Epoxysuccinic acid derivatives
AssigneeTaisho Pharmaceutical Co., Ltd.
InventorsJiro Sawada, Kazunori Hanada, Masaharu Tamai, Shigeo Morimoto, Sadafumi Omura
Life of this patent
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Abstract
The epoxysuccinic acid derivatives of this invention are prepared by esterification of an epoxysuccinic acid or a halide thereof, by partial hydrolysis of an epoxysuccinic acid diester, by amidation of an epoxysuccinic acid monoester, or by hydrolysis of an epoxysuccinic acid amide monoester. These epoxysuccinic acid derivatives have excellent thiol protease inhibitory activity and anti-inflammatory activity without the acceleration of vascular permeability.
Claims14
Trans-epoxysuccinic acid derivatives represented by the general formula ##STR3## wherein (1) R.sup.1 and R.sup.2 are each R.sup.3 wherein R.sup.3 is --O--A.sup.1 --R.sup.4, --O--A.sup.2 --R.sup.5 or --OCH.sub.2 --R.sup.6 wherein A.sup.1 is alkylene containing zero to 4 carbon atoms or said alkylene substituted with methyl, R.sup.4 is cycloalkyl containing 3 to 10 carbon atoms, or said cycloalkyl substituted with one to 3 halogen or methyl, A.sup.2 is alkylene containing 2 or 3 carbon atoms, or alkenylene containing 2 or 3 carbon atoms, R.sup.5 is phenyl, R.sup.6 is furyl, tetrahydrofuryl, thienyl, naphthyl, naphthyl substituted with one or two halogen or methyl, phenyl substituted with one to three halogen, methyl, methoxy, methylenedioxy or trifluoromethyl, or cycloalkenyl containing 5 to 8 carbon atoms, or
- (2) R.sup.1 is hydroxy, R.sup.3 or R.sup.7, and R.sup.2 is hydroxy or R.sup.8 wherein R.sup.3 is as defined above, R.sup.7 is alkoxy containing one to 12 carbon atoms, allyloxy, propargyloxy, phenoxy or benzyloxy, and R.sup.8 is an amino acid residue represented by the general formula
- --NH--A.sup.3 --COR.sup.9
- wherein A.sup.3 is methylene, ethylene, trimethylene, alkylidene containing 2 to 5 carbon atoms or said alkylides substituted with one to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl substituted with hydroxy or halogen, indazolyl, imidazolyl, --COR.sup.10 or --NHR.sup.11 wherein R.sup.10 is amino or --OR.sup.12 wherein R.sup.12 is hydrogen, alkyl containing one to 5 carbon atoms, benzyl or an alkali metal cation, and R.sup.11 is hydrogen, formyl, alkoxycarbonyl containing 2 to 5 carbon atoms, benzyloxycarbonyl, methoxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted by nitro, and R.sup.9 is amino or --OR.sup.13 wherein R.sup.13 is hydrogen, alkyl containing one to 5 carbon atoms, benzyl or an alkali metal cation, with the proviso that R.sup.1 is neither hydroxy, alkoxy containing one to 12 carbon atoms, nor phenoxy when R.sup.2 is hydroxy, and salts thereof when R.sup.1 or R.sup.2 is hydroxy.
Trans-epoxysuccinic acid derivatives represented by the general formula ##STR4## wherein (1) R.sup.1 and R.sup.2 are each R.sup.3 wherein R.sup.3 is --O--A.sup.1 --R.sup.4, --O--A.sup.2 --R.sup.5 or --OCH.sub.2 --R.sup.6 wherein A.sup.1 is alkylene containing zero to 4 carbon atoms or said alkylene substituted with methyl, R.sup.4 is cycloalkyl containing 3 to 10 carbon atoms, or said cycloalkyl substituted with one to 3 halogen or methyl, A.sup.2 is alkylene containing 2 or 3 carbon atoms, or alkenylene containing 2 or 3 carbon atoms, R.sup.5 is phenyl, R.sup.6 is furyl, tetrahydrofuryl, thienyl, naphthyl, naphthyl substituted with one or two halogen or methyl, or phenyl substituted with one to three halogen, methyl, methoxy, methylenedioxy or trifluoromethyl, or cycloalkenyl containing 5 to 8 carbon atoms, or
- (2) R.sup.1 is hydroxy or R.sup.3 and R.sup.2 is hydroxy or R.sup.8 wherein R.sup.3 is as defined above, and R.sup.8 is an amino acid residue represented by the formula
- --NH--A.sup.3 --COR.sup.9
- wherein A.sup.3 is methylene, ethylene, trimethylene, alkylidene, containing 2 to 5 carbon atoms or said alkylidene substituted with one to 3 hydroxy, methyl, thiol, methylthio, benzylthio, phenyl, phenyl substituted with hydroxy or halogen, indazolyl, imidazolyl, --COR.sup.10 or --NHR.sup.11 wherein R.sup.10 is amino or --OR.sup.12 wherein R.sup.12 is hydrogen, alkyl containing one to 5 carbon atoms, benzyl or an alkyl metal cation, and R.sup.11 is hydrogen, formyl, alkoxycarbonyl containing 2 to 5 carbon atoms, benzyloxycarbonyl, methyloxybenzyloxycarbonyl, tosyl, guanyl, or guanyl substituted by nitro, and R.sup.9 is amino or --OR.sup.13 wherein R.sup.13 is hydrogen, alkyl containing one to 5 carbon atoms, benzyl or an alkali metal cation, with the proviso that R.sup.1 is not hydroxy when R.sup.2 is hydroxy, and salts thereof when R.sup.1 or R.sup.2 is hydroxy.
Dependencies are inferred from the claim text.