materials that could be used. Moreover, it was known that even after such a treatment, if the material was immersed, for example, for 2 min into warm water at a temperature of 70° C., the initial shape was always restored. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide a method for modifying a surface layer, by which the surface of various materials that could never be coated and impregnated with aqueous coating materials or aqueous adhesives, even essentially porous materials such as wooden materials, inorganic materials, and ceramic materials, is modified by impregnating water-soluble organic or inorganic matter into the surface, an apparatus for the implementation of the method, and a modified product thus obtained. It is another object of the present invention to resolve the above-described problems inherent to substrate materials having in the surface layer a material that can demonstrate compositional changes, and to provide a substrate material which can be reliably provided with a decorative convex or concave shape such as grooves, without rupturing a decorative material such as paper or a film, in which the decorative convex or concave shape such as grooves is not restored to the original state by the springback even when the material absorbs moisture or moisture is applied thereto after molding, and in which stable plastic deformations that do not change with time after molding can be provided to the wooden portions, and also to a method for the manufacture of such a substrate material, and to a mold for molding. The inventors have conducted a comprehensive study of the methods for surface modification of soft wood, that can increase hardness, fire resistance, and water resistance of the surface, in particular, without providing a coating of a coating material or the like and without loosing or changing the surface design or beauty of the wooden material itself. First, the attention was focused on the impregnation using a solution of an inorganic substance such as colloidal silica, and methods for impregnating the surface layer of a wooden material, in particular, with silica having moisture removed therefrom were thoroughly studied. The results obtained demonstrated that if colloidal silica is applied to the surface of a wooden material and hot steam is brought into contact with the application surface, while continuously supplying thermal energy so that the steam is not liquefied into droplets, then the colloidal silica applied to the surface of the wooden material is impregnated into the surface layer, while creating bubbles. It was also found that the treatment caused absolutely no changes in the design or state of the surface, such as moistening of the surface after the treatment of formation of the coating film, the entire applied solution could be impregnated, and the presence of the silica in the surface layer portion of the wooden material increased hardness and scratch resistance of this portion. Further, with respect to the aqueous coating materials or aqueous adhesives that could not be impregnated into wooden materials, the inventors have also found that if, for example, a heating plate maintained at a high temperature is disposed in the vicinity of the application surface and hot steam is brought into contact therewith so that the steam temperature does not drop and the steam is not liquefied into droplets, then the aqueous coating materials are also impregnated, while forming bubbles, the steam exits the wooden material through guide pipes at the thickness end surface thereof, and the components of the applied aqueous coating material are impregnated into the surface layer of the wooden material, without forming a coating film on the surface, and thereby increase the hardness, fire resistance, and water resistance of the surface. Further, the inventors have also found that in the case of solutions of inorganic or organic matters comprising a mixture of a colloidal silica liquid and a water-soluble coating material or water-soluble adhesive, not only the wooden materials, but also inorganic or ceramic materials that are marketed as various construction materials can be impregnated in the surface layer thereof with the solutions by means of such contact with hot steam It was also found that appropriately selecting a solution of inorganic or organic matters according to the substance which is to be treated makes it possible to provide the surface of wooden materials, inorganic materials, and ceramic materials with properties that were not inherent thereto. The inventors have also found that providing fine grooves on the surface of the object to be treated such as a wooden material or providing pinholes with an appropriate spacing makes it possible to control appropriately the impregnation rate, efficiency, or depth when the above-described steam impregnation in accordance with the present invention is implemented and also to employ a variety of modification treatments corresponding to the properties of the object to be treated or functions which are wished to be provided with respect to various materials. Further, the inventors have also studied whether the moisture content of the objects to be treated such as wooden materials change under the effect of steam brought into contact and water present in the solution of organic or inorganic matter in accordance with the present invention. The results obtained demonstrated that the hot steam apparently supplies energy to the coating material components or silica and partially replaces water present in the solution or the material which is to be treated, but it was confirmed that because the operations are conducted so as to replenish the high-temperature energy, for example, by using a heating plate so that the hot steam can demonstrate the energy supplying function, the moisture content somewhat increased in the process of implementing the above-described steam impregnation in accordance with the present invention, but this moisture evaporated naturally after the treatment and the moisture level became the same as before the treatment. Further, the inventors have also found that the steam impregnation in accordance with the present invention can be similarly employed also when the surface of the material which is to be treated is a veneer pasted, for example, on a laminated material, and a decorative paper or transfer sheet pasted on MDF or the like. The impregnation of the components of the solution of organic or inorganic matter such as water-soluble coating materials can be impregnated not only into the veneer, but also into the surface layer of both the decorative paper or transfer sheet and MDF, and a laminated material having a veneer, decorative paper, or transfer sheet with a high-hardness surface can be manufactured. Furthermore, the inventors have also established that the steam impregnation in accordance with the present invention can be applied to the case in which a laminated material or a MDF having the aforesaid decorative paper or transfer sheet are subjected to press stamping to provide them with surface design grooves or patterns. In particular, in the prior art, when the moisture content of the material fluctuated after molding by press stamping, the entire material was warped or the grooves and pattern lost their shape due to springback. However, it was found that when the steam impregnation in accordance with the present invention is applied, because decorative paper or transfer sheets are modified by the impregnation with the components of the water-soluble coating material, moisture does not migrate into the plastically deformed surface layer portion from the surface side and from the inside, springback is prevented, the molded shape has a very high stability, and a highly functional construction material with high design ability can be manufactured in an easy manner. The inventors have also found that the steam impregnation in accordance with the present invention makes it possible to impregnate liquid paraffin as the solution of organic or inorganic matter into the entire wooden material, that is, to impregnate liquid paraffin uniformly in both the thickness direction and the flat surface direction, thereby resolving the problems inherent to the prior art technology, namely, a long time which is required for application and impregnation, application and suction, and pressure permeation in the case of impregnating a very thin surface layer, and also non-uniformity of the coating and impossibility to impregnate liquid paraffin in the zones at a large depth from the surface. Moreover, the inventors have found that the steam impregnation in accordance with the present invention makes it possible to use water-soluble coating materials or water-soluble adhesives that are polymerizable with UV radiation or electron beam as the solution of organic or inorganic matter and to impregnate them into any material selected from wooden materials, inorganic materials and ceramic materials, and that because the resin components are completely polymerized by irradiation with UV radiation or electron beam after the impregnation, the treated surface layer can be provided with excellent functions such as a high hardness and high corrosion resistance. The above-described information obtained by the inventors demonstrated that with the steam impregnation method employing hot steam and the heating plate, it is possible to control the degree to which the components of solutions of organic or inorganic matter, such as water-soluble coating material, are impregnated into the surface layer. Therefore, a coating film can be formed on the surface by appropriately controlling the temperature of the hot steam and heating plate. Moreover, coating films of water-soluble coating material that have been conventionally considered to have insufficient adhesive properties can be integrated with the same coating material that was previously impregnated and solidified and a water-soluble coating material film with excellent adhesive properties can be formed. The inventors who had developed the above-described steam impregnation method and coating method have also conducted a comprehensive study of roll or press molded shapes such that cause no rupture of the surface layer of the substrate materials themselves or design surface materials provided on the surface thereof and that also produce the molded convex or concave shape such as grooves in which no springback occurs. The results of this study demonstrated that the longitudinal cross-sectional shape of the mold protrusion for forming the groove shape has to be formed entirely, including the tip end of the mold, from circular arc surfaces of appropriate radii, rather than to be a shape composed of straight line sections as the conventional so-called V-like shape or almost V-like shape. Furthermore, the inventors have further studied the longitudinal cross-sectional shape of the mold protrusion. The results obtained demonstrated that the shape is required which is formed entirely, including the tip end of the mold, from circular arc surfaces of appropriate radii, or in which, as in the U-like shape, the length of the portions almost-parallel to the sheet material in the groove width direction is maximum about 1 mm (only in the distal end portion), the almost flat portion of the distal end of the mold is 0.3 to 1 mm, and all other sections are formed by circular arcs of appropriate radii, or in which the straight linear sections are present in the distal end portion and all other sections are formed by circular arcs of appropriate radii, the latter shape being used when the height of the protrusion for forming the groove is above 2 to 2.5 mm. Further, the inventors have also focused their attention on conducting the modification treatment of the surface layer portions so that plastic deformation after the press molding of the groove shape is not restored to the original state under the effect of moisture associated with the springback of plastically deformed portions when the aforesaid mold is used, and have conducted a comprehensive study of such a treatment. The results obtained demonstrated that this object can be attained by impregnating the substrate surface layer with a solution of organic or inorganic matter, for example, components of water-soluble coating material, comprising colloidal silica or SiO 2 fine particles by the previously discovered steam impregnation method. Thus, the inventors have found that in the case of a configuration in which design grooves or patterns are press stamped on the surface as in the laminated materials and MDF materials having the aforesaid decorative paper or printed sheet, in particular, when the moisture content in the material fluctuates after the press stamp molding, the entire material is warped or the grooves and patterns lose their shape due to springback. However, if the steam impregnation method in accordance with the present invention is applied, the decorative paper and resin sheets are modified by impregnation with the components of water-soluble coating materials. Therefore, moisture does not migrate into the plastically deformed surface layer from the surface side and inner side, the springback is prevented, the molded shape is very stable, and a highly functional construction material with high design ability can be manufactured in an easy manner. |
Medicinal compositions containing fc receptor gamma-chain activator |
The present invention provides pharmaceutical compositions comprising, as an active ingredient, a substance capable of activating the γ chain of Fc receptors (FcRγ) (provided that the substance is not an immunoglobulin for intravenous injection), and agents for stimulating myelinogenesis. The invention also provides agents for stimulating the differentiation of oligodendroglial precursor cells, agents for activating Fyn tyrosine kinase, and agents for stimulating the expression of myelin basic protein, all comprising a substance capable of activating FcRγ as an active ingredient. Further, the invention provides a method of detecting myelinogenetic oligodenroglias or precursor cells thereof which comprises using the expression of FcRγ in oligodendroglias or precursor cells thereof as an indicator. |
1. A pharmaceutical composition comprising, as an active ingredient, a substance capable of activating the γ chain of Fc receptors (FcRγ), provided that said substance is not an immunoglobulin for intravenous injection. 2. The pharmaceutical composition of claim 1, wherein the substance capable of activating FcRγ is a ligand for FcRγ, said ligand producing at least one effect selected from the following (A), (B) and (C): (A) stimulating the differentiation of oligodendroglial precursor cells; (B) activating Fyn tyrosine kinase; (C) stimulating the expression of myelin basic protein. 3. The pharmaceutical composition of claim 2, wherein the ligand for FcRγ is an anti-FcRγ antibody. 4. The pharmaceutical composition of claim 1, wherein the substance capable of activating FcRγ is a ligand for any one of Fc receptors capable of coupling to FcRγ, said ligand producing at least one effect selected from the following (a), (b) and (c): (a) stimulating the differentiation of oligodendroglial precursor cells; (b) activating Fyn tyrosine kinase; (c) stimulating the expression of myelin basic protein. 5. The pharmaceutical composition of claim 4, wherein the ligand for any one of Fc receptors capable of coupling to FcRγ is a ligand for type I Fcγ receptor (FcγRI). 6. The pharmaceutical composition of claim 5, wherein the ligand for FcγRI is an anti-FcγRI antibody. 7. The pharmaceutical composition of claim 4, wherein the ligand for any one of Fc receptors capable of coupling to FcRγ is a ligand for type III Fcγ receptor (FcγIII). 8. The pharmaceutical composition of claim 7, wherein the ligand for FcγIII is an anti-FcγRIII antibody. 9. The pharmaceutical composition of claim 1, wherein the substance capable of activating FcRγ is a subclass of IgG having a high binding property to FcγRI. 10. The pharmaceutical composition of claim 9, wherein the subclass of IgG is IgG3. 11. The pharmaceutical composition of claim 1, wherein the substance capable of activating FcRγ is IgG2b. 12. The pharmaceutical composition of claim 1, wherein the composition is for stimulating the differentiation of oligodendroglial precursor cells. 13. The pharmaceutical composition of claim 1, wherein the composition is for activating Fyn tyrosine kinase. 14. The pharmaceutical composition of claim 1, wherein the composition is for stimulating the expression of myelin basic proteins. 15. The pharmaceutical composition of claim 1, wherein the composition is for stimulating myelinogenesis. 16. The pharmaceutical composition of claim 1, wherein the composition is for preventing and/or treating at least one disease selected from the group consisting of demyelinating diseases, dysmyelinating diseases and myelinoclasis. 17. An agent for stimulating myelinogenesis comprising, as an active ingredient, a substance capable of activating FcRγ, provided that said substance is not an immunoglobulin for intravenous injection. 18. An agent for stimulating the differentiation of oligodendroglial precursor cells comprising, as an active ingredient, a substance capable of activating FcRγ. 19. An agent for stimulating Fyn tyrosine kinase comprising, as an active ingredient, a substance capable of activating FcRγ. 20. An agent for stimulating the expression of myelin basic protein comprising, as an active ingredient, a substance capable of activating FcRγ. 21. A method of detecting myelinogenetic oligodendroglias or precursor cells thereof, comprising using the expression of FcRγ in oligodendroglias or precursor cells thereof as an indicator. 22. The method of claim 21, further comprising using as another indicator the expression of at least one marker selected from the group consisting of PDGFαR, MAG, A2B5, 04, 01, MBP, PLP, DM-20, CNPase, MOG, NG2 and AN2 in oligodendroglias or precursor cells thereof. 23. A method of examining FcRγ expression in animal brain tissues or cells by immunohistochemical or immunocytochemical analysis. 24. The method of claim 23, further comprising examining the expression of at least one marker selected from the group consisting of PDGFαR, MAG, A2B5, 04, 01, MBP, PLP, DM-20, CNPase, MOG, NG2 and AN2 in oligodendroglias or precursor cells thereof. 25. A method of examining FcRγ expression in animal brain tissues or cells by a gene amplification method. 26. A method of examining FcRγ expression in animal brain tissues or cells by Western blotting. 27. The method of claim 26, further comprising examining the expression of at least one marker selected from the group consisting of PDGFαR, MAG, A2B5, 04, 01, MBP, PLP, DM-20, CNPase, MOG, NG2 and AN2 in oligodendroglias or precursor cells thereof. 28. An immunohistological or cell-staining reagent kit comprising an anti-FcRγ antibody. 29. The kit of claim 28, further comprising at least one antibody selected from the group consisting of anti-PDGFαR antibody, anti-MAG antibody, A2B5 antibody, 04 antibody, 01 antibody, anti-MBP antibody, anti-PLP antibody, anti-DM-20 antibody, anti-CNPase antibody, anti-MOG antibody, NG2 antibody and AN2 antibody. 30. A Western blotting reagent kit comprising an anti-FcRγ antibody. 31. The kit of claim 30, further comprising at least one antibody selected from the group consisting of anti-PDGFαR antibody, anti-MAG antibody, A2B5 antibody, 04 antibody, 01 antibody, anti-MBP antibody, anti-PLP antibody, anti-DM-20 antibody, anti-CNPase antibody, anti-MOG antibody, NG2 antibody and AN2 antibody. 32. A gene amplification reagent kit comprising at least one pair of primers capable of specifically amplifying the mRNA of FcRγ. |
<SOH> BACKGROUND ART <EOH>Myelin, a multi-layered membranous sheath enwrapping individual axons, is required for both the fast conduction of nerve impulses and for axonal function and integrity (1,2). Myelin is synthesized by oligodendroglia in the central nervous system (CNS), a process occurring shortly after the birth. Defects with myelin cause severe diseases in human; multiple sclerosis (MS) is one of such diseases, characterized by severe loss of myelin in the CNS. Although the disease was first described more than a century ago, both the etiology and cure reman largely unknown and uninvestigated (3). Only recently, a population of oligodendroglial precursor cells was first observed in MS lesions (4). Unraveling mechanisms that enable those endogenous precursor cells to be differentiated and/or strengthened so as to regenerate the lost myelin would prove to be an efficient therapeutic target. Therefore, comprehensive studies for elucidating the mechanism of myelinogenesis are of great importance in the treatment and cure of demyelinating diseases. Myelin is composed of a limited number of myelin proteins. Myelin basic protein (MBP) comprises 30-40% of all myelin proteins within the CNS. MBP is indispensable in myelinogenesis, playing a crucial role in the compaction of the myelin sheath (5). MBP also regulates the expression of other myelin proteins such as myelin-associated glycoprotein (MAG), indicating that MBP is extremely important for myelinogenesis (6). The spontaneous Shiverer mouse, which has a natural knock-out of the MBP gene (7), exhibits severe hypomyelination of CNS axons, leading to premature death within 3 months. Specific isoforms of MBP containing exon 2 of the MBP gene play a regulatory role in myelinogenesis (8), suggesting that the preliminary events of myelinogenesis require MBP. In the process of myelinogenesis, Fyn tyrosine kinase (Fyn) functions as an essential signaling molecule within oligodendroglia (9), stimulating the expression of MBP (10). Mice deficient in Fyn suffer severe decreases in MBP production, resulting in severe dysmyelination (9-11). Fyn, a non-receptor type tyrosine kinase, requires coupling to an adapter molecule in order to receive extracellular signals. Although myelin-associated glycoprotein (MAG) has been proposed as a candidate molecule responsible for the initial triggering of Fyn signals in myelination (9-13), MAG-deficient mice demonstrated only subtle myelin abnormalities (14,15). No significant differences in MBP expression were observed in MAG-deficient mice (14-16), casting doubt on the validity of MAG as the upstream signaling molecule which links extracellular signals to Fyn. Several researchers postulated that compensatory molecules may function in MAG-deficient mice; such molecules, however, have yet to be identified (17,18). It was suggested that MAG is not the trigger of myelinogenesis but that hitherto unknown molecules are responsible for triggering (6). In addition, in vitro studies have revealed that the activation of Fyn during the morphological differentiation of oligodendroglia occurs prior to the first expression of MAG (19). It is MBP that regulates the expression of MAG in vivo (6). It is an object of the present invention to identify the trigger that functionally couples to Fyn to cause the initial expression of MBP, thereby obtaining therapeutic strategies for diseases that result from defects with myelinogenesis. This molecule, i.e. the true trigger of myelinogenesis, must be expressed prior to the expression of MAG (i.e. early in the second week after birth; 6,20). Elucidation of this signal cascade will allow close understanding of the mechanism underlying myelinogenesis. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows FcRγ expressions in oligodendroglial precursor cells (OPC) and immature oligodendroglia in vitro. A: RT-PCR analysis of FcRγ expression. OPC express FcRγ (a) but not CD3ζ (b). Bone marrow-derived mast cells and splenocytes (58) were used as positive controls. Semi-quantitative RT-PCR revealed approximately equal expression levels of FcRγ mRNA in immature oligodendroglia and in mast cells (data not shown). B: Immunocytochemical analysis of FcRγ expression. FcRγ is expressed in A2B5-positive oligodendroglial precursor cells (a, b), O4-positive (c, d), and O1-positive immature oligodendroglias (e, f). Bar: 15 μm. C: Western blotting analysis of FcRγ revealed significant expression in immature oligodendroglia (37) derived from wild type mice (Wt), but not in immature oligodendroglia from FcRγ-deficient mice (FcRγ−/−)(58). FIG. 2 shows distribution of FcRγ-expressing cells in vivo. Coronal sections of the cerebrum indicate that FcRγ-expressing cells are distributed mainly in the SVZ at P0 (a). These cells expand into the white matter at P4 (b), localizing mainly within the white matter at P7 (c). FcRγ-positive cells are observed in the SVZ (subventricular zone), adjacent to the mouse-Musashi-1 (m-Msi-1)-positive cell layer in the VZ (ventricular zone) (41), suggesting that FcRγ-positive cells are derived from neural stem cells (d, e). FcRγ-positive cells are maintained in the adult CNS with a distribution similar to that at P7; the population is localized in the supraventricular area of the white matter and occurs, rarely within the gray matter (f). LV: lateral ventricle, cc: corpus callosum, vz: ventricular zone, svz: subventricular zone, CTX: cerebral cortex, CG: cingulum, CPu: caudate putamen. Bar: 50 μm (c), 25 μm (e), 50 μm (f). FIG. 3 shows that FcRγ-positive cells are derived from the oligodendroglial lineage in vivo. A: Double-labeling of coronal sections of the cerebrum at P0 demonstrates that FcRγ-positive cells are distributed mainly in the SVZ (a). The majority of these cells do not co-localize with GFAP-expressing cells, i.e. the astroglial lineage cells (b). The distribution of Ox-42-positive cells of the microglial lineage is distinct from that of the FcRγ-positive cells (c). Therefore, FcRγ-positive cells at the age of interest are predominantly derived from the oligodendroglial lineage. Panel b is a higher magnification of Panel a (show in box). o: oligodendroglial cells, a: astroglial cells, m: microglial cells. Bar: 50 μm (a, c), 25 μm (b). B: Double-labeling images of coronal sections of the cerebrum at P7 are taken from the pre-myelinated corpus callosum. FcRγ and Fyn co-localize at the cell-membrane (arrowheads; a). MAG co-labels FcRγ-positive oligodendroglia (arrowheads); the expression, however, is stronger at the tips of the cellular processes (b). Bar: 25 μm. C: Identity of FcRγ-positive cells within the adult CNS. FcRγ-MBP-double positive oligodendroglial cells are observed within the white matter, providing a similar pattern to the one seen in the neonatal CNS (a). In contrast, a small subpopulation of GFAP-positive cells, found predominantly within the adult SVZ, is also FcRγ-positive (b). Bar: 25 μm. D: Analysis of serial sections revealed similar patterns (arrows and arrowheads) for FcRγ (a), Fyn (b) and MBP (c). Images obtained from the corpus callosum and from a part of the fornix at P7 indicate those patterns. Unlike Fyn and MBP, FcRγ is also expressed within axons (46). Bar: 50 μm. FIG. 4 shows activation of FcRγ in vitro. A: Following stimulation with an anti-FcRγ antibody for 24 hrs, OPC demonstrated dramatic morphological changes, extending well-developed processes (b). Similar changes were observed when IgG2b, of which epitope is not naturally found in mice (47), was substituted for the antibody (c). These changes were not observed without stimulation (a). Bar: 35 μm. B: Western blotting analysis of MBP and Fyn expression. Cells seen in Panel A were lysed and analyzed. MBP, predominantly the exon-2 containing isoforms (17.0 kD and 21.5 kD), and Fyn were up-regulated in OPC following stimulation with anti-FcRγ antibody (FcRγ; lane 2), as compared to OPC without an activation stimulus (ctrl; lane 1). Stimulation with IgG2b (IgG2b; lane 3) via Fc receptors for IgG, also up-regulated MBP expression but no obvious changes in Fyn were observed; this probably reflects the indirectness of the stimulation process. CNPase, a marker for both OPC and differentiated oligodendroglia, was used as a loading control. C: IgG2b fails to stimulate OPC derived from FcRγ-deficient mice (FcRγ−/−) (58; care b with a), indicating that the changes in OPC as seen in Panel A are dependent on FcRγ expression in the cell. Bar: 35 μm. FIG. 5 shows comparison of wild type (Wt), FcRγ-deficient (FcRγ−/−), Fyn-deficient (Fyn−/−), and MBP-deficient (MBP−/−) mice. A: Coronal sections of the cerebrum are shown at P10. a-d, b-e, and c-f are adjacent sections. The white matter of the cingulum where morphologies of myelin and myelinating oligodendroglia are discernible is selected and photographed. The distribution of MBP is restricted in FcRγ- (b) and Fyn-deficient mice (c), the Fyn-deficient mice showing a more severe phenotype (c). The distribution of MAG-positive immature oligodendroglia (arrowheads) is restricted in all three mutants. The MBP-deficient mice display the most restricted phenotype (g); Fyn-deficient mice have an intermediate phenotype (f); FcRγ-deficient mice are the least affected (e). These observations indicate the existence of FcRγ-Fyn-MBP cascade within myelinating oligodendroglia. Bar: 100 μm. B: Western blotting analysis of MBP in myelin fractions. MBP is reduced in Fyn- and FcRγ-deficient mice at P10 (a) as well as in the adult (b). In the adult CNS, the total amount of MBP is reduced to 40.3% and 60.8% of the wild-type level in Fyn- and FcRγ-deficient mice, respectively (54). Reduction in the exon-2 containing MBP isoforms (17.0 kD and 21.5 kD) was severer than in the remaining isoforms and it decreased to 31.9% and 40.0% of the wild-type level in Fyn- and FcRγ-deficient adult mice, respectively (54). These results correlate with the in vitro results ( FIG. 4 ). C: MAG-positive immature oligodenroglia (6), which have migrated into the cerebral cortex by P10, visualized in each coronal section, are analyzed statistically (55). The cell counts per slice were approximately 44%, 25%, and 12% of the wild type cell count in FcRγ-, Fyn-, and MBP-deficient mice, respectively. This indicates that exon-2 containing MBP isoforms are important for myelinogenesis. FIG. 6 shows dysmyelination in the absence of FcRγ. A: FcRγ is co-stained with PDGF-αR, a marker for OPC (56), in the optic nerve (arrowheads; a), showing FcRγ is expressed in the oligodendroglial lineage cells. No significant differences in the distribution of PDGF-αR-positive cells (arrows) are recognized between FcRγ-deficient (FcRγ−/−)(c) and wild type (b) mice at P10. The border between the SVZ and the white matter is shown. These observations indicate that the initial defect in myelinogenesis as observed at P10 ( FIG. 5 ) results primarily from a failure in myelinogenesis, not in gliogenesis. b and c are counter-stained with methyl green. Bar: 40 μm. B: Statistical analysis of MAG-positive oligodendroglia (6, 55) at later stages of development revealed no remarkable differences between cell numbers at P50 and P90 (a). Even at those times, however, myelin abnormalities were evident; immunohistochemical analysis demonstrated that the levels of MBP (data not shown; see FIG. 5B -b) and PLP in the corpus callosum at P50 were reduced in staining intensity in FcRγ-deficient (c) as compared to the wild type (b). Bar: 40 μm. C: Electron microscopy revealed severe hypomyelination in the dorsal corpus callosum of FcRγ-deficient mice (b), as compared with wild type mice (a) at P67. The ventral corpus callosum of FcRγ-deficient mice displays severe axonal swelling (asterisks) of hypomyelinated axons (d), as compared to the wild type (c). Bar: 2 μm (b), 500 nm (d). FIG. 7 shows co-expression of FcγRI/III and CD45 with FcRγ in oligodedroglia. A: RT-PCR analysis of immature oligodendroglia (37) detected the alpha chain of FcγRI/III, but not the alpha chain of FcεRI, suggesting that the partner of FcRγ is the IgG-specific Fc receptor. Semi-quantitative RT-PCR revealed approximately 1.8-fold (FcγRI) and 0.8-fold (FcγRIII) mRNA expressions in immature oligodendroglia, relative to the expression in bone marrow-derived mast cells (data not shown). B: C5 is expressed in MAG-positive cells (arrowheads). This means CD45 is expressed in oligodendroglia (c). CD45 is co-expressed with Fyn in oligodendroglia during the initial stage of myelinogenesis at P10 (arrowheads; b). CD45 is also co-expressed with FcRγ in enlarging myelin sheaths at P7 (arrowheads; d) and in the adult CNS (arrowheads; a). All images were obtained from the white matter of the CNS (a is the border area between the white matter and the adult SVZ; b and d are from the corpus callosum, and c is from the anterior commisure). Bar: 25 μm. C: CD45 was detected easily by flow cytometry in cultured immature oligodendroglia (37) but not in astrocytes. These results suggest that CD45 is involved in the regulation of the signaling cascade proposed by the present inventors. FIG. 8 shows the mechanism of myelinogenesis proposed by the present inventors. An extracellular signal, such as IgG, triggers FcRγ through its association with an Fc receptor specific to IgG (FcγRI/III). CD45 first activates Fyn. Then, the ITAM phosphorylation of FcRγ proceeds, utilizing Fyn as a tyrosine kinase. This signal consequently stimulates the expression of MBP, particularly the exon-2 containing isoforms. MBP contributes to the regulation of MAG expression as previously reported (6). Polymorphisms in FcγRs (66) and mutations in CD45 (23) are reported to be present in some populations of MS patients. This model can explain both the mechanism of demyelination and the efficacy of IVIg therapy on demyelinating diseases (62). Direct stimulation of FcRγ ( FIG. 4 ) may in future prove to be an effective treatment that will enhance remyelination. FIG. 9 ( a - d ) shows immunohistochemical staining of MBP in 10-day old mouse brains. “Wild”, “FcRγ−/−”, “Fyn−/−” and “FcRγ−/−Fyn−/−” appearing at the upper right corner of individual images represent genotypes. All the mice are of C57B1/6 lineage. The cerebral area from the corpus callosum to the cingulum is photographed. The oval-shaped structure appearing in the lower part of each image represents the hippocampus. As shown in these images, MBP expression levels decrease in the following order: Wild >FcRγ−/− >Fyn−/− >FcRγ−/−Fyn−/−. FIG. 10 ( a - d ), which resembles FIG. 9 , shows staining of MAG. Legends are the same as in FIG. 9 . Panel e shows the brain of MBP-deficient Shiverer mouse (MBP−/−). The present inventors put forth a cascade model of FcRγ→Fyn→MBP. As shown in Panel d in FIG. 9 , MBP is hardly detected when both FcRγ and Fyn are knocked out. Hence, the inventors examined whether the phenotype of the animal that lacking MBP from the beginning would be similar to the phenotype of the double-deficient animal. As it turned out, the MAG expression patterns of MBP deficient mice and Fyn/FcRγ double-deficient mice (FcRγ−/−Fyn−/−) were similar to each other. As shown in the graph in Panel f, they also have similar numbers of MAG-positive immature oligodendroglias. These results demonstrated that FcRγ and Fyn are essential for the expression of MBP. FIG. 11 ( a - d ) shows the cerebral cortex of mice of the indicated genotypes 1.5 months after birth (P1.5M). MBP is stained. Fyn- or FcRγ-deficient mice show (i) slightly thin cerebral cortex and (ii) weak MBP staining. Further, Fyn/FcRγ double-deficient mice show (i) extremely thin cerebral cortex and (ii) substantial fading away of MBP staining. These results suggest that the phenomena at day 10 after birth shown in FIGS. 9 and 10 are not compensated during aging, but remain as a permanent defect. Panels e to h show Nissl staining of mice with the genotypes and ages indicated below individual images. The arrow shows the occurrence of hydrocephalus. The arrow points an area corresponding to the ventricle where accumulation of excessive cerebrospinal fluid is observed. Similar hydrocephalus is observed at P10 though not so severe as at P1.5M. FIG. 12 ( a, b ) shows images of cultured OPCs. Panel a is a phase-contrast image. Panel b shows immunological staining of CD45. Arrows indicate CD45-positive OPCs. On the other hand, arrowheads indicate less stained (rather negative) OPC. Positive cells represent OPCs that have more distinct processes and are more differentiated. Negative cells represent OPCs that are differentiated only slightly. These results suggest that CD45 is expressed in a differentiation-associated manner. Panel c is an image of the brain from a wild-type mouse 7 days after birth, showing an area around the endocyst. MAG-stained oligodendroglias also show CD45-staining (arrows). This indicates that the oligodendroglia is CD45-positive. On the other hand, arrowheads point to those cells which are positive to CD45 alone. These may be cells other than oligodendroglial cells, or they may be undifferenciated oligodendroglia that are yet to express MAG. “Fim” represent the fimbria, and “LV” represents the lateral ventricle. Panesl d and e show CD45 staining. These images were taken in order to examine whether the CD45 antibody used is reacting specifically. In wild-type mice, CD45-positive cells are stained in the white matter, particularly in CC (corpus callosum). In CD45-deficient mice (CD45−/−), no such staining is observed, suggesting that the antibody is reacting specifically. However, even in CD45-deficient mice, the structure called choroids plexus located in the LV (lateral ventricle) is stained with CD45. This site is known as a place where non-specific reaction occurs. CTX: cerebral cortex, CC: corpus callosum, SVZ: subventricular zone. FIG. 13 a shows images of cultured OPCs from wild-type mouse and CD45-deficient mouse (CD45−/−) without stimulation (control) or with 24-hr stimulation using anti-FcRγ antibody. While the wild-type cells display morphological differentiation upon stimulation, CD45-deficient cells do not. These results show that CD45 is necessary for the differentiation of OPC. Panel b shows the results of Western blotting of the cells shown in Panel a. This time, cells were stimulated not only with FcRγ but also with IgG. When stimulated with IgG and FcRγ, wild-type OPC displayed increased MBP expression, but CD45-deficient mouse did not show such increase. These results show that CD45 is necessary for the differentiation of OPC. Panel c shows detection by Western blotting of MBP in myelin fractions extracted from brains of wild-type mouse, CD45-deficient mouse and Fyn-deficient mouse (Fyn−/−) at P10. As seen from this image, CD45-deficient mouse and Fyn-deficient mouse show reduced MBP, as compared to the wild-type mouse. This supports the results of analysis of the tissues (d-h), and also suggests that both CD45 and Fyn are important for myelinogenesis (MBP expression). Panels d and e show myelin in the stria tun of wild-type mouse and CD45-deficient mouse at day 10 after birth by immunohistochemical staining of MBP. “LV” represents the lateral ventricle. CD45-deficient mouse shows decreased expression of MBP. Panels f, g and h show immunohistological staining of MAG at P10. Since CD45 is speculated to be responsible for the activation of Fyn, comparison is made with Fyn-deficient mouse. The wild-type mouse shows a great number of MAG-positive oligodendroglias in the corpus callosum (CC) and cerebral cortex (CTX), whereas CD45-deficient and Fyn-deficient mice show decrease of MAG-positive cells to similar extents. These results support that CD45 is involved in the activation of Fyn. FIG. 14 shows observation of myelin in the striatum of wild-type mouse and CD45-deficient mouse (CD45−/−) at 1.5 months after birth. Immunohistological staining of MBP shows myelin stained in an uneven, spotted manner in CD45-deficient mouse, suggesting disintegration of myelin (or dysmyelination from the beginning). This means that the myelin abnormality shown in FIGS. 12 and 13 still remains at 1.5 months after birth and is not compensated. (The image at P10 is not merely a growth defect.) FIG. 15 shows immunohistochemical staining of MAG in IgG-deficient μMT mouse and wild-type mouse at P7. The images show coronal sections of the cerebrum. The μMT mouse shows reduced myelin, suggesting that IgG is actually required in myelinogenesis as a physiological function. FIG. 16 shows immunohistochemical staining of MAG in IgG-deficient μMT mouse and wild-type mouse at P10. The images show coronal sections of the cerebrum. The μMT mouse shows reduced myelin, suggesting that IgG is actually required in myelinogenesis as a physiological function. FIG. 17 shows immunohistochemical staining of MAG in IgG-deficient μMT mouse and wild-type mouse (Wt) at P50 (adult). The images show inside of the cerebrum. The μMT mouse shows reduced myelin, suggesting that IgG is actually required in myelinogenesis as a physiological function. detailed-description description="Detailed Description" end="lead"? |
Audio decoding device, decoding method, and program |
An energy corrector (105) for correcting a target energy for high-frequency components and a corrective coefficient calculator (106) for calculating an energy corrective coefficient from low-frequency subband signals are newly provided. These processors perform a process for correcting a target energy that is required when a band expanding process is performed on a real number only. Thus, a real subband combining filter and a real band expander which require a smaller amount of calculations can be used instead of a complex subband combining filter and a complex band expander, while maintaining a high sound-quality level, and the required amount of calculations and the apparatus scale can be reduced. |
1. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of complex-valued signals in respective frequency bands to generate low-frequency subband signals; a corrective coefficient extractor for calculating an energy corrective coefficient based on said low-frequency subband signals; an energy corrector for correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combiner for combining real parts of said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 2. An audio decoding apparatus according to claim 1, wherein said corrective coefficient extractor calculates the signal phase of said low-frequency subband signals and calculates the energy corrective coefficient based on said signal phase. 3. An audio decoding apparatus according to claim 1, wherein said corrective coefficient extractor calculates the ratio of the energy of a real part of said low-frequency subband signals and the signal energy of said low-frequency subband signals as the energy corrective coefficient. 4. An audio decoding apparatus according to claim 1, wherein said corrective coefficient extractor averages the phases of samples of said low-frequency subband signals to calculate the energy corrective coefficient. 5. An audio decoding apparatus according to claim 1, wherein said corrective coefficient extractor smooths energy corrective coefficients calculated respectively in said frequency bands. 6. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a corrective coefficient generator for generating a predetermined energy corrective coefficient; an energy corrector for correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 7. An audio decoding apparatus according to claim 6, wherein said corrective coefficient generator generates a random number and uses the random number as said energy corrective coefficient. 8. An audio decoding apparatus according to claim 6, wherein said corrective coefficient generator generates predetermined energy corrective coefficients respectively in the frequency bands. 9. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of complex-valued signals in respective frequency bands to generate low-frequency subband signals; calculating an energy corrective coefficient based on said low-frequency subband signals; correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and combining real parts of said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 10. An audio decoding method according to claim 9, wherein for calculating said corrected target energy, the signal phase of said low-frequency subband signals is calculated, and the energy corrective coefficient is calculated based on said signal phase. 11. An audio decoding method according to claim 9, wherein for calculating said corrected target energy, the ratio of the energy of a real part of said low-frequency subband signals and the signal energy of said low-frequency subband signals is calculated as the energy corrective coefficient. 12. An audio decoding method according to claim 9, wherein for calculating said corrected target energy, the phases of samples of said low-frequency subband signals are averaged to calculate the energy corrective coefficient. 13. An audio decoding method according to claim 9, wherein for calculating said corrected target energy, energy corrective coefficients calculated respectively in said frequency bands are smoothed. 14. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; generating a predetermined energy corrective coefficient; correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 15. An audio decoding method according to claim 14, wherein for generating said energy corrective coefficient, a random number is generated and used as said energy corrective coefficient. 16. An audio decoding method according to claim 14, wherein for generating said energy corrective coefficient, predetermined energy corrective coefficients are generated respectively in the frequency bands. 17. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a complex subband dividing process for dividing said low-frequency audio signal into a plurality of complex-valued signals in respective frequency bands to generate low-frequency subband signals; a corrective coefficient extracting process for calculating an energy corrective coefficient based on said low-frequency subband signals; an energy correcting process for correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combining process for combining real parts of said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 18. A program according to claim 17, wherein in said corrective coefficient extracting process, the signal phase of said low-frequency subband signals is calculated and the energy corrective coefficient is calculated based on said signal phase. 19. A program according to claim 17, wherein in said corrective coefficient extracting process, the ratio of the energy of a real part of said low-frequency subband signals and the signal energy of said low-frequency subband signals is calculated as the energy corrective coefficient. 20. A program according to claim 17, wherein in said corrective coefficient extracting process, the phases of samples of said low-frequency subband signals are averaged to calculate the energy corrective coefficient. 21. A program according to claim 17, wherein in said corrective coefficient extracting process, energy corrective coefficients calculated respectively in said frequency bands are smoothed. 22. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a complex subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a corrective coefficient generating process for generating a predetermined energy corrective coefficient; an energy correcting process for correcting a target energy described by said high-frequency bit stream with said energy corrective coefficient to calculate a corrected target energy; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 23. A program according to claim 22, wherein in said corrective coefficient generating process, a random number is generated and used as said energy corrective coefficient. 24. A program according to claim 22, wherein in said corrective coefficient generating process, predetermined energy corrective coefficients are generated respectively in the frequency bands. 25. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy corrector for correcting a target energy described by said high-frequency bit stream with a predetermined energy corrective coefficient to calculate a corrected target energy; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 26. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy corrector for outputting an energy corrective coefficient for a signal which is generated by copying and processing said low-frequency subband signals; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of the signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, using said energy corrective coefficient; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 27. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy corrector for calculating a corrected target energy using an instruction of said high-frequency bit stream and a predetermined energy corrective coefficient; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 28. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a band expander for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals using an instruction included in said high-frequency bit stream and a predetermined energy corrective coefficient; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 29. An audio decoding apparatus comprising: a bit stream separator for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoder for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband divider for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a band expander for generating a high-frequency subband signal by correcting the signal energy (Er) of a signal which is generated by copying and processing said low-frequency subband signals, rather than a target energy (R) described by said high-frequency bit stream, with the reciprocal (1/a) of a predetermined energy corrective coefficient (a) when a corrected target energy (aR) which is produced by correcting said target energy (R) with said predetermined energy corrective coefficient (a) and the signal energy (Er) are corrected in amplitude such that the corrected target energy (aR) and the signal energy (Er) are equal to each other; and a subband combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 30. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; correcting a target energy described by said high-frequency bit stream with a predetermined energy corrective coefficient to calculate a corrected target energy; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 31. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; outputting an energy corrective coefficient for a signal which is generated by copying and processing said low-frequency subband signals; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of the signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, using said energy corrective coefficient; and combiner for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 32. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; calculating a corrected target energy using an instruction of said high-frequency bit stream and a predetermined energy corrective coefficient; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream; and combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 33. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals using an instruction included in said high-frequency bit stream and a predetermined energy corrective coefficient; and combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 34. An audio decoding method comprising the steps of: separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; decoding said low-frequency bit stream to generate a low-frequency audio signal; dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; generating a high-frequency subband signal by correcting the signal energy (Er) of a signal which is generated by copying and processing said low-frequency subband signals, rather than a target energy (R) described by said high-frequency bit stream, with the reciprocal (1/a) of a predetermined energy corrective coefficient (a) when a corrected target energy (aR) which is produced by correcting said target energy (R) with said predetermined energy corrective coefficient (a) and the signal energy (Er) are corrected in amplitude such that the corrected target energy (aR) and the signal energy (Er) are equal to each other; and combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 35. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy correcting process for correcting a target energy described by said high-frequency bit stream with a predetermined energy corrective coefficient to calculate a corrected target energy; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, at said corrected target energy; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 36. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy correcting process for outputting an energy corrective coefficient for a signal which is generated by copying and processing said low-frequency subband signals; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of the signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream, using said energy corrective coefficient; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 37. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; an energy correcting process for calculating a corrected target energy using an instruction of said high-frequency bit stream and a predetermined energy corrective coefficient; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals as instructed by said high-frequency bit stream; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 38. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a band expanding process for generating a high-frequency subband signal by correcting, in amplitude, the signal energy of a signal which is generated by copying and processing said low-frequency subband signals using an instruction included in said high-frequency bit stream and a predetermined energy corrective coefficient; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. 39. A program for enabling a computer to perform: a bit stream separating process for separating a bit stream into a low-frequency bit stream and a high-frequency bit stream; a low-frequency decoding process for decoding said low-frequency bit stream to generate a low-frequency audio signal; a subband dividing process for dividing said low-frequency audio signal into a plurality of real-valued signals in respective frequency bands to generate low-frequency subband signals; a band expanding process for generating a high-frequency subband signal by correcting the signal energy (Er) of a signal which is generated by copying and processing said low-frequency subband signals, rather than a target energy (R) described by said high-frequency bit stream, with the reciprocal (1/a) of a predetermined energy corrective coefficient (a) when a corrected target energy (aR) which is produced by correcting said target energy (R) with said predetermined energy corrective coefficient (a) and the signal energy (Er) are corrected in amplitude such that the corrected target energy (aR) and the signal energy (Er) are equal to each other; and a subband combining process for combining said low-frequency subband signals and said high-frequency subband signals to produce a decoded audio signal. |
