Indian Patents. 210697:NOVEL PYRAZOLONE COMPOUND AND OPHTHALMIC PLASTIC LENS

Title of Invention	NOVEL PYRAZOLONE COMPOUND AND OPHTHALMIC PLASTIC LENS
Abstract	Provided are novel pyrazolone compounds which have excellent copolymerizability and undergo no elution in an organic solvent when used for an ophthalmic plastic lens and which have an excellent absorption peak in visible light region and function as a reactive yellow dye.

Full Text	SPECIFICATION " Novel Pyrazolone Compound and Ophthalmic Plastic Lens Using the Same The present invention relates to a novel pyrazolone compound, an ophthalmic plastic lens using it and a process for producing an ophthalmic plastic lens. More specifically, the present invention relates to a novel pyrazolone compound which has two functions, capability of reacting with a polymerizable monomer and capability of coloring an obtained polymer in yellow, and which is useful for coloring an ophthalmic plastic lens, an ophthalmic plastic lens using the above pyrazolone compound, particularly, an intraocular lens such as a soft intraocular lens which can be easily inserted through a small incision, and a process for efficiently producing the above ophthalmic plastic lens. A crystalline lens gets colored in yellow as people get old, and the color becomes denser. When the crystalline lens so-colored in yellow is removed, no filter effect works, and there appears a phenomenon that objects look bluish. This phenomenon is called "cyanopsia", and it is a cyanopsia-correcting intraocular lens colored in yellow that corrects the above phenomenon to bring the vision close to the normal vision. As the above cyanopsia-correcting intraocular lens, there has been used a hard lens made of polymethyl methacrylate (PMMA). In recent years, there has been developed a small incision operating method which aims at a simple operation. The present invention relates to a pyrazolone compound and an ophthalmic lens. More specifically, the present invention relates to a novel pyrazolone compound which has two functions, capability of reacting with a polymerizable monomer and capability of colouring an obtained polymer in yellow, and which is useful for coloring an ophthalmic plastic lens, an ophthalmic plastic lens using the above pyrazolone compound, particularly, an intraocular lens such as soft intraocular lens which can be easily inserted through a small incision, and a process for efficiently producing the above ophthalmic lens. A crystalline lens gets colored in yellow as people get old, and the color becomes denser. When the crystalline lens so-colored in yellow is removed, no filter effect works, and there appears a phenomenon that objects look bluish. This phenomenon is called "cyanopsia", and it is a cyanopsia-correcting intraocular lens colored in yellow that corrects the above phenomenon to bring the vision close to the normal vision. As the above cyanopsia-correcting intraocular lens, there has been used a hard lens made of polymethyl methacrylate (PMMA). In recent years there has been developed a small incision operating method which aims at a simple operation, _ structure is indispensable to ophthalmic lenses such as a hydrous contact lens and an oxygen-permeable hard contact lens, particularly to a soft intraocular lens. As a reactive ultraviolet absorbent, a variety of compounds have been developed from the viewpoint of absorption spectrum, solubility, reactivity and durability. However, as a reactive yellow dye, few compounds have been developed, or no satisfactory compound is available. For example, a compound of the formula (II) is known as a reactive yellow dye (JP-A-10-195324). The above compound is satisfactory in view of solubility in various monomers for lenses and copolymerizability therewith. However, the above compound has problems that it has a maximum absorption of spectrum in approximately 350 to 360 nm and that its molecular extinction coefficient is relatively small. That is, the above compound is insufficient in absorption of light in a region of from 400 nm to 500 nm, which absorption is considered effective for correcting cyanopsia. Another problem is that the amount of the above compound to be used is relatively large when it is used. In view of safety and the filter effect, there has been desired a reactive dye which exhibits a sufficient filter effect when a low concentration of it is added. This point is very important for a contact lens which is to come in contact with corneal mucosa and an intraocular lens which is to be implanted in an eye. Under the circumstances, it is an object of the present invention to provide a novel compound which is excellent in solubility in a monomer for a lens and copolymerizability with the monomer, which undergoes no elution during extraction with various solvents, which has an excellent absorption peak in a visible light region when used in an ophthalmic plastic lens and which works sufficiently in a small amount. It is another object of the present invention to provide an ophthalmic plastic lens, particularly an intraocular lens such as a soft intraocular lens, to which the above novel compound is applied. Further, it is another object of the present invention to provide a process for efficiently producing the above ophthalmic plastic lens. Disclosure of the Invention The present' inventor has made diligent studies to achieve the above objects and as a result has found that a compound having a specific structure can fulfill the above objects as a reactive yellow dye. It has been also found that an ophthalmic plastic lens, particularly, an intraocular lens such as a soft intraocular lens, can be efficiently produced by providing a polymerizable material containing the above compound and a monomer for a lens, polymerizing the polymerizable material by a specific method and optionally, cutting and polishing an obtained polymerizate. On the basis of the above findings, the present invention has been completed. That is, according to the present invention. there are provided; (1) A pyrazolone compound having the formula (1), wherein X is phenyl or 4-alkylphenyl, (2) an ophthalmic plastic lens formed by polymerizing a polymerizable material containing the pyrazolone compound of the above formula (I) and a monomer for lens, preferably, an intraocular lens comprising an optic portion including an essential portion formed of the pyrazolone compound of the above formula (I), particularly preferably a soft intraocular lens, (3) a process for the production of an ophthalmic plastic lens, which comprises casting a polymerizable material containing the pyrazolone compound of the above formula (I) and a monomer for a lens into a predetermined mold and polymerizing the polymerizable material, and (4) a process for the production of an ophthalmic plastic lens, which comprises casting a polymerizable material containing the pyrazolone compound of the formula (I) and a monomer for a lens into a central hollow portion of a hard polymer material shaped in the form of a doughnut, polymerizing the polymerizable material and then cutting and polishing a polymerizate integrated with said hard polymer material, to form a hard haptic portion and a soft Accordingly the present invention relates to a pyrazolone compound of formula (1) wherein X is phenyl or 4-alkylphenyl Accordingly the present invention also relates to an ophthalmic plastic intraocular lens obtainable by polymerization of a polymerizable material containing a pyrazolone compound of the formula (1), wherein X is phenyl or 4-alkylphenyl and a monomer selected from a linear or branched alkyl(meth)acrylates, hydrophilic monomers, silicon-containing monomers, and fluorine-containing monomers and casting said polymerization product in a known manner to produce the intraocular lens. wherein X is as defined above. First, methacryloyl chloride (III) and 3-amino-l-phenyl-2-pyra2oline-5-one (IV) are reacted in a solvent containing a hydrogen chloride scavenger or in a hydrogen chloride scavenging solvent such as anhydrous pyridine, to form l-phenyl-3-methacrylamide-5-pyra2olone (V). Then, the l-phenyl-3-methacrylamide-5-pyrazolone (V) is reacted with l-aryl-3-methyl-5-oxo-2-pyra2oline-4-carboaldehyde (VI) in the presence of an acid catalyst, whereby the compound of the formula (I) as an end product can be obtained. In the above reactions, a commercially available methacryloyl chloride is used as a raw material, and desirably, it is used upon distillation. The l-aryl-3-methyl-5-oxo-2-pyra2oline-4-carboaldehyde (VI) can be obtained by reacting l-aryl-3-methyl-2-pyrazoline-5-one with phosphorus oxychloride in dimethylformamide. The acid catalyst can be selected from organic acids such as alkyl-substituted benzenesulfonic acids typified by p-toluenesulfonic acid/ etc., and inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid. A solvent used for the reaction between the compounds (VI) and (V) includes alcohols typified by methanol/ ethanol, propanoic etc., diethyl ether, methylene chloride and 1,2-dichloromethane. These solvents may be used alone or in combination. The ophthalmic plastic lens of the present invention is a product produced by polymerizing a polymerizable material containing the pyrazolone compound of the formula (I) and a monomer for a lens. The product is preferably an intraocular lens, and it is particularly preferably a soft intraocular lens. Examples of the above monomer for a lens include linear or branched alkyl (meth)acrylates (the term '(meth)acrylate" refers to both of acrylate and methacrylate, and used in this sense hereinafter) such as methyl methacrylate, ethyl methacrylate, butyl (meth)acrylate, cyclohexyl methacrylate, lauryl (meth)acrylate/ ethylhexyl (meth)acrylate and phenylethyl (meth)acrylate; hydrophilic monomers typified by 2-hydroxyethyl methacrylate, N-vinylpyrrolidone, dimethylacrylamide and methacrylic acid; silicon-containing monomers typified by tris(trimethylsiloxy)silylpropyl (meth)acrylate, trimethylsiloxydimethylsilylpropyl (meth)acrylate and bis(trimethylsiloxy)methylsilylpropyl (meth)acrylate; and fluorine-containing monomers typified by trifluoroethyl (meth)acrylate, hexafluoroisopropyl (meth)acrylate, perfluorooctylethyloxypropylene (meth)acrylate. These monomers may be used alone or in combination. Further, there may be added (meth)acrylate of a dihydric or higher polyhydric alcohol as a crosslinking agent. The (meth)acrylate of a dihydric or higher polyhydric alcohol includes monomers typified by ethylene glycol di{meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate and trimethylolpropane tri(meth)acrylate• In the polymerizable material, the amount ratio of the pyrazolone compound of the formula (I)/the monomer for a lens is preferably 0,005/100 to 0.10/100 (w/w), particularly preferably 0.01/100 to 0.05/100 (w/w). The above polymerizable material may contain an ultraviolet absorbent and a polymerization initiator. As an ultraviolet absorbent, although not to be specially limited, any ultraviolet absorbent may be used so long as it does not undergo elution and bleeding-out. However, it is preferred to use an ultraviolet absorbent having a monomer structure. The ultraviolet absorbent having a monomer structure is preferably selected from benzotriazole ultraviolet absorbents such as compounds having the following formulae. and benzophenone ultraviolet absorbents such as 2-hydroxy-4-acryloyloxyethoxybenzophenone. These ultraviolet absorbents may be used alone or in combination. The amount of the ultraviolet absorbent based on the monomer for a lens is preferably 0.05 to 5.0 % by weighty particularly preferably 0.5 to 3.0 % by weight. The polymerization initiator is not critical, and it can be selected from generally known radical initiators, including peroxides such as lauroyl peroxide, bis(4-tert-butylcyclohexyl)peroxydicarbonate and l,l-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane, and azo compounds such as 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) and 2,2'-azobis[2-(2-imidazoline-2-yl)propane. Further, a photopolymerization initiator may be used. The amount of the polymerization initiator based on the monomer for a lens is preferably 0.05 to 2.0 % by weight, particularly preferably 0.1 to 0.8 % by weight. The method for producing the ophthalmic plastic lens of the present invention is not specially limited. However/ the ophthalmic plastic lens of the present invention can be efficiently produced according to the following process. The process of the present invention includes two embodiments. In a first method, the polymerizable material containing the pyrazolone compound of the formula (I) and the monomer for a lens and containing an ultraviolet absorbent and a polimerization initiator as required is cast into a shaping mold made, for example, of a metal, plastic or glass in the form of a rod, a plate, a lens, or the like, and the polymerizable material is polymerized by increasing the temperature thereof, preferably, stepwise continuously. In this case, oxygen, etc., in the polymerizable material is replaced with an inert gas such as nitrogen, argon or helium as required, and the mold is closed before the polymerization. An obtained polymerizate is cut and polished as required, to finish it in a lens form. In the above polymerization, the polymerization may be carried out with light such as ultraviolet light or visible light as required. In a second method, a hard polymer material is shaped in the form of a doughnut in advance, and the above polymerizable material is cast into a central hollow portion and polymerized in the same manner as in the above first method. Then, a polymerizate integrated with the above hard polymer material is cut and polished to form a hard haptic portion and a soft optic portion, whereby an ophthalmic plastic lens is produced. The above hard polymer material may be a colored product. In the ophthalmic plastic lens of the present invention, the lens or the optic portion may be modified to have a hydrophilic surface by plasma-treating it with oxygen or air and immersing it in a reducing bath such as an aqueous solution containing sodium thiosulfate. The thus-produced ophthalmic plastic lens of the present invention is not only colored in yellow but also free of bleeding-out a dye (compound of the formula (I)) and elution caused by a solvent. Further, it has a sufficient light absorption in a wavelength region of 400 to 500 nm and is remarkably useful as a cyanopsia-correcting lens. Examples The present invention will be explained more in detail with reference to Examples hereinafter, while the present invention shall not be limited by these Examples. Measuring machines, and the like used in Examples are as follows. Elemental analysis: CHN recorder MT-3 (Yanagimoto Seisakusho)• HPLC analysis: HPLC D-6100 system, supplied by Hitachi Ltd. Column: ODS-2 (5 microns) Infrared absorption spectrum: Fourier transform infrared spectrophotometer FT-700 (K.K. Horiba Seisakusho) Light transmittance factor and ultraviolet-visible light spectrum: Automatic spectrophotometer U-3210 (Hitachi Ltd.) Example 1 (Preparation of pyrazolone compound of the formula (I), reactive yellow dye) (1) Preparation of 3-methyl-5-oxo-l-phenyl-2-pyra20line-4-carboaldehyde (MPCA) 29 Grams of 3-methyl-l-phenyl-2-pyra2oline-5-one and 40 ml of dimethylformamide were charged into a 200-ml three-necked flask, stirred and cooled to 0°C in an ice-acetone bath. Then, 18.5 g of phosphorus oxychloride (POCI3) was placed in a dropping funnel, and while it was maintained at 10 to 20°C, it was dropwise added. After the addition, the mixture was heated for 1 hour, then, a reaction mixture was poured into 600 ml of ice water, and the mixture was allowed to stand for one day and night. A crystal was recovered by suction filtration, fully washed with water and dried to give the captioned compound. Yield: 65 %, Melting point: 178-180°C (documented value: 174-175°C). Corresponding other aldehyde derivatives were also prepared in the same manner as above. (2) Preparation of l-phenyl-3-methacrylamide-5- pyrazolone (PMAP) 17 Grams of l-phenyl-3-amino-5-pyrazolone and 100 ml of pyridine (anhydrous) were charged into a 300-ml three-necked flask, and the stirring of the mixture was initiated at room temperature. 