# US 4,393,228 A · Epoxysuccinic acid derivatives > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 4,393,228 A - Document ID: US4393228A - Status: Granted - Kind: A - Application number: 05/880,180 - Filed: 1978-02-22 - Granted: 1983-07-12 - Earliest claimed: 1977-03-03 - Assignees: Taisho Pharmaceutical Co., Ltd. - Inventors: Jiro Sawada; Kazunori Hanada; Masaharu Tamai; Shigeo Morimoto; Sadafumi Omura - Web page: https://patentgrep.com/patent/US4393228A ## CPC - C07D 303/48: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## 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. ## Claims ### Claim 1 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. ### Claim 2 (depends on 1) A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each --O--A.sup.1 --R.sup.4 wherein A.sup.1 is alkylene containing zero to 4 carbon atoms or said alkylene substituted with methyl, and R.sup.4 is cycloalkyl containing 3 to 10 carbon atoms, or said cycloalkyl substituted with one to 3 halogen or methyl. ### Claim 3 (depends on 1) A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each --O--A.sup.2 --R.sup.5 wherein A.sup.2 is alkylene containing 2 or 3 carbon atoms or alkenylene containing 2 or 3 carbon atoms, and R.sup.5 is phenyl. ### Claim 4 (depends on 1) A compound according to claim 1 wherein R.sup.1 and R.sup.2 are each --OCH.sub.2 --R.sup.6 wherein 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. ### Claim 5 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --O--A.sup.1 --R.sup.4 and R.sup.2 is hydroxy wherein A.sup.1 is alkylene containing zero to 4 carbon atoms or said alkylene substituted with methyl, and R.sup.4 is cycloalkyl containing 3 to 10 carbon atoms, or said cycloalkyl substituted with one to 3 halogen or methyl. ### Claim 6 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --O--A.sup.2 --R.sup.5 and R.sup.2 is hydroxy wherein A.sup.2 is alkylene containing 2 or 3 carbon atoms or alkenylene containing 2 or 3 carbon atoms, and R.sup.5 is phenyl. ### Claim 7 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --OCH.sub.2 --R.sup.6 and R.sup.2 is hydroxy wherein --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. ### Claim 8 (depends on 1) A compound according to claim 1 wherein R.sup.1 is allyloxy, propargyloxy or benzyloxy and R.sup.2 is hydroxy. ### Claim 9 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --O--A.sup.1 --R.sup.4 and R.sup.2 is R.sup.8 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, 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 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 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. ### Claim 10 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --O--A.sup.2 --R.sup.5 and R.sup.2 is R.sup.8 wherein A.sup.2 is alkylene containing 2 or 3 carbon atoms or alkenylene containing 2 or 3 carbon atoms, R.sup.5 is phenyl, 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 alkylide 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 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. ### Claim 11 (depends on 1) A compound according to claim 1 wherein R.sup.1 is --OCH.sub.2 --R.sup.6 and R.sup.2 is R.sup.8 wherein 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 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 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 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. ### Claim 12 (depends on 1) A compound according to claim 1 wherein R.sup.1 is R.sup.7 and R.sup.2 is R.sup.8 wherein 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 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 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. ### Claim 13 (depends on 1) A compound according to claim 1 wherein R.sup.1 is hydroxy and R.sup.2 is R.sup.8 wherein 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 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 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. ### Claim 14 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.