<SOH> BACKGROUND ART <EOH>MPEG-2 AAC (Advanced Audio Coding) which is an international standard process of ISO/IEC is widely known as an audio coding/decoding process for coding an audio signal with high sound quality at a low bit rate. According to conventional audio coding/decoding processes that are typified by the MPEG-2 AAC, a plurality of samples from a time-domain PCM signal are put together into a frame, which is converted into a frequency-domain signal by a mapping transform such as MDCT (Modified Discrete Cosine Transform). The frequency-domain signal is then quantized and subjected to Huffman coding to produce a bit stream. For quantizing the frequency-domain signal, in view of the hearing characteristics of the human being, the quantizing accuracy is increased for more perceptible frequency components of the frequency-domain signal and reduced for less perceptible frequency components of the frequency-domain signal, thus achieving a high sound-quality level with a limited amount of coding. For example, a bit rate of about 96 kbps according to the MPEG-2 AAC can provide the same sound-quality level (at a sampling frequency of 44.1 kHz for a stereophonic signal) as CDs. If a stereophonic signal sampled at a sampling frequency of 44.1 kHz is coded at a lower bit rate, e.g., a bit rate of about 48 kbps, then efforts are made to maximize the subjective sound quality at the limited bit rate by not coding high-frequency components that are of less auditory importance, i.e., by setting their quantized values to zero. However, since the high-frequency components are not coded, the sound-quality level is deteriorated, and the reproduced sound is generally of muffled nature. Attention has been drawn to the band expansion technology for solving the problem of the sound quality deterioration at low bit rates. According to the band expansion technology, a high-frequency bit stream as auxiliary information in a slight amount of coding (generally several kbps) is added to a low-frequency bit stream representative of an audio signal that has been coded at a low bit rate by a coding process such as the MPEG-2 AAC process or the like, thus producing a combined bit stream. The combined bit stream is decoded by an audio decoder as follows: The audio decoder decodes the low-frequency bit stream according to a decoding process such as the MPEG-2 AAC process or the like, producing a low-frequency audio signal that is free of high-frequency components. The audio decoder then processes the low-frequency audio signal based on the auxiliary information represented by the high-frequency bit stream according to the band expansion technology, thus generating high-frequency components. The high-frequency components thus generated and the low-frequency audio signal produced by decoding the low-frequency bit stream are combined into a decoded audio signal that contains the high-frequency components. One example of a conventional audio decoder based on the band expansion technology is a combination of an MPEG-2 AAC decoder and a band expansion technology called SBR as described in document 1, section 5.6 shown below. FIG. 1 of the accompanying drawings illustrates a conventional audio decoder based on the band expansion technology described in document 1. Document 1: “Digital Radio Mondiale (DRM); System Specification” (ETSI TS 101 980 V1. 1.1), published September, 2001, p. 42- 57. The conventional audio decoder shown in FIG. 1 comprises bit stream separator 100 , low-frequency decoder 101 , subband divider 402 , complex band expander 403 , and complex subband combiner 404 . Bit stream separator 100 separates an input bit stream and outputs separated bit streams to low-frequency decoder 101 and complex band expander 403 . Specifically, the input bit stream comprises a multiplexed combination of a low-frequency bit stream representing a low-frequency signal that has been coded by a coding process such as the MPEG-2 AAC process and a high-frequency bit stream including information that is required for complex band expander 403 to generate a high-frequency signal. The low-frequency bit stream is output to low-frequency decoder 101 , and the high-frequency bit stream is output to complex band expander 403 . Low-frequency decoder 101 decodes the input low-frequency bit stream into a low-frequency audio signal, and outputs the low-frequency audio signal to subband divider 402 . Low-frequency decoder 101 decodes the input low-frequency bit stream according to an existing audio decoding process such as the MPEG-2 AAC process or the like. Subband divider 402 has a complex subband dividing filter that divides the input low-frequency bit stream into a plurality of low-frequency subband signals in respective frequency bands, which are output to complex band expander 403 and complex subband combiner 404 . The complex subband dividing filter may comprise a 32-band complex QMF (Quadrature Mirror Filter) bank which has heretofore been widely known in the art. The complex low-frequency subband signals divided in the respective 32 subbands are output to complex band expander 403 and complex subband combiner 404 . The 32-band complex QMF bank processes the input low-frequency bit stream according to the following equation: X k ( m ) = ∑ n = - ∞ ∞ h ( m M - n ) x ( n ) W K1 - ( k + k 0 ) ( n + n 0 ) , 402.1 k = 0 , 1 , … , K1 - 1 W K1 = ⅇ j 2 π K1 402.2 where x(n) represents the low-frequency audio signal, Xk(m) the kth-band low-frequency subband signal, and h(n) the analytic low-pass filter. In this example, K 1 =64. Complex band expander 403 generates a high-frequency subband signal representing a high-frequency audio signal from the high-frequency bit stream and the low-frequency subband signals that have been input thereto, and outputs the generated high-frequency subband signal to complex subband combiner 404 . As shown in FIG. 2 of the accompanying drawings, complex band expander 403 comprises complex high-frequency generator 500 and complex amplitude adjuster 501 . Complex band expander 403 is supplied with the high-frequency bit stream from input terminal 502 and with the low-frequency subband signals from input terminal 504 , and outputs the high-frequency subband signal from output terminal 503 . Complex high-frequency generator 500 is supplied with the low-frequency subband signals and the high-frequency bit stream, and copies the signal in the subband that is specified among the low-frequency subband signals by the high-frequency bit stream, to a high-frequency subband. When copying the signal, complex high-frequency generator 500 may perform a signal processing process specified by the high-frequency bit stream. For example, it is assumed that there are 64 subbands ranging from subband 0 to subband 63 in the ascending order of frequencies, and complex subband signals from subband 0 to subband 19, of those 64 subbands, are supplied as the low-frequency subband signals to input terminal 504 . It is also assumed that the high-frequency bit stream contains copying information indicative of which one of the low-frequency subbands (subband 0 to subband 19) a signal is to be copied from to generate a subband A (A>19), and signal processing information representing a signal processing process (selected from a plurality of processes including a filtering process) to be performed on the signal. In complex high-frequency generator 500 , a complex-valued signal in a high-frequency subband (referred to as “copied/processed subband signal”) is identical to a complex-valued signal in a low-frequency subband indicated by the copying information. If the signal processing information indicates any signal processing need for better sound quality, then complex high-frequency generator 500 performs the signal processing process indicated b the signal processing information on the copied/processed subband signal. The copied/processed subband signal thus generated is output to complex amplitude adjuster 501 . One example of signal processing performed by complex high-frequency generator 500 is a linear predictive inverse filter that is generally well known for audio coding. Generally, it is known that the filter coefficients of a linear predictive inverse filter can be calculated by linearly predicting an input signal, and the linear predictive inverse filter using the filter coefficients operate to whiten the spectral characteristics of the input signal. The reason why the linear predictive inverse filter is used for signal processing is to make the spectral characteristics of the high-frequency subband signal flatter than the spectral characteristics of the low-frequency subband signal from which it is copied. A comparison between the spectral characteristics of low- and high-frequency subband signals of an audio signal, for example, indicates that the spectral characteristics of the high-frequency subband signal are often flatter than the spectral characteristics of the low-frequency subband signal. Therefore, a high-quality band expansion technology can be realized by using the above flattening technique. Complex amplitude adjuster 501 performs a correction specified by the high-frequency bit stream on the amplitude of the input copied/processed subband signal, generating a high-frequency subband signal. Specifically, complex amplitude adjuster 501 performs an amplitude correction on the copied/processed subband signal in order to equalize the signal energy (referred to as “target energy”) of high-frequency components of the input signal on the coding side and the high-frequency signal energy of the signal generated by complex band expander 403 with each other. The high-frequency bit stream contains information representative of the target energy. The generated high-frequency subband signal is output to output terminal 503 . The target energy described by the high-frequency bit stream may be considered as being calculated in the unit of a frame for each subband, for example. Alternatively, in view of the characteristics in the time and frequency directions of the input signal, the target energy may be calculated in the unit of a time divided from a frame with respect to the time direction and in the unit of a band made up of a plurality of subbands with respect to the frequency direction. If the target energy is calculated in the unit of a time divided from a frame with respect to the time direction, then time-dependent changes in the energy can be expressed in further detail. If the target energy is calculated in the unit of a band made up of a plurality of subbands with respect to the frequency direction, then the number of bits required to code the target energy can be reduced. The unit of divisions in the time and frequency directions used for calculating the target energy is represented by a time frequency grid, and its information is described by the high-frequency bit stream. According to another arrangement of complex amplitude adjuster 501 , an additional signal is added to the copied/processed subband signal, generating a high-frequency subband signal. The amplitude of the copied/processed subband signal and the amplitude of the additional signal are adjusted such that the energy of the high-frequency subband signal serves as a target energy. An example of the additional signal is a noise signal or a tone signal. Gains for adjusting the amplitudes of the copied/processed subband signal and the additional signal, on the assumption that either one of the copied/processed subband signal and the additional signal serves as a main component of the generated high-frequency subband signal, and the other as an auxiliary component thereof, are calculated as follows: If the copied/processed subband signal serves as a main component of the generated high-frequency subband signal, then in-line-formulae description="In-line Formulae" end="lead"? G main=sqrt( R/E/ (1 +Q )) in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? G sub=sqrt( R×Q/N /(1 +Q )) in-line-formulae description="In-line Formulae" end="tail"? where Gmain represents the gain for adjusting the amplitude of the main component, Gsub the gain for adjusting the amplitude of the auxiliary component, and E, N the respective energies of the copied/processed subband signal and the additional signal. If the energy of the additional signal is normalized to 1, then N=1. In the above equations, R represents the target energy, Q the ratio of the energies of the main and auxiliary components, R, Q being described by the high-frequency bit stream, and sqrt( ) the square root. If the additional signal serves as a main component of the generated high-frequency subband signal, then in-line-formulae description="In-line Formulae" end="lead"? G main=sqrt( R/N/ (1 +Q )) in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? G sub=sqrt( R×Q/E/ (1 +Q )) in-line-formulae description="In-line Formulae" end="tail"? The high-frequency subband signal can be calculated by weighting the copied/processed subband signal and the additional signal using the amplitude adjusting gains thus calculated and adding the copied/processed subband signal and the additional signal which are thus weighted. Operation of complex amplitude adjuster 501 for amplitude adjustment and advantages thereof will be described in detail with reference to FIG. 3 . The signal phase (phase A in FIG. 3 ) of high-frequency components of the input signal on the coding side and the signal phase (phase B in FIG. 3 ) of the high-frequency subband signal derived from the low-frequency subband signal are entirely different from each other as shown in FIG. 3 . However, since the amplitude of the high-frequency subband signal is adjusted such that its signal energy is equalized to the target energy, the sound quality as it is heard is prevented from being degraded. This is because the human auditory sense is more sensitive to signal energy variations than to signal phase variations. Complex subband combiner 404 has a complex subband combining filter that combines the bands of the low-frequency subband signal and the high-frequency subband signal that have been input thereto. An audio signal generated by combining the bands is output from the audio decoder. The complex subband combining filter that is used corresponds to the complex subband dividing filter used in subband divider 402 . That is, these filters are selected such that a certain signal is divided by a complex subband dividing filter into subband signals, which are combined by a complex subband combining filter to fully reconstruct the original signal (the signal input to the complex subband dividing filter). For example, if the 32-band complex QMF dividing filter bank (K 1 =64) represented by the equation 402.1 is used as the complex subband combining filter, then the following equation 404.1 can be employed: x ( n ) = ∑ m = - ∞ ∞ f ( n - m M ) 1 K2 ∑ k = 0 K2 - 1 X k ( m ) W K2 ( k + k 0 ) ( n + n 0 ) 404.1 where f(n) represents the combining low-pass filter. In this example, K 2 =64. If the sampling frequency for the audio signal output from complex subband combiner 404 is higher than the sampling frequency for the audio signal output from low-frequency decoder 101 according to the band expansion technology, then the filters are selected such that a low-frequency part (down-sampled result) of the audio signal output from complex subband combiner 404 is equal to the audio signal output from low-frequency decoder 101 . Complex subband combiner 404 may employ a 64-band complex QMF combining filter bank (K 2 =128 in the equation 404.1). In this case, the lower-frequency 32 bands employ the output of a 32-band complex QMF combining filter bank as a signal value. The conventional audio decoder has been problematic in that it has a subband divider and a complex subband combiner which require a large amount of calculations, and the required amount of calculations and the apparatus scale are large because the band expansion process is carried out using complex numbers. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram showing an arrangement of a conventional audio decoder; FIG. 2 is a block diagram of complex band expander 403 of the conventional audio decoder; FIG. 3 is a diagram illustrative of an amplitude adjustment process according to the conventional audio decoder; FIG. 4 is a diagram illustrative of an amplitude adjustment process according to the present invention; FIG. 5 is a diagram illustrative of an amplitude adjustment process without energy correction; FIG. 6 is a block diagram of an audio decoding apparatus according to a first embodiment of the present invention; FIG. 7 is a block diagram of an audio decoding apparatus according to a second embodiment of the present invention; and FIG. 8 is a block diagram of band expander 103 according to the present invention. detailed-description description="Detailed Description" end="lead"? |
Multi-step organic light-emissive devices |
A light-emissive device including first and second electrodes, and a light-emissive layer located between the electrodes and containing organic light-emissive material including a plurality of particles spaced from each other by the light-emissive material, at least some of the particles being capable of injecting positive charge carriers into the light-emissive material and at least some of the particles being capable of injecting negative charge carriers into the light-emissive material; whereby electrical charge may pass between the electrodes via at least some of the particles to cause light to be emitted by the light-emissive material between those particles. |
1. A light-emissive device comprising: first and second electrodes, and a light-emissive layer located between the electrodes and comprising organic tight-emissive material including a plurality of particles spaced from each other by the light-emissive material, at least some of the particles being capable of injecting positive charge carriers into the light-emissive material and at least some of the particles being capable of injecting negative charge carriers into the light-emissive material; whereby electrical charge may pass between the electrodes via at least some of the particles to cause light to be emitted by the light-emissive material between those particles. 2. A light-emissive device as claimed in claim 1, wherein each of said particles comprises a first material capable of injecting positive charge carriers into the light-emissive material and a second material capable of injecting negative charge carriers into the light-emissive material. 3. A light-emissive device as claimed in claim 2, wherein the first material has a work function above 4.3 eV. 4. A light-emissive device as claimed in claim 2, wherein the second material has a work function below 3.5 eV. 5. A light-emissive device as claimed in claim 1, wherein each said particle has at least a partial coating of charge transport material. 6. A light-emissive device as claimed in claim 1, wherein the particles are smaller than 100 nm. 7. A light-emissive device as claimed in claim 1, wherein the mean spacing between the particles is in the range from 40 nm to 200 nm. 8. A light-emissive device as claimed in claim 1, wherein the size of the particles is in the range from 0.5 to 0.67 of the mean spacing between the particles. 9. A light-emissive device as claimed in claim 1, wherein the thickness of the light-emissive layer is greater than 500 nm. 10. A light-emissive device as claimed in claim 1, wherein the device is capable of emitting light when a voltage of 20V or greater is applied between the electrodes. 11. A light-emissive device as claimed in claim 1, wherein one of the electrodes comprises a material having a work function less than 3.5 eV and the other electrode comprises a material having a work function above 4.3 eV. 12. A light-emissive device as claimed in claim 1, wherein both of the electrodes comprise regions of a material having a work function less than 3.5 eV and regions of a material having a work function above 4.3 eV. 13. A light-emissive device as claimed in claim 1, wherein both of the electrodes comprise a material having a work function between 3.5 eV and 4.3 eV. 14. A light-emissive device as claimed in claim 12, wherein the device is operable to emit light when the first electrode is biased positively with respect to the second electrode and when the second electrode is biased positively with respect to the first electrode. 15. A method for forming a light-emissive device, comprising: forming a first electrode; depositing over the first electrode a light-emissive layer comprising organic light-emissive material including a plurality of particles spaced from each other by the light-emissive material, at least some of the particles being capable of injecting positive charge carriers into the light-emissive material and at least some of the particles being capable of injecting negative charge carriers into the light emissive material; and forming a second electrode over the light-emissive layer. 16. and 17. (Canceled) 18. A light-emissive device as claimed in claim 3, wherein the second material has a work function below 3.5 eV. 19. A light-emissive device as claimed in claim 7, wherein the size of the particles is in the range from 0.5 to 0.67 of the mean spacing between the particles. 20. A light-emissive device as claimed in claim 13, wherein the device is operable to emit light when the first electrode is biased positively with respect to the second electrode and when the second electrode is biased positively with respect to the first electrode. 21. A light-emissive device as claimed in claim 1, comprising: a glass sheet supporting said anode, one of said anode and said cathode comprising a material having a relatively high work function above 4.3 eV, and the other of said anode and said cathode comprising a material having a relatively low work function below 3.5 eV; and, each of said particles comprising a region of relatively high work function method having a work function above 4.3 eV and a region of a relatively low work function method having a work function below 3.5 eV. 22. A light-emissive device as claimed in claim 21, wherein said relatively high work function is above 4.5 eV. 23. A light-emissive device as claimed in claim 21, wherein said relatively low work function is below 3.0 eV. 24. A light-emissive device as claimed in claim 22, wherein said relatively low work function is below 3.0 eV. 25. A light-emissive device as claimed in claim 21, wherein said high work function method is selected from the group consisting of indium-tin oxide, tin oxide, and gold. 26. A light-emissive device as claimed in claim 21, wherein the particles of relatively high work function method are translucent. 27. A light-emissive device as claimed in claim 21, wherein the particles of relatively high work function method are transparent. 28. A light-emissive device as claimed in claim 21, wherein the light-emissive method is selected from the group consisting of organic polymers, small molecules, and oligomers. 29. A light-emissive device as claimed in claim 28, wherein the light-emissive material is selected from the group consisting of conjugated fluorenes, amines, and copolymers thereof. 30. A light-emissive device as claimed in claim 21, wherein the anode comprises indium-tin oxide. 31. A method of forming a light-emissive device as claimed in claim 21, comprising the steps of: depositing a mixture of said light-emissive material and said particles over the anode to a desired thickness to form an emissive layer: depositing the cathode on the emissive layer; providing electrical connections to the anode and cathode; and encapsulating the device. 32. The method of claim 31, comprising depositing the cathode by evaporative coating. 33. (New) the method of claim 31, wherein the anode comprises indium-tin oxide and the cathode comprises aluminum. 34. The method of claim 31, wherein the emissive layer thickness is about 8 microns. 35. The method of claim 31, comprising encapsulating the device by applying a glass cover sheet over the cathode and an epoxy seal between the glass sheets. |