21 Grams of methacryloyl chloride was placed in a dropping funnel and dropwise added to the above reaction mixture slowly. After the addition, the mixture was stirred for one day and night. The reaction mixture was poured into 500 ml of ice water, the resultant mixture was allowed to stand for one day and night, and a crystal was recovered by suction filtration, fully washed with water and recrystallized from ethanol, to give a captioned compound. Yield: 60 %, Melting point: 170°C (Reference document: UK Patent 875248). (3) Preparation of 4-(5-hydroxy-3-methyl-l- phenyl-4-pyrazolylmethylene)-3-methacrylamino-l-phenyl-2- pyrazoline-5-one (HMPO-H, compound of the formula (I) in which X is phenyl). 0,95 Gram of MPCA obtained in the above (1), 1.2 g of PMAP obtained in the above (2), 100 mg of p-toluenesulfonic acid monohydrate and 30 ml of an ethanol/methylene chloride mixture (weight ratio 4/6) were charged into a 50-ml egg plant type flask and stirred at room temperature for 24 hours. As the reaction proceeded, the reaction mixture became colored in yellow. An acid was neutralized with a sodium hydrogencarbonate aqueous solution, then, the solvent was removed with an evaporator, and a precipitated yellow solid was recovered by suction filtration, fully washed with water and then washed with methanol and hexane. The thus-obtained crystal was dissolved in dimethyl sulfoxide (DMSO), a small amount of water was added to re-precipitate the crystal, and the crystal was fully washed with water and hexane and then dried under reduced pressure to give a captioned compound. Yield: 90 %, Melting point: 243 - 246°C IR (KBr): 3255 cm-1 1666 cm-1 1614 cm-1 1587 cm-1. Elemental analysis: Calculated (as C24H21N5O3); C 67.44, H 4.95, N 16.38 % Found; C 67.54, H 5.05, N 16.46 % HPLC analysis (methanol/water = 9/1): RT 2.80 min. purity 99.5 % Fig. 1 shows ultraviolet-visible light absorption spectrum (dichloroethane). Other compounds of the formula (I) were also prepared in the same manner. The structures of these compounds are shown below. Example 2 (Production of ophthalmic plastic lens) A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP)/ 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of 2,2'-a2obisisobutyronitrile (AIBN) was provided. To the mixture were added 1.50 % by weight, based on the total amount of monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers, of the reactive yellow dye HMPO-H included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and theimally polymerized according to a predetermined polymerization program. The so-obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Fig. 2 shows the light transmittance curve. Example 3 (Production of ophthalmic plastic lens) To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.25 g of AIBN was added 0.015 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I),and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Example 4 (Production of ophthalmic plastic lens) A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers, of the reactive yellow dye HMPO-B included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and thermally polymerized according to a predetermined polymerization program. The so-obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-B which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Example 5 (Production of ophthalmic plastic lens) To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.25 g of a polymerization initiator [2,2'-azobis(2,4-dimethylvaleronitrile), trade names V-65, supplied by Wako Purechemicals K.K.] were added 1.0 % by weight, based on the monomer for a lens, of an ultraviolet absorbent CVPT and 0.015 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-M included in the compound of the formula (I), and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the HMPO-M which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Example 6 A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and thermally polymerized according to a predetermined polymerization program. The so-obtained lenses were plasma-treated with a plasma-treating machine (PA-IOOAT, supplied by Kyoto Denshi Keisoku K.K.) using oxygen as a reaction gas. Then, the lenses were immersed in a 0.5 % by weight of sodium thiosulfate aqueous solution for 1.5 hours at 50°C. The lenses had surfaces remarkably excellent in wettability with water. Further, like the lenses obtained in Example 2, the lenses were free from the elution with any of the solvents used in Example 2, and the solvents were measured for ultraviolet-visible light absorption spectrum, to show no change. Example 7 To a mixture of 98 g of methyl methacrylate (MMA) with 2 g of ethylene glycol dimethacrylate (EDMA) were added 0.03 % by weight, based on the total amount of the monomers, of a reactive blue dye AQ-1 of the formula to be described later and 0.2 % by weight, based on the total amount of the monomer, of AIBN, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was charged into a tube made of polyethylene having a size of 20 mm x 20 cm, and the tube was closed. Then, the polymerizable material was polymerized according to a predetermined temperature program. The resultant polymerizate was cut in the form of a 7 mm-thick button, a portion located within 3 mm from the center of the button-shaped product was removed, to give a doughnut-shaped button made of polymethyl methacrylate (PMMA). Then, a mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM- 5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight/ based on the total amount of the monomers for a lenS, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lenS, of the reactive yellow dye HMPO-H, and the resultant mixture was fully stirred/ to obtain a polymerizable material. The polymerizable material was added to the central portion of the above-prepared doughnut-shaped button made of PMMA/ and thermally polymerized according to a predetermined polymerization program. The resultant polymerizate had a central portion (diameter 3 mm) formed of a soft material colored in yellow and a circumferential portion formed of a hard material colored in blue. Then/ the polymerizate was cut and polished in the form of an intraocular lenS/ to give a one-piece soft intraocular lens having an optic portion formed of a soft yellow material and a haptic portion formed of PMMA. The obtained lens was measured for a light transmittance to show a remarkably excellent light transmittance curve. AQ-1: Comparative Example 1 (Production of comparative ophthalmic lens) A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.7 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers for a lens, of a non-reactive yellow dye MYSG (C.I. Solvent Yellow 93). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was charged into a PP resin mold designed for producing an intraocular lens optical portion and polymerized according to a predetermined polymerization program. Obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). As a result, the elution of the yellow dye was intense, or the elution rate thereof was 100 % in hexane, 60 % in methanol and 30 % in acetone. Fig. 3 shows a light transmittance curve of the obtained lens. Comparative Example 2 (Production of comparative ophthalmic lens) A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.2 % by weight, based on the total amount of the monomers for a lens, of a reactive yellow dye VBCP-o having a formula to be described later. The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was charged into a PP resin mold designed for producing an intraocular lens optical portion, and polymerized according to a predetermined polymerization program. Obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, each solvent was measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the yellow dye was not found in any solvent. However, it was required to add the yellow dye in an amount 10 times as large as the amount of the reactive dye of the present invention for imparting the lens with a yellow color effective for correcting cyanopsia. Fig. 4 shows a light transmittance curve