Indole derivatives

Details Indole derivatives Indole derivatives

1995-09-18

1997-11-11

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514413, 514419, 514278, 514305, 514409, 546133, 548491, 548455, 548407, 548408, C07D45302, A61K 3144

Patent

active

056864612

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 filing of PCT/EP94/00614, filed Mar. 3, 1994. This invention relates to novel indole derivatives to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular it relates to indole derivatives which are potent and specific antagonists of excitatory amino acids.
U.S. Pat. No. 4,960,786 discloses that certain known 2-carboxylic indole derivatives are antagonists of excitatory amino acids. EP-A 0396124 also teaches certain 2-carboxylic indole derivatives as being therapeutically effective in the treatment of CNS disorders resulting from neurotoxic damage or neuredegenerative diseases. Further 3-substituted-2-carboxyindole derivatives which are useful in the treatment of neurodegenerative diseases including cerebrovasular disorders are disclosed in WO92/16205.
We have now found a novel group of 3-substituted-2-carboxyindole derivatives that have a specific antagonist activity at the strychnine insensitive glycine binding site located on the NMDA receptor complex.
Accordingly the present invention provides a compound of formula (I). ##STR2## or a salt, or metabolically labile ester thereof wherein R.sub.1 represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO.sub.2 R.sub.3 or COR.sub.3 wherein R.sub.3 represents hydroxy, methoxy, or amino; m is zero or an integer 1 or 2;
A represents an ethynyl group or an optionally substituted ethenyl group;
X represents a bond or a C.sub.1-4 alkylene chain;
R.sub.2 represents a bridged cycloalkyl or bridged heterocyclic group.
The compounds represented by formula (I) can exist in more than one isomeric form and all possible isomers are included in formula (I). Thus when the group A in compounds of formula (I) is an optionally substituted ethenyl group there can exist cis (Z) and trans (E) isomers and the invention includes all such isomers and mixtures thereof.
For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore unless otherwise stated references to salts includes both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
Suitable physiologically acceptable salts of compounds of the invention include base addition salts and where appropriate acid addition salts. Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium, calcium, and magnesium, and ammonium salts formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
It will be appreciated that the compound of formula (I) may be produced in vivo by metabolism of a suitable prodrug. Such prodrugs may be for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with where appropriate prior protection of any other reactive groups present in the molecule followed by deprotection if required. Examples of such metabolically labile esters include C.sub.1-4 alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl esters) or acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-methoxy-1-methyl-ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxycarbony

REFERENCES:
patent: 4960786 (1990-10-01), Salituro et al.
patent: 5218123 (1993-06-01), Horwell et al.
patent: 5284862 (1994-02-01), Bigge et al.
patent: 5519048 (1996-05-01), Salituro et al.

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