Chimeric protein and its use in electron transfer methods |
A chimeric protein comprises a redox catalytic domain from one source and an electron transfer domain from a different source. The protein is used in a method in which a substrate for the redox catalytic domain is acted on, electrons are transferred between the redox catalytic domain and the electron transfer domain and between the electron transfer domain and an electrode. The flow of current or potential at the electrode may be monitored to determine the presence or amount of a substrate which is an analyte of interest. Alternatively current max be driven through the electrode to drive reaction of the substrate, for instance to detoxify samples. The redox catalytic domain is suitably derived from a cytochrome P450, and the electron transfer domain may be flavodoxin. |
1. Method of electron transfer comprising the steps a) providing a chimeric protein comprising a redox catalytis domain derived from a first source and an electron transfer domain, derived from a second source different to the first source; b) contacting the chimeric protein with a substrate for the catalytic domain, whereby the substrate is acted on by the catalytic domain to form a product, c) contacting the chimeric protein with an electrode; and d) transferring electrons between the electrode and the electron transfer domain and directly between the electron transfer domain and the catalytic domain. 2. Method according to claim 1 in which the redox catalytic domain is a haem-containing domain. 3. A method according to claim 2 in which the haem-containing domain is a monooxygenase domain. 4. A method according to claim 1 in which the electron transfer domain is a haem reductase domain and the electrode is a cathode. 5. A method according to claim lin which the electron transfer domain is a flavoprotein. 6. A method according to claim 5 in which the flavoprotein is flavodoxin from D. vulgaris or an active electron-transferring mutant form thereof. 7. A method according to claim 1 in which electrons are directly transferred from the electrode to the electron transfer domain. 8. A method according to claim 1 in which the chimeric protein additionally comprises a docking sequence having a docking site for the electron transfer domain. 9. A method according to claim 8 in which the electron transfer docking sequence is derived from the same source as the redox catalytic domain. 10. A method according to claim 3 in which the source of the redox domain is a cytochrome P450. 11. A method according to claim 10 in which the redox catalytic domain is derived from a bacterial cytochrome P450 enzyme. 12. A method according to claim 11 in which the enzyme is BM3 of Bacillus megaterium. 13. A method according to claim 1 in which the flow of electrons to or from the electrode is measured using a current or voltage detector. 14. A method according to claim 13 in which the substrate is an analyte of interest and in which the measurement of the flow electrons is used to detect the presence or amount of substrate. 15. A method according to claim 1 in which electrons are driven from the electrode, the substrate is consumed and the product is separated from the chimeric protein and recovered. 16. A method according to claim 15 in which the chimeric protein is immobilised on the electrode, the substrate is initially present in solution in contact with the immobilised enzyme and the product is recovered from solution. 17. A kit comprising a) a chimeric protein comprising a redox catalytic domain derived from a first source and an electron transfer domain derived from a second source different to the first source; and b) an electrode. 18. A kit according to claim 17 which comprises a substrate for the redox catalytic domain. 19. A kit according to claim 17 in which the electron transfer domain and the electrode are selected and arranged such that electrons are transferrable directly from the electrode to the electron transfer domain. 20. A kit according to claim 19 in which the electron transfer domain is immobilised on the cathode. 21. A kit according to claim 20 in which the immobilisation is by a covalent bond from a side chain of an amino acid residue of the electron transfer domain to the electrode surface. 22. A kit according to claim 17 in which the redox catalytic domain is a haem-containing domain. 23. A kit according to claim 22 in which the haem-containing domain is a monooxygenase domain. 24. A kit according to claim 17 in which the electron transfer domain is a haem reductase domain and the electrode is a cathode. 25. A kit according to claim 17 in which the electron transfer domain is a flavoprotein. 26. A kit according to claim 25 in which the flavoprotein is flavodoxin from D. vulgaris or an active electron-transferring mutant form thereof. 27. A kit according to claim 17 in which electrons are directly transferred from the cathode to the electron transfer domain. 28. A kit according to claim 17 in which the chimeric protein additionally comprises a docking domain having a docking site for the electron transfer domain. 29. A kit according to claim 28 in which the docking domain is derived from the same source as the redox catalytic domain. 30. A kit according to claim 17 in which the source of the redox catalytic domain is a cytochrome P450. 31. A kit according to claim 30 in which the redox catalytic domain is derived from a bacterial cytochrome P450 enzyme. 32. A kit according to claim 31 in which the enzyme is BM3 of Bacillus megaterium. 33. A kit according to claim 17 comprising a reaction vessel containing the electrode, a liquid comprising in solution a substrate for the redox catalytic domain and the chimeric protein in a form in which the redox catalytic domain is in contact with the substrate and electrons may be transferred from the cathode to the electron transfer domain, the kit further comprising a current collector electrically connected to the electrode. 34. A kit according to claim 33 which further comprises current and/or voltage monitoring means for detecting a flow of current through the current collector and the electrode and/or the potential of the electrode. |
Composition comprising macrocyclic tetra-amido metal complex as bleaching catalyst |
The present invention provides a laundry bleaching composition comprising: a) a macrocyclic tetra amido N-donor metal-ligand complex (preferably, 5,6-benzo-3,8,11,13-tetraoxo-2,2,9,9,12,12-hexamethyl-1,4,7,10-teraaza-cyclo-tridecane), and b) an alkyl benzene sulphonate surfactant said composition being substantially devoid of any added peroxygen bleach or a peroxy-based or peroxyl-generating bleach system. |
1. A bleaching composition comprising: a) an alkyl benzene sulphonate surfactant, and b) a macrocyclic tetra amido N-donor metal ligand complex, having the structure as shown below: wherein: B1, B3 and B4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C(R), C(R1)(R2) or C(R)2, each R substituent is the same or different from the remaining R substituents, and (1) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (2) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit; M is a transition metal ion: L is an axial ligand; and. Q is an alkali metal or tetra-alkyl ammonium or tetra-phenyl phosphonium counter-ion and. said composition being substantially devoid of any added peroxygen bleach or a peroxy based or peroxyl-generating bleach system. 2. A bleaching composition according to claim 1 wherein the alkyl benzene sulphonate surfactant is present in the composition in an amount sufficient to provide a concentration in a wash liquor of at least 0.05 g/l. 3. A bleaching composition according to claim 1, wherein the macrocyclic tetra-amido N-donor metal-ligand complex catalyst is present in the composition in an amount sufficient to provide a concentration in a wash liquor of 0.005 μm to 100 μm. 4. cancelled 5. A bleaching composition according to claim 1 wherein the axial ligand is selected from the group consisting of water and halide. 6. A bleaching composition according to claim 1, wherein M is selected from the group consisting of Fe, Mn, Cr, Cu, Co, Ni, Mo, V, Zn and W. 7. A bleaching composition according to claim 1 wherein the ligand is 5,6-benzo-3,8,11,13-tetraoxo-2,2,9,9,12,12-hexamethyl-1,4,7,10-tetraaza-cyclo-tridecane. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Oxidation catalysts comprising metal-complexes are well known. Such catalysts have been proposed for use in laundry compositions as components of a bleaching system. These catalysts activate H 2 O 2 or other peroxygen sources. A particular catalyst is disclosed in WO 98/03263, filed 21 Jul. 1997, (Collins et al.), which comprises a macrocyclic (tetra) amido N-donor. The macrocycle is capable of complexing with a metal ion, for example an iron III or IV. The complex also comprises axial ligands and one or more counter ions. One proposed purpose of these catalysts has been to assist in the bleaching of dyestuffs released from articles being laundered. If these dyestuffs are not removed from the wash liquor then they will re-deposit onto articles and cause a loss of colour definition or even catastrophic damage to ‘white’ articles. U.S. Pat. No. 5,853,428, filed 24 Feb. 1997, (Collins et al.) discloses use of similar catalysts in laundry detergent compositions. In both these citations the addition of hydrogen peroxide, or a source thereof, is envisaged as a means of activating the catalyst. Bleaching agents typically present in laundry detergents include percarbonates and/or perborates, which can also act as sources of hydrogen peroxide and/or other peroxyl species. Bleaching catalysts capable of bleaching effectively in the absence of added peroxyl sources have recently become the focus of some interest, for example: WO9965905; WO0012667; WO0012808; WO0029537, and, WO0060045. It is believed that these catalysts have the capability to use atmospheric oxygen as a source of oxidising equivalents. |
<SOH> SUMMARY OF THE INVENTION <EOH>Surprisingly, we have found that dyes can be decolourised by a macrocyclic tetra amido N-donor metal-ligand complex in the absence of added hydrogen peroxide provided that a commercial alkyl benzene sulphonate surfactant is present. Accordingly, the present invention provides a bleaching composition comprising: a) a macrocyclic tetra amido N-donor metal-ligand complex, and, b) an alkyl benzene sulphonate surfactant. said composition being substantially devoid of any added peroxygen bleach or a peroxy-based or peroxyl-generating bleach system. It is particularly advantageous to be able to bleach dyestuffs without the addition of hydrogen peroxide or a source thereof to the composition. Not only does this have savings in terms of cost, but it also removes some of the limitations on formulation which would be brought about by the presence of hydrogen peroxide. The mechanism of the invention is not fully understood. While bleaching occurs (in the absence of added hydrogen peroxide) in the presence of an alkyl benzene sulphonate (ABS) surfactant, it does not occur if the ABS is replaced with an ethoxylated alcohol nonionic surfactant. It is unclear whether some component of the ABS is acting as a primary substrate for the catalyst or whether the oxidising equivalents are eventually derived from atmospheric oxygen. A possible explanation is that relatively slow air oxidation of ABS leads to the formation of hydroperoxides. In the presence of the catalyst these act as a substrate enabling the oxidation of dyestuffs. The term “substantially devoid of any added peroxygen bleach or a peroxy-based or peroxyl-generating bleach system” should therefore be construed within the spirit of the invention. It is preferred that, other than as a component of the surfactant, the composition has as low a content of peroxyl species present as possible. The present invention extends to a method of bleaching a substrate comprising applying to the substrate, in an aqueous medium, the bleaching composition according to the present invention. The present invention extends to a commercial package comprising the bleaching composition according to the present invention together with instructions for its use. The bleaching composition may be contacted to the textile fabric in any suitable manner. For example, it may be applied in dry form, such as in powder form, or in a liquor that is then dried, for example as an aqueous spray-on fabric treatment fluid or a wash liquor for laundry cleaning, or a non-aqueous dry cleaning fluid or spray-on aerosol fluid. Any suitable textile that is susceptible to bleaching or one that one might wish to subject to bleaching may be used. Preferably the textile is a laundry fabric or garment. In a preferred embodiment, the method according to the present invention is carried out on a laundry fabric using an aqueous treatment liquor. In particular, the treatment may be effected in a wash cycle for cleaning laundry. The bleaching method may be carried out by simply leaving the substrate in contact with the bleaching composition for a sufficient period of time. Preferably, however, the bleaching composition is in an aqueous medium, and the aqueous medium on or containing the substrate is agitated. In a particularly preferred embodiment the method according to the present invention is carried out on a laundry fabric using aqueous treatment liquor. In particular the treatment may be effected in, or as an adjunct to, an essentially conventional wash cycle for cleaning laundry. More preferably, the treatment is carried out in an aqueous detergent wash liquor. The bleaching composition can be delivered into the wash liquor from a powder, granule, pellet, tablet, block, bar or other such solid form. The solid form can comprise a carrier, which can be particulate, sheet-like or comprise a three-dimensional object. The carrier can be dispersible or soluble in the wash liquor or may remain substantially intact. In other embodiments, the bleaching composition can be delivered into the wash liquor from a paste, gel or liquid concentrate. A unit dose as used herein is a particular amount of the bleaching composition used for a type of wash. The unit dose may be in the form of a defined volume of powder, granules or tablet. |
Colour-safe fabric treatment compositions |
A composition comprising: a dye transfer inhibition agent, and, a ligand having the structure of formula (I), wherein: B1, B3 and B4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C(R), C(R1)(R2) or C(R)2; each R substituent is the same is the same or different from the remaining R substituents and (1) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (2) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit. Preferably further comprising surfactant and builder, optional peroxygen source. Preferred dye transfer inhibition agents are dye binding polymers selected from polymers and co-polymers of vinylpyrrolidone, vinylpyridine N-oxide, and vinylimidazole, and mixtures thereof. |
1. A composition comprising: a) a dye transfer inhibition agent, and, b) a ligand having the structure: wherein: B1, B3 and B4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C(R), C(R1)(R2) or C(R)2, each R substituent is the same or different from the remaining R substituents and (1) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (2) from a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit. 2. The composition according to claim 1, further comprising a transition metal ion, an axial ligand, and an alkali metal counter-ion. 3. The composition according to claim 2, wherein the axial ligand is selected from the group consisting of water and halide. 4. The composition according to claim 2, wherein the metal is selected from the group consisting of Fe, Mn, Cr, Cu, Co, Ni, Mo, Zn and W. 5. The composition according to any one of claim 1, further comprising a peroxygen source. 6. The composition according to claim 5, wherein the peroxygen source is hydrogen peroxide or a precursor thereof. 7. The composition according to claim 2, further comprising surfactant and builder. 8. The composition according to claim 2 comprising both anionic and nonionic surfactant in a weight ratio (on surfactant) of 10-90% anionic: 90-10% nonionic. 9. The composition according to claim 2, in solid form. 10. The composition according to anyone of claim 1, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 11. The composition according to claim 10, wherein the nitrogen containing dye binding polymer is selected from polymers and co-polymers of vinylpyrrolidone, vinylpyridine N-oxide, vinylimidazole, vinylpyridinium chloride and mixtures thereof, and zwitterionic polymers. 12. The composition according to claim 2, further comprising a peroxygen source. 13. The composition according to claim 3, further comprising a peroxygen source. 14. The composition according to claim 4, further comprising a peroxygen source. 15. The composition according to claim 2, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 16. The composition according to claim 3, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 17. The composition according to claim 5, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 18. The composition according to claim 7, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 19. The composition according to claim 8, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. 20. The composition according to claim 14, wherein the dye transfer inhibiting agent comprises a nitrogen-containing, dye binding polymer. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Oxidation catalysts comprising metal-complexes are well known. One class being macrocyclic ligands, which co-ordinate with a transition metal ion. Such catalysts have been used in laundry compositions as parts of a bleaching system. These catalysts activate H 2 O 2 or other peroxygen sources in water, and are effective at neutral to basic pH. A particular catalyst is disclosed in WO 98/03263, filed 21 Jul. 1997, (Collins), which comprises a macrocyclic (tetra) amido N-donor. The macrocycle is capable of complexing with a metal ion, for example an iron III or IV. U.S. Pat. No. 5,853,428, filed 24 Feb. 1997, (Collins) discloses use of similar catalysts in laundry detergent compositions. Many other metal-based bleach catalysts are known. Bleaching catalysts are of particular utility in the prevention of so-called ‘dye transfer’. This occurs when dyestuffs are released from one region of a cloth article during laundering and later re-adsorbed at another location or on another article. It is advantageous to bleach the dyestuff while it is in aqueous solution, thereby preventing or reducing its transfer. In order to prevent transfer of dyes from one fabric substrate to another fabric substrate during cleaning processes, it is also known and often desired to include dye transfer inhibition agents in detergent compositions. The use of various polymers as dye transfer inhibitors (so-called ‘DTI’ polymers) in laundry detergent compositions and rinse conditioners has been described in the prior art. For example WO-A-0005334 discloses laundry detergents providing dye transfer inhibition benefits. Examples of known DTI polymers include polyvinyl pyrrolidone (PVP), and copolymers of N-vinylpyrrolidone and N-vinylimidazole (PVP/PVI). |
<SOH> SUMMARY OF THE INVENTION <EOH>We have now determined that the combination of a particular class of metal-complexing ligand with a DTI polymer leads to particularly effective compositions for the treatment of fabrics which might otherwise be prone to damage due to dye transfer. Accordingly, a first aspect of the present invention provides a composition comprising: a) a dye transfer inhibition agent, and, b) a ligand having the structure: wherein: B 1 , B 3 and B 4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B 2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C(R), C(R 1 )(R 2 ) or C(R) 2 , each R substituent is the same is the same or different from the remaining R substituents and (i) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit. A further aspect of the present invention subsists in those complexes, which have simple axial ligands (water or halide) and an elemental counter-ion (such as lithium). It is believed that these ligands are environmentally and toxicologically more acceptable than ligands such as trifluoroacetate, tetra-phenylphosphonium and tetra-ethylammonium. Accordingly, a further aspect of the present invention provides a composition comprising: a) a dye transfer inhibition agent, and, b) a bleach activator having the structure: wherein: B 1 , B 3 and B 4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B 2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C(R), C(R 1 )(R 2 ) or C(R) 2 , each R substituent is the same is the same or different from the remaining R substituents, and (i) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit; M is a transition metal ion; L is an axial ligand; and, Q is an alkali metal or tetra-alkyl ammonium or tetra-phenyl phosphonium counter-ion. Preferably, the axial ligand is selected from the group consisting of water and halide. Particularly preferred axial ligands are water and chloride. It is within the scope of the present invention to have a bleach activator, wherein M is selected from the group consisting of Fe, Mn, Cr, Cu, Co, Ni, Mo, V, Zn and W. detailed-description description="Detailed Description" end="lead"? |
Holders for beverage containers |
A holder for a disposable beverage container comprises an arcuate strip of material (1) which is cut at each end to provide a handle opening (3) within which are provided fixing means (5, 6) whereby opposite ends of the strip (1) may be fixed together with handle portions (8) substantially in facing register, the handle opening cut-outs (3) being securable together in overlapping relation so as to be flattenable against a side of a container held by the handle. The arcuate strip of material (1) is suitably cut at each end to provide respectively upwardly (5) and downwardly (6) extending lobes within the handle openings (3), which lobes (5, 6) are slidable into interlocking relationship when the two ends of the strip (1) are brought together face to face, thereby to form the handle (8). |
1. A holder for a beverage container which holder comprises an arcuate strip of material (1) which is cut at each end to provide a handle opening (3) within which are provided fixing means (5,6) whereby opposite ends of the strip (1) may be fixed together with handle portions (8) substantially in facing register, the handle opening cut-outs (3) being securable together in overlapping relation so as to be flattenable against a side of a container held in the holder. 2. A beverage container holder according to claim 1, wherein said arcuate strip (1) is cut at each end to provide respectively upwardly (5) and downwardly (6) extending lobes within the handle openings (3), said lobes (5,6) being slidable into interlocking relationship when the two ends of the strip (1) are brought together face to face, thereby to form the handle (8). 3. A beverage container holder according to claim 1 or 2, wherein an end flap (16,17) is attached to or integral with the handle portion (8) at at least one end of the arcuate strip (1) which end flap (16,17) is foldable double against the handle portion (8) and includes an aperture through which the fixing means (5,6) may operatively extend. 4. A beverage container holder according to any preceding claim and further comprising secondary fixing means comprising interengageable lobes (12,13) attached to upper edges of the handle portions (8). 5. A beverage container holder according to any preceding claim, wherein the strip material (1) is provided with lines of weakness (24) whereby it may be torn to provide a mask. 6. A beverage container holder according to any preceding claim, which carries printed material on at least one side thereof. |