of the obtained lens. VBCP-o Comparative Example 3 (Production of comparative ophthalmic lens) To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.21 g of a polymerization initiator V-65 were added 1.0 % by weight, based on the monomer, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the monomer, of a non-reactive yellow dye MY3G, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Each solvent was measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the yellow dye was intense, or the elution rate thereof was 90 % in acetone, 70 % in methanol and 20 % in hexane. Example 8 (Production of ophthalmic plastic lens) To a mixture of 32 g of n-butyl acrylate (n-BA), 60 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 3 g of ethylene glycol dimethacrylate (EDMA) and 0.3 g of AIBN was added 0.150 % by weight, based on the total amount of monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I), and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into gasket made of polypropylene having a diameter of 15 mm and height of 15 mm, then, heat-sealed and thermally polymerized. The polymerization program was as follows. First the mixture was maintained at 40°C for 10 minutes and then temperature-elevated to 60°C in 40 minutes. Thereafter it was maintained at 60°C for 4 hours and temperature-elevated to 80°C in one hour, and it was maintained at the same temperature for 2 hours. After that, it was temperature-elevated to 100°C in one hour and maintained at the same temperature for 2 hours. Finally it was temperature-elevated to 120°C in one hour and maintained at the same temperature for 2 hours. After that, it was cooled slowly to 30°C in six hours to give a polymerizate having the form of button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Example 9 To a mixture of 90 g of methyl methacrylate (MMA), 10 g of n-butyl anylate (n-BA) and 2 g of ethylene glycol dimethacrylate (EDMA) were added 0.06 % by weight, based on the total amount of the monomers, of a reactive blue dye AQ-1 of the formula to be described above and 0.3 % by weighty based on the total amount of the monomer, of AIBN, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was charged into a tube made of polyethylene having a size of 20 mm X 20 cm, and the tube was closed. Then, the polymerizable material was polymerized according to a predetermined temperature program. That is, the tube in which the polymerizable material was contained was maintained at 40°C for 4 hours and then temperature-elevated to 60°C in 4 hours and maintained at the same temperature for 8 hours. After that, it was temperature-elevated to llO°C in 10 hours and maintained at the same temperature for 8 hours. Finally it was slowly cooled to 40°C in 20 hours to obtain a polymerizate for haptic portion. The resultant polymerizate was cut in the form of a 7 mm-thick button, a portion located within 3 mm from the center of the button-shaped product was removed, to give a doughnut-shaped button. Then, a mixture containing 32 g of n-butyl aerylate (n-BA), 60 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 3 g of ethylene glycol dimethacrylate (EDMA) and 0.3 g of AIBN was provided. To the mixture were added 0.15 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lens, of the reactive yellow dye HMPO-H, and the resultant mixture was fully stirred, to obtain a polymerizable material. The polymerizable material was added to the central portion of the above-prepared doughnut-shaped button, and thermally polymerized according to the polymerization program as described in Example 8. The resultant polymerizate had a central portion (diameter 3 mm) formed of a soft material colored in yellow and a circumferential portion formed of a hard material colored in blue. Then, the polymerizate was cut and polished in the form of an intraocular lens, to give a one-piece soft intraocular lens having an optic portion formed of a soft yellow material and a haptic portion formed of PMMA. The obtained lens was measured for a light transmittance to show a remarkably excellent light transmittance curve, as shown in Fig. 5. The pyrazolone compound of the formula (I) provided by the present invention is a reactive yellow dye which has excellent copolymerizability and which exhibits excellent absorption spectrum in a region of 400 to 500 nm in a small amount. Therefore, the ophthalmic plastic lens of the present invention, obtained by polymerizing a polymerizable material containing the above pyrazolone compound and a monomer for a lens is colored in yellow and is free from the elusion of the yellow dye in an organic solvent, so that it is remarkably useful for an intraocular lens, particularly for a cyanopsia-correcting soft intraocular lens. To sum up, according to present invention, there can be provided an ophthalmic plastic lens remarkably excellent in view of function and safety. WE CLAIM: 1. A pyrazolone compound of the formula (I), wherein X is phenyl or 4-alkylphenyl. 2. The pyrazolone compound as claimed in claim 1, wherein the 4-alkylphenyl is p-tolyl, 4-ethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-isobutylphenyl, 4-sec-butylphenyl or 4-tert-butylphenyl 3. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) exhibits keto-enol tautomerism. 4. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) has solubility in, and copolymerizability with, a monomer for a lens. 5. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) is a reactive yellow dye having light absorption spectrum in a region of 400 to 500 nm. 6. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) is substantially free from elution with a solvent when used for an ophthalmic plastic lens. 7. An ophthalmic plastic intraocular lens obtainable by polymerization of a polymerizable material containing a pyrazolone compound of the formula (1), wherein X is phenyl or 4-alkylphenyl and a monomer selected from a linear or branched alkyl(meth)acrylates, hydrophilic monomers, silicon-containing monomers, and fluorine-containing monomers and casting said polymerization product in a known manner to produce the intraocular lens. 8. The ophthalmic plastic lens as claimed in claim 7, wherein the intraocular lens is a soft intraocular lens. 9. The ophthalmic plastic lens as claimed in claim 7, wherein the intraocular lens is a cyanopsia-correcting intraocular lens. 10. The ophthalmic plastic lens as claimed in claim 7, wherein the polymerizable material contains the pyrazolone compound of the formula (I) and the monomer for a lens in a pyrazolone compound/monomer amount ratio of 0.005/100 to 0.10/100 w/w. 11. The ophthalmic plastic lens as claimed in claim 7, wherein the polymerizable material contains an ultraviolet absorbent and a polymerization initiator. 12. The ophthalmic plastic lens as claimed in claim 11, wherein the ultraviolet absorbent has a monomer structure. 13. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerizable material contains the ultraviolet absorbent in an amount of 0.05 to 5.0 % by weight based on the monomer for a lens. 14. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerization initiator is a radical-generating agent selected from a peroxide or a diazo compound or a photopolymerization initiator. 15. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerizable material contains the polymerization initiator in an amount of 0.05 to 2.0 % by weight based on the monomer for a lens. 16. The ophthalmic plastic lens as claimed in claim 7, wherein the ophthalmic plastic lens substantially does not cause elution of the pyrazolone compound of the formula (I), an ultraviolet absorbent and a polymerization initiator and has light absorption spectrum in a region of 400 to 500 nm. 17. The ophthalmic plastic lens as claimed in claim 7, wherein the lens or its optic portion is modified to have a hydrophilic surface by plasma-treating the lens or the optic portion with oxygen or air and immersing it in a reducing bath. 18. A pyrazolone compound of the formula (I) substantially as herein described and exemplified. 19. An ophthalmic plastic intraocular lens substantially as herein described and exemplified.

