Patent EA-000894-B1 (EA)
Title: substituted bicyclohexanecarboxylic acids and derivatives thereof as excitatory amino acid receptor antagonists, method for producing and use thereof
Inventor: DOMINGUEZ-FERNANDRZ CARMEN
IPC: A61P25/24
Filed: 1996-11-12
Abstract: 1. A compound of the formula   in which X represents a bond, S, O or NR<a>; and R represents a (1-4C) alkyl group or phenyl (1-4C) alkyl or diphenyl (1-4C) alkyl, in which phenyl ring is unsubstituted or substituted by one, two or three substituents selected independently from halogen, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) fluoroalkyl, (1-4C) fluoroalkoxy, phenyl, phenoxy, 3-trifluoromethylphenoxy and 4-chlorophenoxy; R<a> represents hydrogen or a group of formula (CO)nR<b>; n is O or 1; and R<b> is as defined for R; or a non-toxic metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in claim 1, in which R represents benzyl or diphenylmethyl in which any phenyl ring is unsubstituted or substituted as defined in claim 1. 3. A compound as claimed in claim 1, in which R represents methyl, phenylpropyl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,3-difluorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,5-difluorobenzyl, 3,4-difluorobenzyl, 2,3,4-trifluorobenzyl, 2-chlorobenzyl, 3-dichlorobenzyl, 4-chlorobenzyl, 2,3-dichlorobenzyl, 2-chloro-5-trifluoromethylbenzyl, 3-chloro-4-fluorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-fluoro-3-methylbenzyl, 3-fluoro-2-methylbenzyl, 3,5-dimethylbenzyl, 4-isopropylbenzyl, 2,4-dimethylbenzyl, 2,5-dimethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-fluoro-4-methoxybenzyl, 3-methyl-4-methoxybenzyl, 4-trifluoromethylbenzyl, 3-fluoro-5-trifluoromethylbenzyl, 3-trifluoromethoxybenzyl, 3-tetrafluoroethoxybenzyl, 4-phenylbenzyl, 3-phenoxybenzyl, 3-(3-trifluoromethyl-phenoxy)benzyl, 3-(4-chlorophenoxy)benzyl, and diphenylmethyl. 4. A compound as claimed in any one of claims 1 to 3, in which X represents a bond. 5. A compound as claimed in any one of claims 1 to 4, which has the stereochemistry shown below.   6. A process for the preparation of a compound of formula I which comprises  (a) hydrolyzing a compound of formula II   in which R<1> represents a hydrogen atom or an acyl group and R<2> represents a carboxyl group or an esterified carboxyl group, or a salt thereof;  (b) hydrolyzing a compound of formula III   in which R<3> represents a carboxyl group or an esterified carboxyl group, and R<4> and R<5> each independently represent a hydrogen atom, a (2-6C) alkanoyl group, a (1-4C) alkyl group, a (3-4C) alkanoyl group or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a salt thereof; or (c) deprotecting a compound of formula IV   in which R<6> represents a hydrogen atom or a nitrogen protecting group and each of R<7> and R<8> independently represent a hydrogen atom or a carboxyl protecting group, or a salt thereof;  whereafter, if necessary and/or desired  (i) resolving the compound of formula I; (ii) converting the compound of formula I into a non-toxic metabolically labile ester or amide thereof; and/or; (iii) converting the compound of formula I or a non-toxic metabolically labile ester or amide thereof into a pharmaceutically acceptable salt thereof. 8. A compound of formula    in which X and R are as defined in Claim 1, R<1> represents a hydrogen atom or an acyl group and R<2> represents a carboxyl group or an esterified carboxyl group, or a salt thereof. 9. A compound of formula    in which X and R are as defined in claim 1, R<3> represents a carboxyl group or an esterified carboxyl group, and R<4> and R<5> each independently represent a hydrogen atom, a (2-6C) alkanoyl group, a (1-4C) alkyl group, a (3-4C) alkanoyl group or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a salt thereof. 10. A compound of formula    in which X and R are as defined in claim 1, R<6> represents a hydrogen atom or a nitrogen protecting group and each of R<7> and R<8> independently represent a hydrogen atom or a carboxyl protecting group, or a salt thereof.