Vehicle corner module and assembly comprising such module |
A truck/or vehicle corner module (51) comprises a knuckle (1) and a kingpin (53), which is rotatable with respect to the knuckle (1), said kingpin (53) being provided with means for immovable connection (55, 58) to the fork shaped end (34) of a vehicle suspension (35). The kingpin (53) has opposite ends (55), which are to bear against and fixed between the facing surfaces (56) of the teeth (32, 33) of the fork shaped end (34). |
1. Truck/or vehicle corner module, comprising a knuckled and a kingpin, which is rotatable with respect to the knuckle, said kingpin being provided with means for immovable connection to the fork shaped end of a vehicle suspension, characterized in that the kingpins has opposite ends which are to bear against and fixed between the facing surfaces of the teeth of the fork shaped end. 2. Module according to claim 1, wherein the opposite ends of the kingpin and the respective opposite fork surfaces are of a corresponding shape. 3. Module according to claim 1, wherein the opposite ends of the kingpin have screwthreaded bores for accommodation of a respective connection screwy. 4. Module according to claim 1, wherein the kingpin is supported with respect to the knuckle by means of rolling element bearings. 5. Module according to claim 4, wherein the outer ring(s) of the rolling element bearings is (are) supported on a correspondingly shaped bore of the knuckle. 6. Module according to claim 5, wherein two rolling elements bearings are provided, which have a split outer ring or a common outer ring. 7. Module according to claim 6, wherein the outer ring and the bore of the knuckle have a corresponding stepped shape, the wider part of said stepped shape being positioned above the narrower shaped part. 8. Module according to claim 6, wherein the rolling element bearings are taper roller bearings in back-to-back arrangement or “O” arrangement. Rolling bearings have full complement roller sets. 9. Module according to claim 6, wherein the inner raceways of the bearings are integrated in the kingpin. 10. Assembly comprising a modules according to claim 1 and a vehicle suspensions with a fork shaped end, the kingpin of said module being fixedly connected to said fork shaped end, characterised in that the kingpin has opposite ends, which are clamped between the facing surfaces of the teeth of the fork shaped end. 11. Assembly according to claim 10, wherein the teeth of the fork shaped end have bolt holes, and the opposite ends of the kingpin have screwthreaded bores, the kingpins being connected to the fork shaped end by means of bolts inserted through the bolt holes and screwed into the corresponding screwthreaded holes. |
Display device and display method |
The present invention relates to a display apparatus and a display method that enable multiple users to view high resolution moving images from various viewing points of the users. A light-control screen 25 is rotated, and projectors 211 to 21N irradiate the screen 25 from various directions with light rays corresponding to image data captured from those directions. In this case, when the forward direction of the light-control screen 25 is aligned with the projecting direction of one of the projectors 21n, an image corresponding to light rays emitted from the projector 21n is displayed on the light-control screen 25. The present invention may be applied to a display apparatus for displaying images. |
1. A display apparatus comprising: a screen which receives light rays to display images corresponding to the light rays; driving means for rotating the screen around or on a predetermined rotational axis thereof; and irradiating means for irradiating the screen with the light rays corresponding to the images from various directions. 2. The display apparatus according to claim 1, wherein the screen comprises: a diffusing plate for diffusing the received light rays; and at least one optical filter that transmits only a portion of the light rays diffused by the diffusing plate, the portion of the light rays traveling in a predetermined direction. 3. The display apparatus according to claim 2, wherein the screen has said at least one optical filter disposed on both surfaces or one of the surfaces of the diffusing plate, which is flat. 4. The display apparatus according to claim 1, wherein the irradiating means comprises a plurality of light-emitting means for emitting the light rays corresponding to the images, the plurality of light-emitting means surrounding the rotational axis of the screen and being disposed within the same plane. 5. The display apparatus according to claim 4, wherein the plurality of light-emitting means are disposed such that optical axes of the light-emitting means converge at one point on the rotational axis of the screen. 6. The display apparatus according to claim 1, wherein the irradiating means comprises: wide-angle light-emitting means for emitting the light rays corresponding to the images at wide angles; and reflecting means for reflecting the light rays emitted from the wide-angle light-emitting means toward the screen. 7. The display apparatus according to claim 1, wherein the irradiating means irradiates the screen with the light rays corresponding to the images of the object captured by a plurality of image-capturing means for capturing images of an object, the plurality of image-capturing means surrounding the object and being disposed within the same plane. 8. The display apparatus according to claim 7, wherein the irradiating means irradiates the screen with the light rays corresponding to the images, the light rays being released from the various directions that correspond to positions of the plurality of light-capturing means with respect to the object. 9. The display apparatus according to claim 8, wherein the irradiating means comprises a plurality of light-emitting means for emitting the light rays corresponding to the images of the object captured by the plurality of image-capturing means. 10. The display apparatus according to claim 9, wherein the plurality of light-emitting means are disposed such that the positional relationships of the optical axes of the light-emitting means are similar to the positional relationships of the optical axes of the plurality of light-capturing means. 11. The display apparatus according to claim 7, wherein the irradiating means comprises: wide-angle light-emitting means for emitting the light rays corresponding to the images at wide angles; reflecting means for reflecting the light rays emitted from the wide-angle light-emitting means toward the screen; and converting means for converting the images of the object captured by the plurality of image-capturing means into images to be displayed on the screen such that the captured images are equivalent to the display images, the displayed images being displayed on the screen when the light rays reflected by the reflecting means are received by the screen, wherein the wide-angle light-emitting means emits the light rays corresponding to the images converted by the converting means. 12. The display apparatus according to claim 7, further comprising: combining means for combining images each captured by at least two sets of the plurality of image-capturing means, and for outputting the combined image, wherein the irradiating means irradiates the screen with light rays corresponding to the combined image. 13. The display apparatus according to claim 7, further comprising the plurality of image-capturing means. 14. The display apparatus according to claim 1, wherein the screen receives light rays entering only from a predetermined direction and diffuses the light rays to display the images. 15. The display apparatus according to claim 1, wherein the screen receives and diffuses the light rays to display the images and projects only a portion of the light rays corresponding to the images, the portion of the light rays traveling in a predetermined direction. 16. The display apparatus according to claim 1, wherein the driving means rotates the screen according to the number of directions from which the light rays are emitted toward the screen by the irradiating means, and according to the frequency of irradiation of the irradiating means. 17. A display method comprising the steps of: rotating a screen around or on a predetermined rotational axis thereof, the screen receiving light rays to display images corresponding to the light rays; and irradiating the screen with light rays corresponding to the images from various directions. 18. A display apparatus which receives light rays to display images corresponding to the light rays, comprising: a diffusing plate which diffuses received light rays to display images corresponding to the light rays; and an optical filter that transmits only a portion of the light rays diffused by the diffusing plate, the portion of the light rays traveling in a predetermined direction. 19. The display apparatus according to claim 18, wherein the diffusing plate is flat, and said at least one optical filter is disposed on both surfaces of or one of the surfaces of the diffusing plate. 20. A display method of displaying images corresponding to received light rays, comprising the steps of: displaying images corresponding to light rays, the light rays being received and diffused by a diffusing plate for diffusing received light rays; and transmitting only a portion of the light rays diffused by the diffusing plate, the portion of the light rays traveling in a predetermined direction. |
<SOH> BACKGROUND ART <EOH>One known 3D display system that presents images viewable from various viewing points of multiple users is, for example, the Integral Photography (IP) 3D-image system developed by NHK (Japan Broadcasting Corporation). FIG. 1 illustrates an example of the IP 3D-image system. In the IP 3D-image system, a camera (video camera) 2 captures an image of an object through a lens array 201 . As shown in FIG. 2A in plan view and FIG. 2B in cross-sectional view, the lens array 201 has multiple microlenses disposed in a plane. The camera 202 captures the image of the object through each of the lenses. In the IP 3D-image system, a display apparatus 203 , such as a liquid crystal display, displays the image captured by the camera 202 . A lens array 204 is disposed over the front face of a display screen of the display apparatus 203 . The lens array 204 has the same structure as the lens array 201 . A user sees the image displayed on the display apparatus 203 through the lens array 204 . Thus, the user is able to view the image of the object of a certain viewing point. This means that the image captured by the camera 202 is a combination of image elements (referred to as microlens image-elements hereinafter) of the object seen through the microlenses of the lens array 201 . Thus, the image displayed on the display apparatus 203 is a combination of the microlens image-elements. The combination of the microlens image-elements is viewed from a certain viewing point through the lens array 204 having the same structure as the lens array 201 . The image of the object seen from that viewing point is therefore formed of pixels which are formed of the microlens image-elements seen through the microlenses of the lens array 204 . Accordingly, the IP 3D-image system presents images that can be viewed from various viewing points of multiple users. To briefly (or theoretically) describe the IP 3D-image system, an image of an object seen from a certain viewing point is formed of pixels that are formed by combining microlens image-elements of the microlenses of the lens array 204 . This means that the image resolution presented to a user depends on the microlenses of the lens arrays 201 and 204 . However, there are limits to reducing the size of the microlenses and also to the number of the microlenses, thus leading to difficulties in providing users with images having high resolution. Another 3D display system that presents images viewable from various viewing points of multiple users is, for example, Zebra Imaging developed by Zebra Imaging, Inc. Zebra Imaging uses holography technology to present high-resolution images that can be viewed from various viewing points of multiple users. However, because the images displayed using Zebra Imaging are holograms, the production of the images requires many hours for calculation, thus leading to difficulties in displaying moving images. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates an example of an IP 3D-image system; FIG. 2A is a plan view of a lens array 1 and a lens array 4 ; FIG. 2B is a cross-sectional view of the lens array 1 and the lens array 4 ; FIG. 3 illustrates a first embodiment of an image-capturing/display system employing the present invention; FIG. 4 is a block diagram of an image-capturing apparatus 1 ; FIG. 5 illustrates a flow chart describing the operation of the image-capturing apparatus 1 ; FIG. 6 is a block diagram of a display apparatus 2 ; FIG. 7 is a cross-sectional view of a first configuration of a light-control screen 25 ; FIG. 8 is a perspective view of optical filter films 55 and 56 ; FIG. 9 illustrates the optical characteristics of the optical filter films 55 and 56 ; FIG. 10A is a diagram to describe the image display on an optical display device 20 ; FIG. 10B is a diagram to describe the image display on the optical display device 20 ; FIG. 11 is a flow chart describing the operation of the display apparatus 2 ; FIG. 12 is a cross-sectional view of a second configuration of the light-control screen 25 ; FIG. 13 is a cross-sectional view of a third configuration of the light-control screen 25 ; FIG. 14A illustrates the positional relationship between projectors 21 n and users; FIG. 14B illustrates the positional relationship between projectors 21 n and users; FIG. 15 illustrates an example of the optical display device 20 ; FIG. 16 illustrates an optical path of a light ray according to the optical display device 20 ; FIG. 17 is a block diagram of an example of a signal processor 22 ; FIG. 18 illustrates an equidistant projection fish-eye lens; FIG. 19 is a diagram illustrating a light ray projected from a fish-eye lens 75 ; FIG. 20 is a diagram illustrating the traveling direction of a light ray R represented by angles θ and φ; FIG. 21 is a block diagram of an example of a signal processor 12 ; FIG. 22 is a block diagram of another example of the signal processor 22 ; FIG. 23 is a block diagram of a second embodiment of the image-capturing/display system employing the present invention; FIG. 24 illustrates optical image-capturing devices 10 , and 102 , respectively, capturing images of objects S 1 and S 2 ; FIG. 25 illustrates an optical display device 20 displaying a combination of the images of the objects S 1 and S 2 ; FIG. 26 is a plan view of another example of the optical display device 20 ; FIG. 27 is a block diagram of an embodiment of a computer employing the present invention; FIG. 28A illustrates a result of comparing the image-capturing/display system employing the present invention with the IP 3D-image system and Zebra Imaging; FIG. 28B illustrates another result of comparing the image-capturing/display system employing the present invention with the IP 3D-image system and Zebra Imaging; FIG. 28C illustrates another result of comparing the image-capturing/display system employing the present invention with the IP 3D-image system and Zebra Imaging; and FIG. 28D illustrates another result of comparing the image-capturing/display system employing the present invention with the IP 3D-image system and Zebra Imaging. detailed-description description="Detailed Description" end="lead"? |
Liquid or gel product dispenser forming a metering stick |
The invention concerns a liquid or gel product dispenser, comprising a reservoir (R) supporting a pump body (1) including in its lower part an intake valve (2) and provided with a piston (3) mobile along an axis, defining with said body a metering chamber communicating with at least an ejection orifice defined in an axially mobile dispensing nozzle at the end of said reservoir, said piston is coupled by friction with said dispensing nozzle, which is axially mobile in both directions by manual actuation, relative to said reservoir; said metering chamber comprises a lower section (10a) and an upper section (10b), both sections communicating via a conduit (30) arranged across said piston and a closure valve (5) is arranged between said piston and said nozzle. |
1. A liquid or gel product dispenser, of the type comprising a reservoir supporting a pump body comprising at the bottom an inlet valve and provided with a piston movable along an axis, which delimits, with said body, a metering chamber which communicates with at least one discharge orifice defined in an axially displaceable dispensing nozzle at the end of said reservoir, wherein said piston is coupled frictionally to said dispensing nozzle, which nozzle is axially displaceable in both directions relative to said reservoir by manual actuation, between two predetermined positions, wherein said metering chamber comprises, on the one hand, a lower compartment defined between said body and said piston and, on the other hand, an upper compartment defined between the piston and said nozzle, the two compartments communicating via a duct formed through said piston and wherein a sealing valve is arranged between said piston and said nozzle to isolate said metering chamber from said orifice. 2. The dispenser as claimed in claim I, wherein said nozzle takes the form of a cap arranged so as partially to enclose said reservoir, said cap having an upper wall, substantially perpendicular to said axis, in which said discharge orifice is provided. 3. The dispenser as claimed in claim 1, wherein said piston bears a collar, external to the pump body, which slides inside said nozzle while compressing the product in the upper compartment. 4. The dispenser as claimed in claim 2, wherein said collar of the piston comprises an upper shoulder extended at its periphery and downward by a lateral skirt, said lateral skirt sliding inside said nozzle. 5. The dispenser as claimed in claim 4, wherein the lower edge of said skirt is provided with a retaining ring which cooperates with the upper flange of the body to provide the limit stop for the collar in the raised position. 6. The dispenser as claimed in claim 1, wherein the lower end of said piston is shaped so as to lock said inlet valve in the closed position. 7. The dispenser as claimed in claim 3, wherein said discharge orifice is formed through the upper wall of the nozzle in line with said collar of said piston. 8. The dispenser as claimed in claim 2, wherein said discharge orifice is formed through the upper wall of the nozzle in the axis of the central duct of said piston. 9. The dispenser as claimed in claim 2, wherein said sealing valve comprises a sealing element protruding from the inner face of said upper wall of the nozzle and capable of engaging the top part of the central duct of the piston. 10. The dispenser as claimed in claim 8, wherein said sealing valve comprises a sealing element borne by the piston and capable of engaging in the discharge orifice. 11. The dispenser as claimed in claim 1, wherein the pump body is provided at the top with a peripheral groove in which an annular sealing lip connected externally to said piston slides axially. 12. The dispenser as claimed in claim 1, wherein said reservoir comprises a bottle which accommodates an internal support bush for the pump body and on which the dispensing nozzle is fitted movably. 13. The dispenser as claimed in claim 1, wherein the internal wall of said reservoir comprises a set of flexible stop fins which cooperate with complementary fins borne by the nozzle. 14. A product dispenser comprising: a reservoir for holding said product to be dispensed; a dispensing nozzle at one end of said reservoir, said nozzle axially displaceable relative to said reservoir and defining at least one discharge orifice; a pump body comprising an inlet valve; a piston axially displaceable relative to said reservoir and said nozzle, said piston defining a lower compartment between said body and said piston and an upper compartment between said piston and said nozzle, the two compartments connected to form a metering chamber in fluid flow communication with said at least one of said discharge orifices; and a sealing valve for isolating said metering chamber from said at least one discharge orifice. 15. The dispenser as claimed in claim 14, wherein said nozzle comprises a cap partially enclosing said reservoir. 16. The dispenser as claimed in claim 15, wherein said piston comprises a collar forming a seal against an inside wall of said nozzle to permit compression of said product in said upper compartment during dispensing of said product. 17. The dispenser as claimed in claim 16, wherein said collar of the piston comprises an upper shoulder extended at its periphery and downward by a lateral skirt, said lateral skirt sliding inside said nozzle. 18. The dispenser as claimed in claim 14, wherein a lower end of said piston cooperates with said body to close said inlet valve. 19. The dispenser as claimed in claim 14, wherein said metering chamber communicates with at least one discharge orifice via a flow path through said piston, and wherein said sealing valve comprises a sealing element protruding from an inner face of said nozzle for engaging said piston to obstruct said flow path. 20. The dispenser as claimed in claim 14, wherein said sealing valve comprises a sealing element borne by said piston for engaging in said at least one discharge orifice. |
Alpha-ketoamide derivatives as cathepsin k inhibitors |
Biaryl ketoamide derivatives, which are useful as cathepsin K inhibitors are described herein. The described invention also includes methods of making such biaryl ketoamide derivatives as well as methods of using the same in the treatment of disorders, including osteoporosis, associated with enhanced bone turnover which can ultimately lead to fracture. |