Full Text

SPECIFICATION "
Novel Pyrazolone Compound and Ophthalmic Plastic Lens Using the Same

The present invention relates to a novel pyrazolone compound, an ophthalmic plastic lens using it and a process for producing an ophthalmic plastic lens. More specifically, the present invention relates to a novel pyrazolone compound which has two functions, capability of reacting with a polymerizable monomer and capability of coloring an obtained polymer in yellow, and which is useful for coloring an ophthalmic plastic lens, an ophthalmic plastic lens using the above pyrazolone compound, particularly, an intraocular lens such as a soft intraocular lens which can be easily inserted through a small incision, and a process for efficiently producing the above ophthalmic plastic lens.

A crystalline lens gets colored in yellow as people get old, and the color becomes denser. When the crystalline lens so-colored in yellow is removed, no filter effect works, and there appears a phenomenon that objects look bluish. This phenomenon is called "cyanopsia", and it is a cyanopsia-correcting intraocular lens colored in yellow that corrects the above phenomenon to bring the vision close to the normal vision. As the above cyanopsia-correcting intraocular lens, there has been used a hard lens made of polymethyl methacrylate (PMMA).
In recent years, there has been developed a small incision operating method which aims at a simple operation.

The present invention relates to a pyrazolone compound and an ophthalmic lens. More specifically, the present invention relates to a novel pyrazolone compound which has two functions, capability of reacting with a polymerizable monomer and capability of colouring an obtained polymer in yellow, and which is useful for coloring an ophthalmic plastic lens, an ophthalmic plastic lens using the above pyrazolone compound, particularly, an intraocular lens such as soft intraocular lens which can be easily inserted through a small incision, and a process for efficiently producing the above ophthalmic lens.
A crystalline lens gets colored in yellow as people get old, and the color becomes denser. When the crystalline lens so-colored in yellow is removed, no filter effect works, and there appears a phenomenon that objects look bluish. This phenomenon is called "cyanopsia", and it is a cyanopsia-correcting intraocular lens colored in yellow that corrects the above phenomenon to bring the vision close to the normal vision. As the above cyanopsia-correcting intraocular lens, there has been used a hard lens made of polymethyl methacrylate (PMMA).
In recent years there has been developed a small incision operating method which aims at a simple operation, _

structure is indispensable to ophthalmic lenses such as a hydrous contact lens and an oxygen-permeable hard contact lens, particularly to a soft intraocular lens.
As a reactive ultraviolet absorbent, a variety of compounds have been developed from the viewpoint of absorption spectrum, solubility, reactivity and durability. However, as a reactive yellow dye, few compounds have been developed, or no satisfactory compound is available.
For example, a compound of the formula (II) is known as a reactive yellow dye (JP-A-10-195324).

The above compound is satisfactory in view of solubility in various monomers for lenses and copolymerizability therewith. However, the above compound has problems that it has a maximum absorption of spectrum in approximately 350 to 360 nm and that its molecular extinction coefficient is relatively small. That is, the above compound is insufficient in absorption of light in a region of from 400 nm to 500 nm, which absorption is considered effective for correcting cyanopsia. Another problem is that the amount of the above compound to be used is relatively large when it is used.
In view of safety and the filter effect, there has been desired a reactive dye which exhibits a sufficient filter effect when a low concentration of it is added. This point is very important for a contact lens which is to

come in contact with corneal mucosa and an intraocular lens which is to be implanted in an eye.
Under the circumstances, it is an object of the present invention to provide a novel compound which is excellent in solubility in a monomer for a lens and copolymerizability with the monomer, which undergoes no elution during extraction with various solvents, which has an excellent absorption peak in a visible light region when used in an ophthalmic plastic lens and which works sufficiently in a small amount.
It is another object of the present invention to provide an ophthalmic plastic lens, particularly an intraocular lens such as a soft intraocular lens, to which the above novel compound is applied.
Further, it is another object of the present invention to provide a process for efficiently producing the above ophthalmic plastic lens.
Disclosure of the Invention
The present' inventor has made diligent studies to achieve the above objects and as a result has found that a compound having a specific structure can fulfill the above objects as a reactive yellow dye. It has been also found that an ophthalmic plastic lens, particularly, an intraocular lens such as a soft intraocular lens, can be efficiently produced by providing a polymerizable material containing the above compound and a monomer for a lens, polymerizing the polymerizable material by a specific method and optionally, cutting and polishing an obtained polymerizate. On the basis of the above findings, the present invention has been completed.
That is, according to the present invention.

there are provided;
(1) A pyrazolone compound having the formula (1),

wherein X is phenyl or 4-alkylphenyl,
(2) an ophthalmic plastic lens formed by
polymerizing a polymerizable material containing the
pyrazolone compound of the above formula (I) and a monomer
for lens, preferably, an intraocular lens comprising an
optic portion including an essential portion formed of the
pyrazolone compound of the above formula (I), particularly
preferably a soft intraocular lens,
(3) a process for the production of an ophthalmic plastic lens, which comprises casting a polymerizable material containing the pyrazolone compound of the above formula (I) and a monomer for a lens into a predetermined mold and polymerizing the polymerizable material, and
(4) a process for the production of an ophthalmic plastic lens, which comprises casting a polymerizable material containing the pyrazolone compound of the formula (I) and a monomer for a lens into a central hollow portion of a hard polymer material shaped in the form of a doughnut, polymerizing the polymerizable material and then cutting and polishing a polymerizate integrated with said hard polymer material, to form a hard haptic portion and a soft

Accordingly the present invention relates to a pyrazolone compound of formula
(1)
wherein X is phenyl or 4-alkylphenyl

Accordingly the present invention also relates to an ophthalmic plastic intraocular lens obtainable by polymerization of a polymerizable material containing a pyrazolone compound of the formula (1),

wherein X is phenyl or 4-alkylphenyl and a monomer selected from a linear or branched alkyl(meth)acrylates, hydrophilic monomers, silicon-containing monomers, and fluorine-containing monomers and casting said polymerization product in a known manner to produce the intraocular lens.

wherein X is as defined above.
First, methacryloyl chloride (III) and 3-amino-l-phenyl-2-pyra2oline-5-one (IV) are reacted in a solvent containing a hydrogen chloride scavenger or in a hydrogen chloride scavenging solvent such as anhydrous pyridine, to form l-phenyl-3-methacrylamide-5-pyra2olone (V). Then, the l-phenyl-3-methacrylamide-5-pyrazolone (V) is reacted with l-aryl-3-methyl-5-oxo-2-pyra2oline-4-carboaldehyde (VI) in the presence of an acid catalyst, whereby the compound of the formula (I) as an end product can be obtained.
In the above reactions, a commercially available methacryloyl chloride is used as a raw material, and desirably, it is used upon distillation. The l-aryl-3-methyl-5-oxo-2-pyra2oline-4-carboaldehyde (VI) can be obtained by reacting l-aryl-3-methyl-2-pyrazoline-5-one with phosphorus oxychloride in dimethylformamide.
The acid catalyst can be selected from organic

acids such as alkyl-substituted benzenesulfonic acids typified by p-toluenesulfonic acid/ etc., and inorganic acids such as sulfuric acid, hydrochloric acid and phosphoric acid. A solvent used for the reaction between the compounds (VI) and (V) includes alcohols typified by methanol/ ethanol, propanoic etc., diethyl ether, methylene chloride and 1,2-dichloromethane. These solvents may be used alone or in combination.
The ophthalmic plastic lens of the present invention is a product produced by polymerizing a polymerizable material containing the pyrazolone compound of the formula (I) and a monomer for a lens. The product is preferably an intraocular lens, and it is particularly preferably a soft intraocular lens.
Examples of the above monomer for a lens include linear or branched alkyl (meth)acrylates (the term '(meth)acrylate" refers to both of acrylate and methacrylate, and used in this sense hereinafter) such as methyl methacrylate, ethyl methacrylate, butyl (meth)acrylate, cyclohexyl methacrylate, lauryl (meth)acrylate/ ethylhexyl (meth)acrylate and phenylethyl (meth)acrylate; hydrophilic monomers typified by 2-hydroxyethyl methacrylate, N-vinylpyrrolidone, dimethylacrylamide and methacrylic acid; silicon-containing monomers typified by tris(trimethylsiloxy)silylpropyl (meth)acrylate, trimethylsiloxydimethylsilylpropyl (meth)acrylate and bis(trimethylsiloxy)methylsilylpropyl (meth)acrylate; and fluorine-containing monomers typified by trifluoroethyl (meth)acrylate, hexafluoroisopropyl (meth)acrylate, perfluorooctylethyloxypropylene (meth)acrylate. These monomers may be used alone or in combination. Further, there may be added (meth)acrylate of

a dihydric or higher polyhydric alcohol as a crosslinking agent. The (meth)acrylate of a dihydric or higher polyhydric alcohol includes monomers typified by ethylene glycol di{meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate and trimethylolpropane tri(meth)acrylate•
In the polymerizable material, the amount ratio of the pyrazolone compound of the formula (I)/the monomer for a lens is preferably 0,005/100 to 0.10/100 (w/w), particularly preferably 0.01/100 to 0.05/100 (w/w).
The above polymerizable material may contain an ultraviolet absorbent and a polymerization initiator. As an ultraviolet absorbent, although not to be specially limited, any ultraviolet absorbent may be used so long as it does not undergo elution and bleeding-out. However, it is preferred to use an ultraviolet absorbent having a monomer structure. The ultraviolet absorbent having a monomer structure is preferably selected from benzotriazole ultraviolet absorbents such as compounds having the following formulae.

