Indole derivatives

Details Indole derivatives Indole derivatives

1996-03-29

1998-06-02

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514404, 514380, 514392, 514414, 546201, 548243, 5483121, 5483647, 548468, A61K 3140, A61K 31445, C07D40106, C07D41306

Patent

active

057600597

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/03359 filed Oct. 12, 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. 4960786 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 discloses resulting from neurotoxic damage or neurodegenerative 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 con the N-methyl-D-aspartate (NMDA) receptor complex.
Accordingly the present invention provides a compound of formula (I) ##STR2## or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO.sub.2 R.sub.2 or COR.sub.2 wherein R.sub.2 represents hydroxy, methoxy, amino, alkylamino, or dialkylamino; m is zero or an integer 1 or 2; heterocyclic or optionally substituted phenyl or fused bicyclic carbocylic group; Y(CH.sub.2).sub.q wherein Y is O, selected from C.sub.1-6 alkyl optionally substituted by hydroxy, amino, alkylamino or dialkylamino, or which chains may be substituted by the group .dbd.O; 1, 2 or3.
The compound represented by formula (I) can exist in more than one isomeric form and all possible is are included in formula (I) unless otherwise specified. Thus in compounds of formula (I) the exocyclic double bond can exist in the cis or trans configuration and the invention includes both 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 salts, 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).
Suitable acid addition salts may be formed with organic acid and inorganic acids e.g. hydrochloric acid.
The compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
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 esterificaton of the carboxylic acid group 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 t-butyl esters esters, C.sub.3-6 alkenyl esters e.g. allyl substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholin)ethyl esters or acyloxyalkyl esters such as, acyloxymethyl or 1-acylo

REFERENCES:
patent: 5145845 (1992-09-01), Johnson et al.
patent: 5256673 (1993-10-01), Bottcher et al.
patent: 5334606 (1994-08-01), MacLeod
patent: 5418237 (1995-05-01), Bottcher et al.
patent: 5532241 (1996-07-01), Bottcher et al.

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