1. A compound of Formula (I): or a salt, solvate, or physiologically functional derivative thereof: wherein A is the group defined by (Q3)p-(Q2)n-(Q1)-(Q)m-, wherein Q is CH2 and m is 0, 1, or 2, or Q is OCH2 and m is 1, or Q is N(R′)CH2 and m is 1, where R′ is hydrogen or C1-C6 alkyl; Q1 is aryl or heteroaryl; Q2 is CH2 and n is 0, or 1, or Q2 is CH2O and n is 1, or Q2 is N(R′) and n is 1, where R′ is hydrogen or C1-C6 alkyl; Q3 is aryl or heteroaryl and p is 0 or 1; R1 is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with C1-C6 alkyl; D is O or S; R2 is hydrogen or —NR3R4; R3, R6, and R7 are independently selected from hydrogen or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl, —C(O)R5, —C(O)OR5, —S(O)2R5; R5 is hydrogen, C1-C6 alkyl, or —NR6R7; Z is the group defined by —(X)m—(X1), wherein X is C(R″)(R′″), wherein R″ is hydrogen or C1-C6 alkyl, R′″ is hydrogen or C1-C6 alkyl, and m is 0, 1, or 2; and X1 is aryl, heteroaryl, or heterocyclyl. 2. A compound of Formula (II): or a salt, solvate, or physiologically functional derivative thereof: wherein A is the group defined by (Q3)p-(Q2)n-(Q1)-(Q)m-, wherein Q is CH2 and m is 0, 1, or 2, or Q is OCH2 and m is 1, or Q is N(R′)CH2 and m is 1, where R′ is hydrogen or C1-C6 alkyl; Q1 is aryl or heteroaryl; Q2 is CH2 and n is 0, or 1, or Q2 is CH2O and n is 1, or Q2 is N(R′) and n is 1, where R′ is hydrogen or C1-C6 alkyl; Q3 is aryl or heteroaryl and p is 0 or 1; R1 is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with C1-C6 alkyl; D is O or S; R2 is hydrogen or —NR3R4; R3, R6, and R7 are independently selected from hydrogen or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl, —C(O)R5, —C(O)OR5, —S(O)2R5; R5 is hydrogen, C1-C6 alkyl, or —NR6R7; Z is the group defined by —(X)m—(X1), wherein X is C(R″)(R′″), wherein R″ is hydrogen or C1-C6 alkyl, R′″ is hydrogen or C1-C6 alkyl, and m is 0, 1, or 2, and X1 is aryl, heteroaryl, or heterocyclyl. 3-12. (canceled) 13. A compound as claimed in claim 1, wherein Q1 is selected from the group wherein R8 and R9 are independently selected from hydrogen, halogen, or C1-C3 haloalkyl. 14-16. (canceled) 17. A compound as claimed in claim 1, wherein Q1 is selected from the group 18. A compound as claimed in claim 1, wherein Q1 is 19. (canceled) 20. A compound as claimed in claim 1, wherein Q1 is selected from 21. A compound as claimed in claim 1, wherein Q1 is 22. A compound as claimed in claim 1, wherein Q1 is wherein each R is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. 23-27. (canceled) 28. A compound as claimed in claim 1, wherein Q3 is selected from the group wherein R8 and R9 are independently selected from halogen or C1-C3 haloalkyl. 29. A compound as claimed in claim 1, wherein Q3 is wherein R8 and R9 are independently selected from halogen or C1-C3 haloalkyl. 30-31. (canceled) 32. A compound as claimed in claim 1, wherein Q3 is selected from the group 33. A compound as claimed in claim 1, wherein Q3 is selected from the group 34-39. (canceled) 40. A compound as claimed in claim 1, wherein D is O. 41-46. (canceled) 47. A compound as claimed in claim 1, wherein X1 is 48. (canceled) 49. A compound as claimed in claim 1, wherein X1 is 50. A compound as claimed in claim 1, selected from the group consisting of: (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{oxo[(1H-pyrazol-5-ylmethyl)amino]acetyl}pentylcarbamate; (1R)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-[oxo(1H-pyrazol-3-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)propyl(1S)-1-[oxo(1H-pyrazol-3-ylamino)acetyl]pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-{oxo[(3-pyridinylmethyl)amino]acetyl}pentylcarbamate; (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-[oxo(2-pyridinylamino)acetyl]pentylcarbamate; (1S)-1-{[4-(4-fluorophenyl)-1H-imidazol-1-yl]methyl}-2,2-dimethylpropyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]butyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-2,2-dimethyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]butyl(1S)-1-(oxo{[( 1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-2-methyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2-methyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2,2-dimethyl-1-[(4-phenyl-1H-imidazol-1-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-2,2-dimethyl-1-[(4-phenyl-1H-imidazol-1-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2,2-dimethyl-1-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)propyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1S)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-[oxo(2-pyridinylamino)acetyl]pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-[[(1-methyl-1H-pyrazol-5-yl)amino](oxo)acetyl]pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-{oxo[(4-pyridinylmethyl)amino]acetyl}pentylcarbamate; (1R)-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,2-dimethylpropyl(1S)-1-(oxo{[(3S)-2-oxopiperidinyl]amino}acetyl)pentylcarbamate; (1R)-2,2-dimethyl-1-(2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}ethyl)propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-(1H-benzimidazol-1-ylmethyl)-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)propyl(1S)-1-{oxo[(2-oxo-1,3-oxazolidin-3-yl)amino]acetyl}pentylcarbamate; (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-(1,3-benzothiazol-2-yl)-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-3-ylamino)acetyl]pentylcarbamate; (1R)-1-(1,3-benzothiazol-2-yl)-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-i H-pyrazol-1-yl]methyl}propyl(1S)-1-[oxo(1,3-thiazol-2-ylamino)acetyl]pentylcarbamate; (1S)-1-[(4-benzyl-1H-imidazol-1-yl)methyl]-2,2-dimethylpropyl(1R)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-[(4-benzyl-1H-imidazol-1-yl)methyl]-2,2-dimethylpropyl(1R)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-[[(5-isoxazolylmethyl)amino](oxo)acetyl]pentylcarbamate; (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}propyl(1S)-1-{oxo[(2-oxo-1,3-oxazolidin-3-yl)amino]acetyl}pentylcarbamate; (1R)-2,2-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-1-[1,1′-biphenyl]-3-yl-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-[1,1′-biphenyl]-3-yl-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; 1-(4,7-diethoxy-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropyl(1S)-1-[(1H-pyrazol-5-ylamino)carbonyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-[oxo(1,3-thiazol-2-ylamino)acetyl]pentylcarbamate; (1S)-1-{[4-(benzyloxy)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-{[4-(aminocarbonyl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-{[4-(1H-imimidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-({4-[3,5-bis(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]butylcarbamate; (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-[oxo(1,3-thiazol-2-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-[5-(3-pyridinyl)-1,3,4-oxadiazol-2-yl]propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-[5-(3-pyridinyl)-1,3,4-oxadiazol-2-yl]propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-[5-(4-pyridinyl)-1,3,4-oxadiazol-2-yl]propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; and (1R)-2,2-dimethyl-1-[5-(4-pyridinyl)-1,3,4-oxadiazol-2-yl]propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; or a salt, solvate, or physiologically functional derivative thereof. 51. A compound as claimed in claim 1, selected from the group consisting of: (1S)-2,2-dimethyl-1-(3-thien-2-ylphenyl)propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-2,2-dimethyl-1-(3-thien-2-ylphenyl)propyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-[oxo(pyridin-2-ylamino)acetyl]pentylcarbamate; (1S)-1-[5-(2,6-dichloropyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-1-[5-(2,6-dichloropyridin-4-yl)-1,3,4-oxadiazol-2-yl]-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-(4,7-diethoxy-1-methyl-1H-benzimidazol-2-yl)-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1R)-1-{5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-1-{5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}-2,2-dimethylpropyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; (1S)-2,2-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}butyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; and (1R)-2,2-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}butyl(1S)-1-[oxo(1H-pyrazol-5-ylamino)acetyl]pentylcarbamate; or a salt, solvate, or physiologically functional derivative thereof. 52. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1, or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. 53. A method of treating a disorder in a mammal, said disorder being characterized by enhanced bone turnover which can ultimately lead to fracture, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in claim 1 or a salt, solvate or a physiologically functional derivative thereof. 54. A method of treating a disorder in a mammal, said disorder being characterized by bone loss, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in claim 1 or a salt, solvate or a physiologically functional derivative thereof. 55-56. (canceled) 57. A method of treating osteoporosis, comprising: administering to said mammal a therapeutically effective amount of a compound as claimed in claim 1, or a salt, solvate or physiologically functional derivative thereof. 58. A method of treating osteoporosis, comprising: administering to said mammal therapeutically effective amounts of (i) a compound as claimed in claim 1, or a salt, solvate or physiologically functional derivative thereof and (ii) at least one bone building agent. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to biaryl ketoamide derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such biaryl ketoamide derivatives are inhibitors of serine and cysteine proteases. Particularly, such biaryl ketoamide derivatives are inhibitors of cysteine proteases of the papain superfamily. More particularly, the ketoamides of the present invention are inhibitors of cathepsin family cysteine proteases such as cathepsin K. Such biaryl ketoamide derivatives are useful in the treatment of diseases associated with serine and cysteine protease activity, more particularly, in the treatment of diseases associated with cathepsin family cysteine proteases, for instance in the treatment of diseases associated with cathepsin K activity. Osteoclasts are multinuclear cells of hematopoietic lineage, which function in the process of bone resorption. Typically, bone resorption proceeds as described following. The osteoclasts adhere to a bone surface and form a tight sealing zone. This activity is followed by extensive membrane ruffling on the surface of the osteoclasts. Such action creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way a resorption pit is formed. At the completion of this cycle osteoblasts remodel the bone; that is, deposit a new protein matrix which is subsequently mineralized at this zone. Normally, a balance exists between the processes of bone resorption and new bone formation during remodeling. This normal balance of bone resorption and bone formation may be disrupted resulting in a net loss of bone in each cycle of remodeling. Such net bone loss may lead to osteoporosis. Osteoporosis is characterized by reduced bone mass and disruptions in the microarchitecture of the bone. These characteristics may lead to fractures, which can result from a minimal amount of trauma. Typical sites of fractures include vertebral bodies, distal radius, and the proximal femur. However, because those suffering from osteoporosis have general skeletal weakness, fractures may occur at other sites. Since osteoporosis is characterized by an increase in bone resorption with respect to bone remodeling, therapeutic agents that suppress bone resorption would be expected to provide a suitable treatment for osteoporosis. Administration of estrogens or calcitonin has been the bone resorption suppression treatment typically employed. However, these treatments do not always achieve the desired effect. Consequently, there is a continuing need for therapeutic agents which can attentuate bone resorption in a subject in need of such attenuation. Cathepsin K, which has also been called cathepsin O, cathepsin O2, and cathepsin X, is a member of the cysteine cathepsin family of enzymes, which are part of the papain superfamily of cysteine proteases. Other distinct cysteine protease cathepsins, designated cathepsin B, cathepsin C, cathepsin F, cathepsin H, cathepsin L, cathepsin O, cathepsin S, cathepsin V (also called L2), cathepsin W. Et cathepsin Z (also called cathepsin X), have also been described in the literature. The Cathepsin K polypeptide and the cDNA encoding such polypeptide has been disclosed in U.S. Pat. No. 5,501,969. A crystal structure for cathepsin K has also been disclosed in PCT Patent Application WO 97/16177, published May 9, 1997. It has been reported that cathepsin K is abundantly expressed in osteoclasts under normal conditions and may be the major cysteine protease present in these cells. (See Tezuka, et al., J. Biol. Chem., 1994, 269, 1106; Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi, et al., FEBS Lett., 1995, 357,129.) This abundant selective expression of cathepsin K in osteoclasts suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, such as osteoporosis. The selective inhibition of cathepsin K may also be useful in treating other diseases. Such disorders include autoimmune diseases such as rheumatoid arthritis, osteoarthritis, neoplastic diseases, parasitic diseases, and atherosclerosis. For instance, cathepsin K is expressed in the synovium and synovial bone destruction sites of patients with rheumatoid arthritis (see Votta, B. J. et al.; J. Bone Miner. Res. 1997, 12, 1396; Hummel, K. M. et al., J. Rheumatol. 1998, 25,1887; Nakagawa, T. Y. et al., Immunity 1999, 10, 207; Otsuka, T.et al., S. J. Antibiot. 1999, 52, 542; Li, Z.et al, Biochemistry 2000, 39, 529; Diaz, A. et al, Mol. Med. 2000, 6, 648; Moran, M. T.et al., Blood 2000, 96, 1969). Cathepsin K levels are elevated in chondroclasts of osteoarthritic synovium (See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588; Lang, A. et al., J. Rheumatol. 2000, 27, 1970). Neoplastic cells also have been shown to express cathepsin K (see Littlewood-Evans, A. J. et al, J. A. Cancer Res. 1997, 57, 5386; Komarova, E. A., et al., Oncogene 1998, 77, 1089; Santamaria, I., et al., Cancer Res. 1998, 58, 1624; Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460; Kirschke, H.et al., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M.et al., Clin. Cancer Res. 2000, 6, 2064). Cysteine protease inhibitors have been suggested as chemotherapy for parasitic diseases (see McKerrow, J. H. Int. J. Parasitol. 1999, 29, 833; Selzer, P. M.et al., Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11015; Caffrey, C. R.et al, Curr. Drug Targets 2000, 1, 155; Du, X.et al., Chem. Biol. 2000, 7, 733; Hanspal, M. Biochim. Biophys. Acta 2000, 1493, 242; Werbovetz, K. A. Curr. Med. Chem. 2000, 7, 835). Elastolytic cathepsins S and K are shown to be expressed in human atheroma (see Sukhova, G. K.et al., J. Clin. Invest. 1998, 102, 576-583; Parks, W. C. J. Clin. Invest. 1999, 104, 1167; Shi, G.-P.et al., J. Clin. Invest. 1999, 104, 1191; Cao, H.et al., J. Hum. Genet. 2000, 45, 94). The present inventors have now discovered novel biaryl ketoamide derivative compounds, which are inhibitors of serine and cysteine protease activities, more particularly, cathepsin family cysteine protease activities, and most particularly, cathepsin K activity. Such biaryl ketoamide derivatives are useful in the treatment of disorders associated with serine and cysteine protease activity, including osteoporosis, Paget's disease, hypercalcemia of malignancy, metabolic bone disease, osteoarthritis, rheumatoid arthritis, periodontitis, gingivitis, atherosclerosis, and neoplastic diseases associated with cathepsin K activity. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>In a first aspect of the present invention, there is provided a compound of Formula (I): or a salt, solvate, or physiologically functional derivative thereof: wherein A is the group defined by (Q 3 ) p -(Q 2 ) n -(Q 1 )-(Q) m -, wherein Q is CH 2 and m is 0, 1, or 2, or Q is OCH 2 and m is 1, or Q is N(R′)CH 2 and m is 1, where R′ is hydrogen or C 1 -C 6 alkyl; Q 1 is aryl or heteroaryl; Q 2 is CH 2 and n is 0, or 1, or Q 2 is CH 2 O and n is 1, or Q 2 is N(R′) and n is 1, where R′ is hydrogen or C 1 -C 6 alkyl; Q 3 is aryl or heteroaryl and p is 0 or 1; R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl substituted with C 1 -C 6 alkyl; D is O or S; R 2 is hydrogen or —NR 3 R 4 ; R 3 , R 6 , and R 7 are independently selected from hydrogen or C 1 -C 6 alkyl; R 4 is hydrogen, C 1 -C 6 alkyl, —C(O)R 5 , —C(O)OR 5 , —S(O) 2 R 5 ; R 5 is hydrogen, C 1 -C 6 alkyl, or —NR 6 R 7 ; Z is the group defined by —(X) m —(X 1 ), wherein X is C(R″)(R′″), wherein R″ is hydrogen or C 1 -C 6 alkyl, R′″ is hydrogen and C 1 -C 6 alkyl, and m is 0, 1, or 2; and X 1 is aryl, heteroaryl, or heterocyclyl. In a second aspect of the present invention, there is provided a compound of Formula (II): or a salt, solvate, or physiologically functional derivative thereof: wherein A is the group defined by (Q 3 ) p -(Q 2 ) n -(Q 1 )-(Q) m -, wherein Q is CH 2 and m is 0, 1, or 2, or Q is OCH 2 and m is 1, or Q is N(R′)CH 2 and m is 1, where R′ is hydrogen or C 1 -C 6 alkyl; Q 1 is aryl or heteroaryl; Q 2 is CH 2 and n is 0, or 1, or Q 2 is CH 2 O and n is 1, or Q 2 is N(R′) and n is 1, where R′ is hydrogen or C 1 -C 6 alkyl; Q 3 is aryl or heteroaryl and p is 0 or 1; R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl substituted with C 1 -C 6 alkyl; D is O or S; R 2 is hydrogen or —NR 3 R 4 ; R 3 , R 6 , and R 7 are independently selected from hydrogen or C 1 -C 6 alkyl; R 4 is hydrogen, C 1 -C 6 alkyl, —C(O)R 5 , —C(O)OR 5 , —S(O) 2 R 5 ; R 5 is hydrogen, C 1 -C 6 alkyl, or —NR 6 R 7 ; Z is the group defined by —(X) m —(X 1 ), wherein X is C(R″)(R′″), wherein R″ is hydrogen or C 1 -C 6 alkyl, R′″ is hydrogen and C 1 -C 6 alkyl, and m is 0, 1, or 2; and X 1 is aryl, heteroaryl, or heterocyclyl. In a third aspect of the present invention, there is provided a pharmaceutical composition, comprising: a therapeutically effective amount of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. In a fourth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being characterized by bone loss, comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof. In a fifth aspect of the present invention, there is provided a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof for use in therapy. In a sixth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder characterized by bone loss. In a seventh aspect of the present invention, there is provided a method of treating osteoporosis, comprising: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof. In an eighth aspect of the present invention, there is provided a method of treating osteoporosis, comprising: administering to said mammal therapeutically effective amounts of (i) a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof and (ii) at least one bone building agent such as parathyroid hormone (PTH). detailed-description description="Detailed Description" end="lead"? |
Device for applying free-flowing material to a substrate moveable with respect thereto |
A device for dispensing fluid material onto a substrate including a base body with a flow channel for receiving the fluid material and a movable valve body positioned in the flow channel. The valve body is movable in a downstream direction into an open position to release a flow of the fluid material into the flow channel and is movable in an upstream direction into a closed position to interrupt the flow of the fluid material into the flow channel. A drive device moves the valve body between the open position and the closed position. A cylindrical chamber is positioned in the flow channel and the valve body includes a piston movable within the cylindrical chamber. The piston is sealed within the cylindrical chamber in such a way that when the piston moves in a first direction within the cylindrical chamber, the fluid material is displaced from the flow channel and when the piston is moved in a second direction opposite to the first direction, the fluid material is drawn into the flow channel. |
1-23. Canceled. 24. A device for dispensing fluid material onto a substrate, comprising: a base body including a flow channel for receiving the fluid material, a movable valve body positioned in said flow channel, said valve body movable in a downstream direction into an open position to release a flow of the fluid material into said flow channel, and movable in an upstream direction into a closed position to interrupt the flow of the fluid material into said flow channel, a drive device configured to move said valve body between the open position and the closed position, a cylindrical chamber in said flow channel, said valve body including a piston movable within said cylindrical chamber, said piston sealed within said cylindrical chamber in such a way that when said piston moves in a first direction within said cylindrical chamber, the fluid material is displaced from said flow channel and when said piston is moved in a second direction opposite to said first direction, the fluid material is drawn into said flow channel. 25. The device of claim 24, wherein said piston is positioned downstream from said cylindrical chamber in the open position and is positioned in said cylindrical chamber in the closed position, and the movement of the piston from the open position to the closed position draws the fluid material into said flow channel. 26. The device of claim 24, further comprising a valve seat configured to engage with portion of said valve body positioned upstream from said piston when said valve body is in the closed position. 27. The device of claim 24, wherein said valve body further comprises a guide section spaced from said piston and said flow channel includes guide surfaces, said guide section contacting said guide surfaces for guiding said valve body laterally as said valve body moves between the open and closed positions. 28. The device of claim 27, wherein said guide section further comprises a triangular cross section, and said guide surfaces further comprise portions of a cylinder. 29. The device of claim 24, further comprising a tapered section on said valve body positioned downstream from said piston. 30. The device of claim 24, further comprising a sleeve, said cylindrical chamber and said guide surfaces being formed in said sleeve. 31. The device of claim 24, wherein said drive device further comprises a second piston coupled to said valve body and operative to move said valve body between the open and closed positions. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Dispensing devices such as application heads, are utilized in industry, for example, in order to coat areas of film or foil substrates with liquid adhesive such as hot melt adhesive. The fluid material flows out of a source of material, normally a reservoir, into the flow channel of the device, passes through a valve body, and continues to flow to a nozzle arrangement with an outlet opening. Frequently a so-called intermittent application is performed, meaning that intervals in which the valve body is in the open position and material is applied to the substrate alternate with intervals in which the valve body is in the closed position, so that the application of material is interrupted. Often, very short intervals are used in intermittent applications in order to realize application zones at very small distances from each other. The application pattern that is produced on the substrate is normally subject to the requirement that a material application zone on the substrate have sharply delimited edges. In the case of a large-area application with the help of a known slit nozzle arrangement, it is especially desired that not only the lateral edges (in the direction of motion of the substrate relative to the application device) but also the front and rear edges of a material application zone be sharply delimited. A prerequisite for such sharp delimitation of the front and rear edges is that the valve body of the valve arrangement is moved quickly into its closed position, so that the flow of material from the outlet opening is interrupted uniformly quickly. When the valve arrangement is opened, in order to attain a sharp boundary line at the front edge of a material application zone it is necessary for the valve arrangement to open quickly and for the application of material to begin without delay. A needle valve has been used for this purpose, having a needle with a needle tip as a valve body, which may be brought into contact with a valve seat that conforms to the shape of the needle tip. To close the valve arrangement, the needle (under electro-pneumatic actuation) is moved in the direction of the valve seat and comes into contact with the latter, so that the flow cross section of the flow channel is closed and the flow of material is thereby interrupted. During the closing motion of the needle tip, some adhesive is moved downstream by the needle tip in the direction of the outlet opening. As a result, the application of material to the substrate is not interrupted as abruptly as would be necessary to produce a sharp boundary line in the end area of an application zone. An “afterdrip” from the outlet opening during closure of the valve arrangement cannot be prevented. A reduction of such an afterdrip of material from the outlet opening was achieved by an application head known from the published patent EP-A-0 850 697, in which a valve body that is enlarged compared to a valve shaft is moved upstream to close the valve arrangement, i.e., counter to the direction of flow of the material in the open position in the direction of the outlet opening of a nozzle arrangement. The result of this arrangement is that during the closing motion of the valve body, because of adhesion of the material to the enlarged valve body, and because of material being drawn along, there is a slight backflow of material upstream. A relatively abrupt interruption of the flow of material from the outlet opening results and it is largely possible to prevent afterdripping. The object of the present invention is to further improve intermittent dispensing devices such that the flow of material out of an outlet opening is interrupted more abruptly, and in particular afterdripping may be prevented even more effectively resulting in very sharply delimited material application zones or application patterns on a substrate. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a device for dispensing fluid material onto a substrate. The device includes a base body including a flow channel for receiving the fluid material and a movable valve body positioned in the flow channel. The valve body is movable in a downstream direction into an open position to release a flow of the fluid material into the flow channel and is movable in an upstream direction into a closed position to interrupt the flow of the fluid material into the flow channel. A drive device moves the valve body between the open position and the closed position. A cylindrical chamber is positioned in the flow channel and the valve body includes a piston movable within the cylindrical chamber. The piston is sealed within the cylindrical chamber in such a way that when the piston moves in a first direction within the cylindrical chamber, the fluid material is displaced from the flow channel and when the piston is moved in a second direction opposite to the first direction, the fluid material is drawn into the flow channel. In other aspects of the invention, the piston is positioned downstream from the cylindrical chamber in the open position and is positioned in the cylindrical chamber in the closed position. The movement of the piston from the open position to the closed position draws the fluid material into the flow channel. A valve seat engages with portion of the valve body positioned upstream from the piston when the valve body is in the closed position. The valve body further comprises a guide section spaced from the piston and the flow channel includes guide surfaces. The guide section contacts the guide surfaces for guiding the valve body laterally as the valve body moves between the open and closed positions. The guide section further comprises a triangular cross section, and the guide surfaces further comprise portions of a cylinder. A tapered section on the valve body is positioned downstream from the piston. The cylindrical chamber and the guide surfaces are formed in a sleeve. The drive device further comprises a second piston coupled to the valve body and operative to move the valve body between the open and closed positions. Various additional aspects will become more readily apparent by reviewing the following detailed description of the preferred embodiments. |