and benzophenone ultraviolet absorbents such as 2-hydroxy-4-acryloyloxyethoxybenzophenone. These ultraviolet absorbents may be used alone or in combination. The amount of the ultraviolet absorbent based on the monomer for a lens is preferably 0.05 to 5.0 % by weighty particularly preferably 0.5 to 3.0 % by weight.
The polymerization initiator is not critical, and it can be selected from generally known radical initiators, including peroxides such as lauroyl peroxide, bis(4-tert-butylcyclohexyl)peroxydicarbonate and l,l-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane, and azo compounds such as 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) and 2,2'-azobis[2-(2-imidazoline-2-yl)propane. Further, a photopolymerization initiator may be used. The amount of the polymerization initiator based on the monomer for a lens is preferably 0.05 to 2.0 % by weight, particularly preferably 0.1 to 0.8 % by weight.
The method for producing the ophthalmic plastic lens of the present invention is not specially limited.

However/ the ophthalmic plastic lens of the present invention can be efficiently produced according to the following process.
The process of the present invention includes two embodiments. In a first method, the polymerizable material containing the pyrazolone compound of the formula (I) and the monomer for a lens and containing an ultraviolet absorbent and a polimerization initiator as required is cast into a shaping mold made, for example, of a metal, plastic or glass in the form of a rod, a plate, a lens, or the like, and the polymerizable material is polymerized by increasing the temperature thereof, preferably, stepwise continuously. In this case, oxygen, etc., in the polymerizable material is replaced with an inert gas such as nitrogen, argon or helium as required, and the mold is closed before the polymerization. An obtained polymerizate is cut and polished as required, to finish it in a lens form. In the above polymerization, the polymerization may be carried out with light such as ultraviolet light or visible light as required.
In a second method, a hard polymer material is shaped in the form of a doughnut in advance, and the above polymerizable material is cast into a central hollow portion and polymerized in the same manner as in the above first method. Then, a polymerizate integrated with the above hard polymer material is cut and polished to form a hard haptic portion and a soft optic portion, whereby an ophthalmic plastic lens is produced. The above hard polymer material may be a colored product.
In the ophthalmic plastic lens of the present invention, the lens or the optic portion may be modified to have a hydrophilic surface by plasma-treating it with

oxygen or air and immersing it in a reducing bath such as an aqueous solution containing sodium thiosulfate.
The thus-produced ophthalmic plastic lens of the present invention is not only colored in yellow but also free of bleeding-out a dye (compound of the formula (I)) and elution caused by a solvent. Further, it has a sufficient light absorption in a wavelength region of 400 to 500 nm and is remarkably useful as a cyanopsia-correcting lens.
Examples
The present invention will be explained more in detail with reference to Examples hereinafter, while the present invention shall not be limited by these Examples.
Measuring machines, and the like used in Examples are as follows.
Elemental analysis: CHN recorder MT-3 (Yanagimoto Seisakusho)•
HPLC analysis: HPLC D-6100 system, supplied by Hitachi Ltd.
Column: ODS-2 (5 microns)
Infrared absorption spectrum: Fourier transform infrared spectrophotometer FT-700 (K.K. Horiba Seisakusho)
Light transmittance factor and ultraviolet-visible light spectrum: Automatic spectrophotometer U-3210 (Hitachi Ltd.)
Example 1 (Preparation of pyrazolone compound of the
formula (I), reactive yellow dye)
(1) Preparation of 3-methyl-5-oxo-l-phenyl-2-pyra20line-4-carboaldehyde (MPCA)
29 Grams of 3-methyl-l-phenyl-2-pyra2oline-5-one

and 40 ml of dimethylformamide were charged into a 200-ml three-necked flask, stirred and cooled to 0°C in an ice-acetone bath. Then, 18.5 g of phosphorus oxychloride (POCI3) was placed in a dropping funnel, and while it was maintained at 10 to 20°C, it was dropwise added. After the addition, the mixture was heated for 1 hour, then, a reaction mixture was poured into 600 ml of ice water, and the mixture was allowed to stand for one day and night. A crystal was recovered by suction filtration, fully washed with water and dried to give the captioned compound. Yield: 65 %, Melting point: 178-180°C (documented value: 174-175°C).
Corresponding other aldehyde derivatives were also prepared in the same manner as above.
(2) Preparation of l-phenyl-3-methacrylamide-5-
pyrazolone (PMAP)
17 Grams of l-phenyl-3-amino-5-pyrazolone and 100 ml of pyridine (anhydrous) were charged into a 300-ml three-necked flask, and the stirring of the mixture was initiated at room temperature. 21 Grams of methacryloyl chloride was placed in a dropping funnel and dropwise added to the above reaction mixture slowly. After the addition, the mixture was stirred for one day and night. The reaction mixture was poured into 500 ml of ice water, the resultant mixture was allowed to stand for one day and night, and a crystal was recovered by suction filtration, fully washed with water and recrystallized from ethanol, to give a captioned compound. Yield: 60 %, Melting point: 170°C (Reference document: UK Patent 875248).
(3) Preparation of 4-(5-hydroxy-3-methyl-l-
phenyl-4-pyrazolylmethylene)-3-methacrylamino-l-phenyl-2-
pyrazoline-5-one (HMPO-H, compound of the formula (I) in

which X is phenyl).
0,95 Gram of MPCA obtained in the above (1), 1.2 g of PMAP obtained in the above (2), 100 mg of p-toluenesulfonic acid monohydrate and 30 ml of an ethanol/methylene chloride mixture (weight ratio 4/6) were charged into a 50-ml egg plant type flask and stirred at room temperature for 24 hours. As the reaction proceeded, the reaction mixture became colored in yellow. An acid was neutralized with a sodium hydrogencarbonate aqueous solution, then, the solvent was removed with an evaporator, and a precipitated yellow solid was recovered by suction filtration, fully washed with water and then washed with methanol and hexane. The thus-obtained crystal was dissolved in dimethyl sulfoxide (DMSO), a small amount of water was added to re-precipitate the crystal, and the crystal was fully washed with water and hexane and then dried under reduced pressure to give a captioned compound. Yield: 90 %, Melting point: 243 - 246°C
IR (KBr): 3255 cm-1 1666 cm-1 1614 cm-1 1587 cm-1. Elemental analysis:
Calculated (as C24H21N5O3); C 67.44, H 4.95, N 16.38 %
Found; C 67.54, H 5.05, N 16.46 % HPLC analysis (methanol/water = 9/1): RT 2.80 min. purity 99.5 %
Fig. 1 shows ultraviolet-visible light absorption spectrum (dichloroethane).
Other compounds of the formula (I) were also prepared in the same manner. The structures of these compounds are shown below.