Novel cancer marker and uses therefor in the diagnosis of cancer |
Provided are novel cancer markers for the diagnosis of cancer in humans and non-human mammalian subjects, specifically a cancer marker comprising a negatively-charged molecule with a mass/charge (m/z) ratio of about 991. The cancer marker of the invention may be used to determine the presence of one or more cancerous cells or tumors in a biological sample by assaying the sample for a reduced level of said cancer marker. |
1. A cancer marker comprising a negatively-charged molecule with a m/z ratio of about 991 that is present at a reduced level in a subject having a cancer compared to a healthy subject, or a derivative of said negatively-charged molecule. 2. The cancer marker of claim 1 in isolated form. 3. The cancer marker of claim 1, wherein the negatively charged molecule comprises carbohydrate, phosphate or sulfate. 4. The cancer marker of claim 3, wherein the negatively-charged molecule comprises a carbohydrate moiety O-linked or N-linked in situ to a proteinaceous moiety or is linked in situ to a lipid moiety. 5. The cancer marker of claim 1 wherein the derivative comprises a fragment of the negatively-charged molecule. 6. The cancer marker of claim 5 wherein the fragment has a m/z ratio selected from the group consisting of about 241, about 644, about 705, about 749, and about 947. 7. The cancer marker of claim 6 comprising at least two of said fragments. 8. The cancer marker of claim 6 comprising at least three of said fragments. 9. The cancer marker of claim 6 comprising at least four of said fragments. 10. The cancer marker of claim 6 comprising a fingerprint of all of said fragments. 11. The cancer marker of claim 1 wherein the derivative comprises the negatively-charged molecule covalently attached to a fluorescent ligand, enzyme ligand, radioactive ligand, peptide ligand, or antibody ligand. 12. A method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, or the level established for a healthy subject, wherein a reduced level of said cancer marker or derivative relative to the level in the healthy subject, or the level established for a healthy subject, is indicative of cancer. 13. A method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of an internal standard added to the test sample, wherein a reduced level of said cancer marker or derivative relative to the level of the internal standard is indicative of cancer. 14. A method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; relative to the level of another marker in the same test sample, wherein a change in the ratio of the cancer marker to the another marker is indicative of cancer. 15. The method of of claim 12 wherein the level of the cancer marker, internal standard or another marker is determined by mass spectrometry or chromatography techniques. 16. The method of claim 15 wherein the cancer is of neuroectodermal origin. 17. The method of claim 15 wherein the cancer is selected from the group consisting of carcinoma, lymphoma, and sarcoma. 18. The method of claim 15 wherein the cancer is a melanoma. 19. The method of claim 15 wherein the cancer is adenocarcinoma. 20. The method of claim 15 wherein the cancer is a colon cancer. 21. The method of claim 15 wherein the test sample and/or the control sample is a bodily fluid or a fraction thereof. 22. The method of claim 21 wherein the bodily fluid is blood. 23. The method of claim 21 wherein the fraction is serum or a derivative fraction thereof. 24. The method of claim 12, further comprising determining the abundance of the cancer marker in either the test sample or control sample, and/or the relative abundance of the cancer marker in said samples. 25. The method of claims 12, further comprising the first step of obtaining the sample. 26. The method of claim 12, further comprising confirming the identity of the cancer marker by determining its fragmentation profile. 27. A method of monitoring cancer treatment in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject being treated for cancer, said cancer marker comprising a negatively charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, the level established for a healthy subject, wherein an increased level is indicative of successful treatment. 28. A method of diagnosing recurrence of cancer following successful treatment in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject treated for cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, the level established for a healthy subject or the level in a sample from the subject following successfully treated for cancer, wherein a reduced level is indicative of recurrence of cancer. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In spite of numerous advances in medical research, cancer remains a major cause of death worldwide, and there is a need for rapid and simple methods for the early diagnosis of cancer, to facilitate appropriate remedial action by surgical resection, radiotherapy, chemotherapy, or other known treatment methods. The availability of good diagnostic methods for cancer is also important to assess patient responses to treatment, or to assess recurrence due to re-growth at the original site or metastases. The characterization of cancer markers, such as, for example, oncogene products, growth factors and growth factor receptors, angiogenic factors, proteases, adhesion factors and tumor suppressor gene products, etc, can provide important information concerning the risk, presence, status or future behavior of cancer in a human or non-human mammalian subject Determining the presence or level of expression or activity of one or more cancer markers can assist the differential diagnosis of patients with uncertain clinical abnormalities, for example by distinguishing malignant from benign abnormalities. Furthermore, in patients presenting with established malignancy, cancer markers can be useful to predict the risk of future relapse, or the likelihood of response in a particular patient to a selected therapeutic course. Even more specific information can be obtained by analyzing highly specific cancer markers, or combinations of markers, which may predict responsiveness of a patient to specific drugs or treatment options. It is well known that aberrant glycosylation is a common feature for most cancer types, and drastic changes to serine/threonine-linked glycan (i.e. O-glycan) levels may occur in cancer patients. “O-glycan” is a glycoprotein wherein N-acetylgalactosamine is added to serine and/or threonine residues of nascent protein. Cancer patients may, for example, have a reduced level of common O-glycan core structures, enhanced levels of sialylated glycan or ganglioside, or decreased modification to sialic acid. The synthesis of specific peptide moieties of O-glycans may also be altered in cancer patients, thereby modifying O-glycan levels, since the peptide moieties of glycoproteins in part direct the synthesis of O-glycans. Alternatively, sialyltransferase activities may be enhanced in cancer patients, thereby producing hyper-sialylated O-glycans. Generally, tumor-specific antigens are high molecular weight or high molecular mass molecules (>10,000 Da) that are either expressed specifically on a cancer cell or expressed at elevated levels on cancer cells compared to normal cells. However, there are low molecular weight (<10,000 Da) tumor-specific antigens which are often glycolipids, more particularly sphingolipids, that comprise polylactosamine structures. A “glycolipid” is simply a lipid or fatty acid molecule having one or more carbohydrate moieties. “Sphingolipids” are lipids comprising a fatty acid residue, a polar head group, and sphingosine (4-sphingenine) or a related base, including ceramide, and its derivatives, sphingomyelin (i.e. ceramide that comprises a phosphocholine moiety on the hydroxyl group), or the glycosphingolipids (i.e. ceramide comprising a carbohydrate moiety on the hydroxyl group), including a ganglioside. A “ganglioside” is a glycosphingolipid that contains sialic acid (i.e. a glycolipid wherein a fatty acid-substituted sphingosine is linked to an oligosaccharide that comprises D-glucose, D-galactose, N-acetylgalactosamine and/or N-acetylneuraminic acid) and which is expressed in the majority of mammalian cell membranes. Gangliosides are mono-, di-, tri, or poly-sialogangliosides, depending upon the extent of glycosylation with sialic acid. In accordance with standard nomenclature, the terms “GMn”, “GDn”, “GTn”, are used, wherein “G” indicates a ganglioside; “M” indicates a monosialyl ganglioside, “D” indicates a disialyl ganglioside, and “T” indicates a trisialyl ganglioside; and wherein “n” is a numeric indicator having a value of at least 1, or an alphanumeric indicator having a value of at least 1a (e.g. 1a, 1b, 1c, etc), indicating the binding pattern observed for the molecule [Lehninger, In: Biochemistry, pp. 294-296 (Worth Publishers, 1981); Wiegandt, In: Glycolipids: New Comprehensive Biochemistry, pp. 199-260 (Neuberger et al., ed., Elsevier, 1985)]. Polylactosamines are usually classified into two categories according to their polylactosamine unit structure, in particular Type 1 polylactosamines comprising galactosyl-(∃1-3,) N-acetylglucosamine, or alternatively, Type 2 polylactosamines comprising galactosyl (∃1-4) N-acetylglucosamine. Gangliosides, such as, for example, GM2 (Livingston et al., Proc. Natl. Acad. Sci. USA 84, 2911-2915, 1987), GD2 (Schulz, et al., Cancer Res. 44, 5914-5920, 1984), or GD3 (Cheresh et al., Proc. Natl. Acad. Sci. USA 81, 5767-5771, 1984; Reisfeld et al., In: Immunity to Cancer (M. S. Mitchell, Ed), pp 69-84, 1985), have been identified as prominent cell surface constituents of various tumors of neuroectodermal origin, such as, for example, malignant melanoma, neuroblastoma, glioma, soft tissue sarcoma and small cell carcinoma of the lung. These gangliosides are absent, or present at only low levels, in most normal tissues. The role of gangliosides as tumor-specific antigens is also discussed, for example, by Ritter and Livingston, et al., Sem. Canc. Biol. 2, 401-409, 1991; Chatterjee et al., U.S. Pat. No. 5,977,316 issued Nov. 2, 1999; Hakomori Cancer Res. 45, 2405-2414,1985; Miraldi In: Seminars in Nuclear Medicine XIX, 282-294, 1989; and Hamilton et al, Int J. Cancer 53, 1-8, 1993. A common tumor-associated antigen found in major cancers are gangliosides that comprise the Type 2 chain polylactosamine structure, or alternatively, the fucosylated form. For example, the gangliosides sialyl-Lewis A and sialyl-Lewis X are involved in the adhesion of cancer cells to vascular endothelial cells, and contribute to the hematogenous metastasis of cancer. Sialyl-Lewis A is frequently expressed in cancers of the colon, pancreas and biliary tract, whilst sialyl-Lewis X is commonly expressed in cancers of the breast, lung, liver and ovary. The degree of expression of the carbohydrate ligands of sialyl-Lewis A or sialyl-Lewis X at the surface of cancer cells is well correlated with the frequency of hematogenous metastasis and prognostic outcome of patients with cancers. On the other hand, gangliosides comprising the Type 1 polylactosamine structure, such as, for example, 2-3 sialyl Lewis A, are abundant in normal cells and tissues, and are also cancer-associated. Levery et al (U.S. Pat. No. 6,083,929 issued Jul. 2, 2000) teach that extended forms of lacto-series Type 1 chain, with or without sialyl and/or fucosyl residues, are present in cancer tissues. Levery et al (ibid.) showed that an isoform isolated from the glycolipid fraction of the colon adenocarcinoma cell line Colo205 comprised the following glycosphingolipid units: homodimeric LewisA, heterodimeric LewisB-LewisA, and extended sialyl LewisA-LewisA, the latter of which is suggested as a tumor-associated glycosphingolipid and potential tumor marker. However, despite the progress in identifying sialylated antigens for the detection of cancer, there remains a clear need for cancer markers to assist in the diagnosis of cancers, and the detection of specific cancer types. In particular, notwithstanding the perturbation of glycosylation observed in cancer, there are few, if any, known cancer markers that are not necessarily sialylated compounds or O-linked glycoproteins, and/or are not tumor-specific antigens. A preferred characteristic of a cancer marker is that it is readily amenable to detection using rapid or high throughput analytical methods, such as, for example, mass spectrometry, or high pressure liquid chromatography (HPLC)-mass spectrometry. Furthermore, a suitable cancer marker should be amenable to detection in a bodily fluid (e.g. blood, serum, urine, mucus, saliva, sweat, tears or other fluid secretion), thereby facilitating the use of non-invasive assays for routine testing. |
<SOH> SUMMARY OF THE INVENTION <EOH>In work leading up to the present invention, the inventors sought to identify both high and low molecular weight/mass cancer markers in the bodily fluids of humans and non-human mammalian subjects, and to develop related high throughput diagnostic methods for the detection of malignancies associated with a reduced level of such cancer markers in a bodily fluid, wherein such diagnostics did not depend upon the isolation of a molecular probe, such as, for example, an antibody or nucleic acid probe, and/or did not require a time-consuming binding step using such a molecular probe. Accordingly the first aspect of the present invention provides a cancer marker comprising a negatively-charged molecule with a m/z ratio of about 991 that is present at a reduced level in a subject having a cancer compared to a healthy subject, or a derivative of said negatively-charged molecule. A second aspect of the present invention provides a method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, or the level established for a healthy subject, wherein a reduced level of said cancer marker or derivative relative to the level in the healthy subject, or the level established for a healthy subject, is indicative of cancer. A third aspect of the present invention provides a method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of an internal standard added to the test sample, wherein a reduced level of said cancer marker or derivative relative to the level of the internal standard is indicative of cancer. A fourth aspect of the present invention provides a method of diagnosing or detecting cancer in a human or non-human mammalian subject comprising determining the level of a cancer marker in a test sample from a subject suspected of having cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; relative to the level of another marker in the same test sample, wherein a change in the ratio of the cancer marker to the another marker is indicative of cancer. A fifth aspect of the present invention provides a method of monitoring cancer treatment in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject being treated for cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, the level established for a healthy subject, wherein an increased level is indicative of successful treatment. A sixth aspect of the present invention provides a method of diagnosing recurrence of cancer following successful treatment in a human or non-human mammalian subject comprising: (i) determining the level of a cancer marker in a test sample from a subject treated for cancer, said cancer marker comprising a negatively-charged molecule having a m/z ratio of about 991 or a derivative thereof; and (ii) comparing the level of the cancer marker or derivative at (i) to the level of the cancer marker or derivative in a control sample from a healthy subject, the level established for a healthy subject or the level in a sample from the subject following successfully treated for cancer, wherein a reduced level is indicative of recurrence of cancer. |
Electric connector for the motor of a hermetic compressor and its manufacturing process |
An electric connector for the motor of a hermetic compressor and its manufacturing process, said motor carrying in the stator (6) thereof a female connector (10) for electric connection and being mounted inside a shell (1) to which is affixed a power inlet plug (8) for connection to an external current supply source, said connector comprising an electric insulating body to be engaged to the female connector (10) and carrying: a plurality of binding posts (31) connecting and affixing a first end portion (21) of each respective conductor (20), which has a second end portion (22) to be connected to a power inlet plug (8) of the shell (1); and fixation means to be fitted into engagement receiving means provided in the female connector (10), in order to immobilize said parts against relative movements, said male connector (30) being obtained by over-injecting insulating material to each first end portion (21) of each conductor (20) connected to the insulating body of the male connector (30), in order to immobilize said conductors (20). |
1. An electric connector for the motor of a hermetic compressor, said motor carrying in the stator (6) thereof a female connector (10) for electric connection and being mounted inside a shell (1) to which is affixed a power inlet plug (8) for connection to an external current supply source, characterized in that it comprises an electric insulating body to be engaged to the female connector (10) and carrying: a plurality of binding posts (31) connecting and affixing a first end portion (21) of each respective conductor (20), which has a second end portion (22) to be connected to a power inlet plug (8) of the shell (1); and fixation means to be fitted into engagement receiving means provided in the female connector (10), in order to immobilize said parts against relative movements. 2. The connector according to claim 1, characterized in that the insulating body is in a single piece. 3. The connector according to claim 2, characterized in that the fixation means are defined by teeth (35) provided in the insulating body of the male connector (30) and which are resiliently deformed during the engagement of the male connector (30) to the female connector (10) and until each tooth (35) is engaged in a respective engagement receiving means provided in the female connector (10). 4. The connector according to claim 3, characterized in that the insulating body of the male connector (30) presents a prismatic form, with lateral walls (32) projecting from a rear wall (33), and with at least part of the confronting lateral walls thereof being provided with said teeth (35) and elastically deformable in the region where the respective teeth (35) are provided. 5. The connector according to claim 4, characterized in that the insulating body of the male connector (30) includes at least one internal wall (34) provided with a tooth (35). 6. The connector according to claim 5, characterized in that the insulating body of the male connector (30) includes a tooth (35) on each lateral wall (32) confronting with a respective internal wall (34). 7. The connector according to claim 1, characterized in that the engagement receiving means are windows produced in lateral walls of the body of the female connector (10). 8. The connector according to claim 1, characterized in that the insulating body of the male connector (30) includes retaining means that immobilize the first end portion of each conductor (20). 9. The connector according to claim 8, characterized in that the retaining means are defined by projections (36) provided from the rear wall (33) of the insulating body of the male connector (30), surrounding an adjacent portion of one of the lateral walls (32) of said insulating body. 10. A process for manufacturing an electric connector for the motor of a hermetic compressor, said motor carrying in the stator (6) thereof a female connector (10) for electric connection and being mounted inside a shell (1) to which is affixed a power inlet plug (8) for connection to an external current supply source, characterized in that it comprises the steps of: a—providing an electric insulating body carrying a plurality of binding posts (31) connecting and affixing a first end portion of each respective conductor (20), which has a second end portion to be connected to the power inlet plug (8) of the shell (1); b—mounting electric contact terminals of each conductor (20) to the binding posts (31) mounted to the electric insulating body of the male connector (30); and c—over-injecting an insulating material to each first end portion (21) of each conductor (20) connected to the insulating body of the male connector (30), in order to immobilize said conductors. 11. Process, according to claim 10, characterized in that the step “b” is carried out in a mold that receives an injection of plastic. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The motor of a hermetic compressor usually comprises, mounted inside its hermetic shell, a rotor and a stator, the latter being formed by a main coil and a secondary coil, said motor being fed by an electric current from a power source external to said hermetic shell, by connecting an appropriate wiring to a power inlet plug mounted external to the hermetic shell and which is electrically connected to the stator of the electric motor. In a known construction, in order to connect the stator to the power inlet plug of the hermetic shell, through the interior of the latter, some copper wires of the stator, generally three, are connected to a cable by clamping a metallic piece, which is exposed inside the compressor and joins each copper wire to the cable that is then connected to the shell. After clamping the two parts together, for each wire, the formed assembly receives a thermal retractile insulating cover that protects said connection thus obtained. After the connection, the whole assembly is positioned inside the coils that form the motor. This construction presents some disadvantages, such as difficult automation, for example in the clamping steps, which also results in low quality of the obtained electric connections, with a high number of defects and rejections, for example due to low efficiency of the desired connection and to failures in the manufacturing process of said connection. In this construction, there is a connection provided directly to the connector attached to the stator of the electric motor. In such solution, after fitting the cable to the connector attached to the stator, the assembly receives a metallic clamp that bites the cables to the connector. In order to effectively accomplish this type of connection, it is necessary to prevent the relative movement of the connected parts defined by the male connector and the female connector that is affixed to the stator. The relative movement existing between the attached parts allows fatigue of contacts to occur, which can increase the voltage drop in the connection region, or even cause rupture of said connection. Furthermore, the occurrence of movement may cause temperature increase at the connection region and a consequent short-circuit, resulting in general failure of the connection. Some known constructions that use a male connector and a female connector to make the contact between the electric motor and the power inlet plug of the hermetic shell have visible sharp metallic ends located inside the compressor and which can be energized. Such energized ends may attract metallic filings eventually existing inside the shell of the compressor and which may provoke short-circuit within the latter. In other known construction, the electric connections from the motor to the shell of the compressor occur through a male connector that presents a cover portion closing a bottom portion. In this construction, the fitting of the male connector to the female connector occurs with great relative movement between said parts, which is inherent to the construction of the connection itself. In this construction, the electric cable presents a connection that allows great relative movement between the connected parts. This construction presents a metallic male connecting terminal that only provides an electric contact to the female connector, with no fixation being made between the parts defined by the male connecting terminal and the female connector. In this construction, the male connecting terminal defines only a structure that carries the electric terminals of the supply cable, which does not impart rigidity to the male connector. The male connector of this construction presents two component parts, one of them being a bottom portion, on which are placed the electric terminals of the supply cable and which receives a closing portion to be locked on the bottom portion. Such construction presents fitting gaps between said fitted parts that allow the occurrence of relative movements and vibrations. In this construction, the male contacts are not rigidly attached inside the compressor in the stator, and this non-rigid fixation is what allows the relative movement to occur. On the other hand, the connection between the binding posts of both the male and female connectors do not present a steady fixation either, with said binding posts being only mutually fitted, which does not assure stability to the connection. The existence of movement permits the occurrence of voltage drop that generates temperature increase (to about 100° C.). Other disadvantage of the above-mentioned connection refers to the process in the assembly line. In order to carry out this assembly, the connectors should be perfectly aligned, so that their terminals are also perfectly aligned and contacting each other. Otherwise, the connection will not allow the desired contact to take place and, besides this fact, the connection may be damaged. In case of poor contact, problems such as vibrations and relative movements will also occur, as discussed above. |
<SOH> SUMMARY OF THE INVENTION <EOH>These and other objects are attained by a male connector for the motor of a hermetic compressor, said motor carrying in the stator thereof a female connector for electric connection, and being mounted inside a shell to which is affixed a power inlet plug for connection to an external current supply source, said male connector comprising an electric insulating body to be engaged to the female connector and carrying: a plurality of binding posts connecting and affixing a first end portion of each respective conductor, which has a second end portion to be connected to the power inlet plug of the shell; and fixation means to be fitted into engagement receiving means provided in the female connector, in order to immobilize said parts against relative movements. The male connector of the present invention is manufactured by a process comprising the steps of: a—providing an electric insulating body carrying a plurality of binding posts connecting and affixing a first end portion of each respective conductor, which has a second end portion to be connected to a power inlet plug of the shell; b—mounting electric contact terminals of each conductor to the binding posts mounted in the electric insulating body of the male connector; and c—over-injecting insulating material to each first end portion of each conductor connected to the insulating body of the male connector, in order to immobilize said conductors, with the step “b” being carried out in a mold that receives an injection of plastic. |
Safety device for a motor vehicle seat |
In order a safety device for a motor vehicle seat having a seat cushion part and a backrest, the backrest having a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel, and an airbag module is integrated into the backrest, said airbag module being arranged in that region of the backrest which faces the side wall structure of the motor vehicle in such a manner that an airbag is deployed when there is an impact between a driver and the side wall of the motor vehicle, said safety device ensuring a reliable and reproducible emergence of the airbag, it is proposed to arrange the airbag module to the rear of the backrest frame, when looking from the side wall of the motor vehicle. |
1. A safety device for a motor vehicle seat having a seat cushion part and a backrest, the backrest having a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel, and an airbag module is integrated into the backrest, said airbag module being arranged in that region of the backrest which faces the side wall structure of the motor vehicle in such a manner that an airbag is deployed when there is an impact between a driver and the side wall of the motor vehicle, wherein the frame at least partially surrounds the airbag module and the airbag module is arranged to the rear of the frame, when looking from the side wall structure of the motor vehicle. 2. The safety device as claimed in claim 1, wherein the airbag module has a housing which at least partially surrounds the airbag in the folded up state. 3. The safety device as claimed in claim 2, wherein the housing surrounds the airbag in its region which faces rearward, as seen in the direction of travel, and in the side regions. 4. The safety device as claimed in claim 3, wherein a plate is provided in the region in which the housing does not surround the airbag module. 5. The safety device as claimed in claim 4, wherein the plate is connected at least on one side to the frame. 6. The safety device as claimed in claim 5, wherein an airbag outlet opening b is provided between the frame and padding. 7. The safety device as claimed in claim 6, wherein the frames and padding are not connected to each other in the region of the airbag outlet opening. 8. The safety device as claimed in claim 7, wherein the padding is of elastic design in the region of the airbag outlet opening b in such a manner that it releases the outlet opening b when the airbag is deployed. 9. The safety device as claimed in claim 8, wherein the airbag outlet opening b is arranged in that region of the backrest which faces the side wall structure. 10. The safety device as claimed in claim 6, wherein the airbag outlet opening b is arranged in that region of the backrest which faces the side wall structure. 11. The safety device as claimed in claim 6, wherein the padding is of elastic design in the region of the airbag outlet opening b in such a manner that it releases the outlet opening b when the airbag is deployed. 12. The safety device as claimed in claim 1, wherein an airbag outlet opening b is provided between the frame and padding. 13. The safety device as claimed in claim 1, wherein a plate is provided in the region in which the housing does not surround the airbag module. 14. The safety device as claimed in claim 1, wherein the housing surrounds the airbag in its region which faces rearward, as seen in the direction of travel, and in the side regions. 15. A safety device for a motor vehicle seat including a seat cushion part, a backrest having a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel, the safety device comprising: an airbag module including an airbag, the airbag module being integrated into the backrest and arranged in a region of the backrest which faces a side wall structure of the motor vehicle, wherein the airbag module is at least partially surrounded the frame and is arranged to the rear of the frame when looking from the side wall structure of the motor vehicle. 16. The safety device as claimed in claim 15, wherein the airbag module includes a housing which at least partially surrounds the airbag when the airbag is in a folded-up state. 17. The safety device as claimed in claim 16, wherein the housing surrounds the airbag in a rear region and side regions of the airbag. 18. The safety device as claimed in claim 17, further comprising a plate in a region of the airbag that is not surrounded by the housing of the airbag module. 19. The safety device as claimed in claim 18, wherein the plate is connected at least on one side to the frame of the seat. 20. The safety device as claimed in claim 19, wherein an airbag outlet opening is provided between the frame and padding. 21. The safety device as claimed in claim 20, wherein the frames and padding are not connected to each other at the airbag outlet opening. 22. The safety device as claimed in claim 21, wherein the padding is of elastic design in a region of the airbag outlet opening in such a manner that it releases the outlet opening b when the airbag is deployed. 23. The safety device as claimed in claim 22, wherein the airbag outlet opening is arranged in the region of the backrest which faces the side wall structure. 24. A motor vehicle seat comprising a seat cushion part; a backrest including a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel, the safety device comprising; an airbag module including an airbag, the airbag module being integrated into the backrest and arranged in a region of the backrest which faces a side wall structure of the motor vehicle, wherein the airbag module is at least partially surrounded the frame and is arranged to the rear of the frame when looking from the side wall structure of the motor vehicle. 25. The motor vehicle seat as claimed in claim 24, wherein the airbag module includes a housing which at least partially surrounds the airbag when the airbag is in a folded-up state. 26. The motor vehicle seat as claimed in claim 25, wherein the housing surrounds the airbag in a rear region and side regions of the airbag. 27. The motor vehicle seat as claimed in claim 26, further comprising a plate in a region of the airbag that is not surrounded by the housing of the airbag module. 28. The motor vehicle seat as claimed in claim 27, wherein the plate is connected at least on one side to the frame. 29. The motor vehicle seat as claimed in claim 28, further comprising an airbag outlet opening between the frame and padding. 30. The motor vehicle seat as claimed in claim 29, wherein the frames and padding are not connected to each other at the airbag outlet opening. 31. The motor vehicle seat as claimed in claim 30, wherein the padding is of elastic design in a region of the airbag outlet opening in such a manner that it releases the outlet opening b when the airbag is deployed. 32. The motor vehicle seat as claimed in claim 31, wherein the airbag outlet opening is arranged in the region of the backrest which faces the side wall structure. 33. A method of making a safety device, comprising: integrating an airbag module into a region of a vehicle seat's backrest which faces a side wall structure of the motor vehicle; at least partially surrounding the airbag module with a frame of the backrest; and arranging the airbag module to the rear of the frame when looking from the side wall structure of the motor vehicle. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a safety device for a motor vehicle seat. Safety devices of this type are known, for example, from the utility model DE 200 17 919 U1. They are suitable for a motor vehicle seat having a seat cushion part and a backrest. The backrest has a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel. An airbag module is integrated into the backrest and is arranged in that region of the backrest which faces the side wall structure of the motor vehicle. The airbag is deployed when there is an impact between a driver and the side wall structure of the motor vehicle, for example the B-pillar and/or the side door. In the known safety device, the airbag module is arranged between the frame and the backrest cover, so that it is placed to the rear of the backrest cover and in front of the frame, as seen from the side wall structure. An airbag outlet opening is provided in the region in which the backrest cover and padding butt against each other. This known arrangement has the disadvantage that, if there is a side impact, structural parts penetrating the interior of the motor vehicle may jeopardize the interference-free emergence of the airbag. This situation may occur, for example, if the penetrating parts butt against the backrest cover and deform it, and the airbag outlet opening is thus concealed or the airbag module arranged to the rear of the backrest cover is damaged. Deformation of the backrest cover is possible, since the backrest cover serves to line the motor vehicle seat and is therefore not of sufficiently stable design. Against this background, it is the object of the present invention to develop a safety device in such a manner that reliable and reproducible emergence of the airbag is ensured. This object is achieved according to the invention by a safety device for a motor vehicle seat that includes a seat cushion part, a backrest having a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel. The safety device includes an airbag module that has an airbag, and the airbag module is integrated into the backrest and arranged in a region of the backrest which faces a side wall structure of the motor vehicle. The airbag module 11 is at least partially surrounded the frame 5 and is arranged to the rear of the frame 5 when looking from the side wall structure of the motor vehicle. Accordingly, the invention is distinguished by the fact that the airbag module is arranged, as seen from the side wall structure, to the rear of the backrest frame—i.e. to the rear of its supporting part in the backrest. The effect of this arrangement is that the airbag module is shielded against forces acting from the direction of the side wall structure. In addition, an airbag outlet opening can be effectively protected against penetrating structural parts and it can therefore be ensured that the opening is always free for an airbag to emerge. The backrest frame is preferably designed in such a manner that virtually no deformation occurs. In the event of a lateral application of force, the entire backrest together with the seat cushion part is rather displaced in the direction of the center of the motor vehicle than the frame is lastingly deformed. A backrest frame of this type can consist, for example, of magnesium diecasting. A further advantage of the invention can be seen in the fact that the construction is very simple because no additional measures are necessary in order to ensure that the airbag deploys reliably. On the contrary, existing parts of the backrest are used in order to bring this about. Accordingly, the arrangement according to the invention of the airbag module in the backrest ensures that the airbag is deployed or emerges considerably more reliably. According to one embodiment, the airbag module has a housing which at least partially surrounds the airbag, for example in the rear region and in the side regions. Since the housing does not completely surround the airbag module, it therefore has a relatively wide opening. This means that the housing provides a relatively small resistance to the deploying airbag thus assisting a reliable deployment. A plate can be provided in the region in which the housing does not surround the airbag module. This plate serves, on the one hand, to close the airbag housing and therefore to provide a certain protection in the inoperative state to the airbag components arranged in the housing. Furthermore, it serves to damp the first thrust of the deploying airbag, with the result that the airbag emerges at a moderate speed. Finally, the plate enables the airbag to emerge. When, during deployment, the airbag presses against the plate, the plate is bent up and pushes the backrest components, which join the plate, for example the padding, to the side. For this purpose, the plate is preferably arranged on that side of the frame which faces away from the outer contour of the seat that faces the side wall structure. The plate can be connected on one side fixedly to the frame of the backrest. When the airbag emerges, this fixed connection forms a hinge about which the plate moves. However, it is also conceivable for the plate to be connected directly to the airbag housing and for it to be pivoted open from this connection. The function of the plate may also be fulfilled by other components of the backrest. If, for example, the padding is arranged on a padding support, then it is conceivable for this padding support, which is likewise arranged between the padding and airbag module, to take over the closing, damping and opening. According to a further embodiment, the frame at least partially surrounds the airbag module. The frame preferably surrounds the airbag module in the regions in which the housing surrounds the airbag. This arrangement enables the airbag to be protected in a particularly reliable manner against actions from the outside—in particular from the rear and from the side, as a result of which damage to the airbag module is prevented, ensuring an interference-free deployment of the airbag. This arrangement is therefore particularly advantageous because no additional elements are necessary in order to achieve this protection. The airbag is simply arranged in structures which are already present. In addition, the frame can serve as a guiding device by being aligned in such a manner that it predetermines the direction of deployment. The outlet or the outlet opening for the airbag may be provided, for example, between the frame and padding. The material combination of a rigid frame and elastic padding, which are also coordinated with each other in terms of their shape, makes it possible for an outlet opening for an airbag to be provided in a particularly simple manner without the use of additional components. If the frame and padding are not connected to each other in the region of the outlet opening, the padding is deformed, during the deployment of the airbag, by the force which the airbag applies to it, and thereby releases the path for the emergence of the airbag. The arrangement according to the invention is visually attractive because the opening is not seen. In addition, neither seams nor other known closure elements are necessary. As a result, firstly, a simple and therefore also cost-effective solution is proposed. Secondly, elements which may obstruct the emergence of the airbag are not provided. The outlet opening may be arranged, for example, in that region of the motor vehicle seat which faces the side wall structure. If the direction of deployment points obliquely forward, a particularly advantageous positioning of the airbag arises during the deployment and in the deployed state. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a safety device for a motor vehicle seat. Safety devices of this type are known, for example, from the utility model DE 200 17 919 U1. They are suitable for a motor vehicle seat having a seat cushion part and a backrest. The backrest has a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel. An airbag module is integrated into the backrest and is arranged in that region of the backrest which faces the side wall structure of the motor vehicle. The airbag is deployed when there is an impact between a driver and the side wall structure of the motor vehicle, for example the B-pillar and/or the side door. In the known safety device, the airbag module is arranged between the frame and the backrest cover, so that it is placed to the rear of the backrest cover and in front of the frame, as seen from the side wall structure. An airbag outlet opening is provided in the region in which the backrest cover and padding butt against each other. This known arrangement has the disadvantage that, if there is a side impact, structural parts penetrating the interior of the motor vehicle may jeopardize the interference-free emergence of the airbag. This situation may occur, for example, if the penetrating parts butt against the backrest cover and deform it, and the airbag outlet opening is thus concealed or the airbag module arranged to the rear of the backrest cover is damaged. Deformation of the backrest cover is possible, since the backrest cover serves to line the motor vehicle seat and is therefore not of sufficiently stable design. Against this background, it is the object of the present invention to develop a safety device in such a manner that reliable and reproducible emergence of the airbag is ensured. This object is achieved according to the invention by a safety device for a motor vehicle seat that includes a seat cushion part, a backrest having a frame, a backrest cover, which faces rearward as seen in the direction of travel, and padding which faces forward, as seen in the direction of travel. The safety device includes an airbag module that has an airbag, and the airbag module is integrated into the backrest and arranged in a region of the backrest which faces a side wall structure of the motor vehicle. The airbag module 11 is at least partially surrounded the frame 5 and is arranged to the rear of the frame 5 when looking from the side wall structure of the motor vehicle. Accordingly, the invention is distinguished by the fact that the airbag module is arranged, as seen from the side wall structure, to the rear of the backrest frame—i.e. to the rear of its supporting part in the backrest. The effect of this arrangement is that the airbag module is shielded against forces acting from the direction of the side wall structure. In addition, an airbag outlet opening can be effectively protected against penetrating structural parts and it can therefore be ensured that the opening is always free for an airbag to emerge. The backrest frame is preferably designed in such a manner that virtually no deformation occurs. In the event of a lateral application of force, the entire backrest together with the seat cushion part is rather displaced in the direction of the center of the motor vehicle than the frame is lastingly deformed. A backrest frame of this type can consist, for example, of magnesium diecasting. A further advantage of the invention can be seen in the fact that the construction is very simple because no additional measures are necessary in order to ensure that the airbag deploys reliably. On the contrary, existing parts of the backrest are used in order to bring this about. Accordingly, the arrangement according to the invention of the airbag module in the backrest ensures that the airbag is deployed or emerges considerably more reliably. According to one embodiment, the airbag module has a housing which at least partially surrounds the airbag, for example in the rear region and in the side regions. Since the housing does not completely surround the airbag module, it therefore has a relatively wide opening. This means that the housing provides a relatively small resistance to the deploying airbag thus assisting a reliable deployment. A plate can be provided in the region in which the housing does not surround the airbag module. This plate serves, on the one hand, to close the airbag housing and therefore to provide a certain protection in the inoperative state to the airbag components arranged in the housing. Furthermore, it serves to damp the first thrust of the deploying airbag, with the result that the airbag emerges at a moderate speed. Finally, the plate enables the airbag to emerge. When, during deployment, the airbag presses against the plate, the plate is bent up and pushes the backrest components, which join the plate, for example the padding, to the side. For this purpose, the plate is preferably arranged on that side of the frame which faces away from the outer contour of the seat that faces the side wall structure. The plate can be connected on one side fixedly to the frame of the backrest. When the airbag emerges, this fixed connection forms a hinge about which the plate moves. However, it is also conceivable for the plate to be connected directly to the airbag housing and for it to be pivoted open from this connection. The function of the plate may also be fulfilled by other components of the backrest. If, for example, the padding is arranged on a padding support, then it is conceivable for this padding support, which is likewise arranged between the padding and airbag module, to take over the closing, damping and opening. According to a further embodiment, the frame at least partially surrounds the airbag module. The frame preferably surrounds the airbag module in the regions in which the housing surrounds the airbag. This arrangement enables the airbag to be protected in a particularly reliable manner against actions from the outside—in particular from the rear and from the side, as a result of which damage to the airbag module is prevented, ensuring an interference-free deployment of the airbag. This arrangement is therefore particularly advantageous because no additional elements are necessary in order to achieve this protection. The airbag is simply arranged in structures which are already present. In addition, the frame can serve as a guiding device by being aligned in such a manner that it predetermines the direction of deployment. The outlet or the outlet opening for the airbag may be provided, for example, between the frame and padding. The material combination of a rigid frame and elastic padding, which are also coordinated with each other in terms of their shape, makes it possible for an outlet opening for an airbag to be provided in a particularly simple manner without the use of additional components. If the frame and padding are not connected to each other in the region of the outlet opening, the padding is deformed, during the deployment of the airbag, by the force which the airbag applies to it, and thereby releases the path for the emergence of the airbag. The arrangement according to the invention is visually attractive because the opening is not seen. In addition, neither seams nor other known closure elements are necessary. As a result, firstly, a simple and therefore also cost-effective solution is proposed. Secondly, elements which may obstruct the emergence of the airbag are not provided. The outlet opening may be arranged, for example, in that region of the motor vehicle seat which faces the side wall structure. If the direction of deployment points obliquely forward, a particularly advantageous positioning of the airbag arises during the deployment and in the deployed state. |
Process to allow electrical and mechanical connection of an electrical device with a face equipped with contact pads |
A method of manufacturing an electrical device that is electrically and mechanically connectable to another electrical device, the electrical device having a face equipped with contact pads, wherein the method includes: a layer-application step in which an adhesive layer is applied on the face equipped with contact pads, the adhesive layer being composed of a substance with adhesive properties; an opening-creation step in which an opening is created through the adhesive layer at the level of a contact pad; an opening-filing step in which the opening is filled with a conductive material so that the opening is substantially filled with the conductive material so as to form a conductive path the volume of which is defined by the opening. |
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