Example 2 (Production of ophthalmic plastic lens)
A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP)/ 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of 2,2'-a2obisisobutyronitrile (AIBN) was provided. To the mixture were added 1.50 % by weight, based on the total amount of monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers, of the reactive yellow dye HMPO-H included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and theimally polymerized according to a predetermined polymerization program. The so-obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve. Fig. 2

shows the light transmittance curve.
Example 3 (Production of ophthalmic plastic lens)
To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.25 g of AIBN was added 0.015 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I),and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve.
Example 4 (Production of ophthalmic plastic lens)
A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by

weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers, of the reactive yellow dye HMPO-B included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and thermally polymerized according to a predetermined polymerization program. The so-obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-B which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve.
Example 5 (Production of ophthalmic plastic lens)
To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.25 g of a polymerization initiator [2,2'-azobis(2,4-dimethylvaleronitrile), trade names V-65, supplied by Wako Purechemicals K.K.] were added 1.0 % by weight, based on the monomer for a lens, of an ultraviolet absorbent CVPT and 0.015 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-M included in the compound of the formula (I), and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was

cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the HMPO-M which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve.
Example 6
A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was placed in a PP resin mold designed for producing an intraocular lens optic portion, and thermally polymerized according to a

predetermined polymerization program. The so-obtained lenses were plasma-treated with a plasma-treating machine (PA-IOOAT, supplied by Kyoto Denshi Keisoku K.K.) using oxygen as a reaction gas. Then, the lenses were immersed in a 0.5 % by weight of sodium thiosulfate aqueous solution for 1.5 hours at 50°C. The lenses had surfaces remarkably excellent in wettability with water. Further, like the lenses obtained in Example 2, the lenses were free from the elution with any of the solvents used in Example 2, and the solvents were measured for ultraviolet-visible light absorption spectrum, to show no change.
Example 7
To a mixture of 98 g of methyl methacrylate (MMA) with 2 g of ethylene glycol dimethacrylate (EDMA) were added 0.03 % by weight, based on the total amount of the monomers, of a reactive blue dye AQ-1 of the formula to be described later and 0.2 % by weight, based on the total amount of the monomer, of AIBN, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was charged into a tube made of polyethylene having a size of 20 mm x 20 cm, and the tube was closed. Then, the polymerizable material was polymerized according to a predetermined temperature program. The resultant polymerizate was cut in the form of a 7 mm-thick button, a portion located within 3 mm from the center of the button-shaped product was removed, to give a doughnut-shaped button made of polymethyl methacrylate (PMMA).
Then, a mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-

5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by weight/ based on the total amount of the monomers for a lenS, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lenS, of the reactive yellow dye HMPO-H, and the resultant mixture was fully stirred/ to obtain a polymerizable material. The polymerizable material was added to the central portion of the above-prepared doughnut-shaped button made of PMMA/ and thermally polymerized according to a predetermined polymerization program. The resultant polymerizate had a central portion (diameter 3 mm) formed of a soft material colored in yellow and a circumferential portion formed of a hard material colored in blue. Then/ the polymerizate was cut and polished in the form of an intraocular lenS/ to give a one-piece soft intraocular lens having an optic portion formed of a soft yellow material and a haptic portion formed of PMMA. The obtained lens was measured for a light transmittance to show a remarkably excellent light transmittance curve. AQ-1:

Comparative Example 1 (Production of comparative ophthalmic lens)
A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.7 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the total amount of the monomers for a lens, of a non-reactive yellow dye MYSG (C.I. Solvent Yellow 93). The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was charged into a PP resin mold designed for producing an intraocular lens optical portion and polymerized according to a predetermined polymerization program. Obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). As a result, the elution of the yellow dye was intense, or the elution rate thereof was 100 % in hexane, 60 % in methanol and 30 % in acetone. Fig. 3 shows a light transmittance curve of the obtained lens.
Comparative Example 2 (Production of comparative ophthalmic lens)
A mixture containing 42 g of n-butyl acrylate (n-BA), 52 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 5 g of ethylene glycol dimethacrylate (EDMA) and 0.33 g of AIBN was provided. To the mixture were added 1.5 % by

weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent T-150 and 0.2 % by weight, based on the total amount of the monomers for a lens, of a reactive yellow dye VBCP-o having a formula to be described later. The resultant mixture was fully stirred with passing nitrogen gas, to obtain a polymerizable material. The polymerizable material was charged into a PP resin mold designed for producing an intraocular lens optical portion, and polymerized according to a predetermined polymerization program. Obtained lenses were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 lenses were immersed in methanol, 10 lenses were immersed in acetone and 10 lenses were immersed in hexane). Then, each solvent was measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the yellow dye was not found in any solvent. However, it was required to add the yellow dye in an amount 10 times as large as the amount of the reactive dye of the present invention for imparting the lens with a yellow color effective for correcting cyanopsia. Fig. 4 shows a light transmittance curve of the obtained lens. VBCP-o

Comparative Example 3 (Production of comparative ophthalmic lens)

To a mixture of 70 g of 2-hydroxyethyl methacrylate (HEMA) with 0.21 g of a polymerization initiator V-65 were added 1.0 % by weight, based on the monomer, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the monomer, of a non-reactive yellow dye MY3G, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was cast into a gasket made of polyethylene having a diameter of 15 mm and a height of 15 mm, then, heat-sealed and thermally polymerized at 60°C for 12 hours, at 90°C for 3 hours and at 100°C for 12 hours, to give a polymerizate having the form of a button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Each solvent was measured for ultraviolet-visible light absorption spectrum. As a result, the elution of the yellow dye was intense, or the elution rate thereof was 90 % in acetone, 70 % in methanol and 20 % in hexane.
Example 8 (Production of ophthalmic plastic lens)
To a mixture of 32 g of n-butyl acrylate (n-BA), 60 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 3 g of ethylene glycol dimethacrylate (EDMA) and 0.3 g of AIBN was added 0.150 % by weight, based on the total amount of monomers for a lens, of an ultraviolet absorbent T-150 and 0.02 % by weight, based on the monomer for a lens, of the reactive yellow dye HMPO-H included in the compound of the formula (I), and the resultant mixture was fully

stirred to obtain a polymerizable material. The polymerizable material was cast into gasket made of polypropylene having a diameter of 15 mm and height of 15 mm, then, heat-sealed and thermally polymerized. The polymerization program was as follows. First the mixture was maintained at 40°C for 10 minutes and then temperature-elevated to 60°C in 40 minutes. Thereafter it was maintained at 60°C for 4 hours and temperature-elevated to 80°C in one hour, and it was maintained at the same temperature for 2 hours. After that, it was temperature-elevated to 100°C in one hour and maintained at the same temperature for 2 hours. Finally it was temperature-elevated to 120°C in one hour and maintained at the same temperature for 2 hours. After that, it was cooled slowly to 30°C in six hours to give a polymerizate having the form of button. The polymerizate was cut to a thickness of 1 mm, and the thus-prepared pieces were immersed in each of 10 ml of methanol, 10 ml of acetone and 10 ml of hexane at room temperature for 72 hours (10 pieces were immersed in methanol, 10 pieces were immersed in acetone and 10 pieces were immersed in hexane). Then, the solvents were measured for ultraviolet-visible light absorption spectrum. As a result, the elusion of the HMPO-H which was a yellow dye was not found in any solvent. Further, the obtained lenses were measured for a light transmittance to show a remarkably excellent light transmittance curve.
Example 9
To a mixture of 90 g of methyl methacrylate (MMA), 10 g of n-butyl anylate (n-BA) and 2 g of ethylene glycol dimethacrylate (EDMA) were added 0.06 % by weight, based on the total amount of the monomers, of a reactive blue dye

AQ-1 of the formula to be described above and 0.3 % by weighty based on the total amount of the monomer, of AIBN, and the resultant mixture was fully stirred to obtain a polymerizable material. The polymerizable material was charged into a tube made of polyethylene having a size of 20 mm X 20 cm, and the tube was closed. Then, the polymerizable material was polymerized according to a predetermined temperature program.
That is, the tube in which the polymerizable material was contained was maintained at 40°C for 4 hours and then temperature-elevated to 60°C in 4 hours and maintained at the same temperature for 8 hours. After that, it was temperature-elevated to llO°C in 10 hours and maintained at the same temperature for 8 hours. Finally it was slowly cooled to 40°C in 20 hours to obtain a polymerizate for haptic portion. The resultant polymerizate was cut in the form of a 7 mm-thick button, a portion located within 3 mm from the center of the button-shaped product was removed, to give a doughnut-shaped button.
Then, a mixture containing 32 g of n-butyl aerylate (n-BA), 60 g of phenylethyl methacrylate (PEMA), 8 g of perfluorooctylethyloxypropylene methacrylate (HRM-5131HP), 3 g of ethylene glycol dimethacrylate (EDMA) and 0.3 g of AIBN was provided. To the mixture were added 0.15 % by weight, based on the total amount of the monomers for a lens, of an ultraviolet absorbent CVPT and 0.02 % by weight, based on the total amount of the monomers for a lens, of the reactive yellow dye HMPO-H, and the resultant mixture was fully stirred, to obtain a polymerizable material. The polymerizable material was added to the central portion of the above-prepared doughnut-shaped

button, and thermally polymerized according to the polymerization program as described in Example 8. The resultant polymerizate had a central portion (diameter 3 mm) formed of a soft material colored in yellow and a circumferential portion formed of a hard material colored in blue. Then, the polymerizate was cut and polished in the form of an intraocular lens, to give a one-piece soft intraocular lens having an optic portion formed of a soft yellow material and a haptic portion formed of PMMA. The obtained lens was measured for a light transmittance to show a remarkably excellent light transmittance curve, as shown in Fig. 5.
The pyrazolone compound of the formula (I) provided by the present invention is a reactive yellow dye which has excellent copolymerizability and which exhibits excellent absorption spectrum in a region of 400 to 500 nm in a small amount. Therefore, the ophthalmic plastic lens of the present invention, obtained by polymerizing a polymerizable material containing the above pyrazolone compound and a monomer for a lens is colored in yellow and is free from the elusion of the yellow dye in an organic solvent, so that it is remarkably useful for an intraocular lens, particularly for a cyanopsia-correcting soft intraocular lens. To sum up, according to present invention, there can be provided an ophthalmic plastic lens remarkably excellent in view of function and safety.

WE CLAIM:
1. A pyrazolone compound of the formula (I),

wherein X is phenyl or 4-alkylphenyl.
2. The pyrazolone compound as claimed in claim 1, wherein the 4-alkylphenyl is p-tolyl, 4-ethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-isobutylphenyl, 4-sec-butylphenyl or 4-tert-butylphenyl
3. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) exhibits keto-enol tautomerism.
4. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) has solubility in, and copolymerizability with, a monomer for a lens.
5. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) is a reactive yellow dye having light absorption spectrum in a region of 400 to 500 nm.
6. The pyrazolone compound as claimed in claim 1, wherein the compound of the formula (I) is substantially free from elution with a solvent when used for an ophthalmic plastic lens.

7. An ophthalmic plastic intraocular lens obtainable by polymerization of a
polymerizable material containing a pyrazolone compound of the formula (1),

wherein X is phenyl or 4-alkylphenyl and a monomer selected from a linear or branched alkyl(meth)acrylates, hydrophilic monomers, silicon-containing monomers, and fluorine-containing monomers and casting said polymerization product in a known manner to produce the intraocular lens.
8. The ophthalmic plastic lens as claimed in claim 7, wherein the intraocular lens is a soft intraocular lens.
9. The ophthalmic plastic lens as claimed in claim 7, wherein the intraocular lens is a cyanopsia-correcting intraocular lens.

10. The ophthalmic plastic lens as claimed in claim 7, wherein the polymerizable material contains the pyrazolone compound of the formula (I) and the monomer for a lens in a pyrazolone compound/monomer amount ratio of 0.005/100 to 0.10/100 w/w.
11. The ophthalmic plastic lens as claimed in claim 7, wherein the polymerizable material contains an ultraviolet absorbent and a polymerization initiator.
12. The ophthalmic plastic lens as claimed in claim 11, wherein the ultraviolet absorbent has a monomer structure.

13. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerizable
material contains the ultraviolet absorbent in an amount of 0.05 to 5.0 % by weight
based on the monomer for a lens.
14. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerization
initiator is a radical-generating agent selected from a peroxide or a diazo compound or
a photopolymerization initiator.
15. The ophthalmic plastic lens as claimed in claim 11, wherein the polymerizable
material contains the polymerization initiator in an amount of 0.05 to 2.0 % by weight
based on the monomer for a lens.
16. The ophthalmic plastic lens as claimed in claim 7, wherein the ophthalmic plastic lens substantially does not cause elution of the pyrazolone compound of the formula (I), an ultraviolet absorbent and a polymerization initiator and has light absorption spectrum in a region of 400 to 500 nm.
17. The ophthalmic plastic lens as claimed in claim 7, wherein the lens or its optic portion is modified to have a hydrophilic surface by plasma-treating the lens or the optic portion with oxygen or air and immersing it in a reducing bath.

18. A pyrazolone compound of the formula (I) substantially as herein described and exemplified.
19. An ophthalmic plastic intraocular lens substantially as herein described and exemplified.

Documents:

251-mas-2000-abstract.pdf

251-mas-2000-claims filed.pdf

251-mas-2000-claims grand.pdf

251-mas-2000-correspondence other.pdf

251-mas-2000-correspondence po.pdf

251-mas-2000-declaration complete.pdf

251-mas-2000-description complete filed.pdf

251-mas-2000-description complete grand.pdf

251-mas-2000-drawings.pdf

251-mas-2000-form 1.pdf

251-mas-2000-form 3.pdf

251-mas-2000-other documents.pdf

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Patent Number

210697

Indian Patent Application Number

251/MAS/2000

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

08-Oct-2007

Date of Filing

03-Apr-2000

Name of Patentee

M/S. HOYA HEALTHCARE CORPORATION

Applicant Address

5-1 NISHI-SHINJUKU 6-CHOME SHINJUKU-KU TOKYO 160-0023 JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	HIDETOSHI IWAMOTO	HOYA HEALTHCARE CORPORATION,5-1 NISHI-SHINJUKU 6-CHOME,SHINJUKU-KU,TOKYO 160-0023,JAPAN

PCT International Classification Number

C07D 23 1/52

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	H11-99685	1999-04-07	Japan