Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-09
1999-07-06
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548467, 548492, C07D20942, C07D40512, C07D40112, A61K 3140
Patent
active
059198117
DESCRIPTION:
BRIEF SUMMARY
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.
WO92/16205 describes 3-substituted 2-carboxyindole derivatives which are useful in the treatment of neurodegenerative diseases. WO92/21153 also describes novel 3-substituted 2-carboxyindole derivatives which are potent antagonists at the strychnine insensitive glycine binding site located on the N-methyl-D-aspartate (NMDA) receptor complex and hence useful in the treatment of neurodegeneative diseases.
We have now found a further novel group of 3-substituted 2-carboxyindole derivative that have a specific antagonist activity at the strychnine insensitive glycine binding site located upon the NMDA receptor complex coupled with an advantageous pharmacological profile of activity.
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.4 or COR.sub.4 wherein R.sub.4 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; aryl or heterocyclic group; attached represent a 5-7 membered heterocyclic ring which may contain an additional heteroatom selected from oxygen sulphur or nitrogen;
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 the compound of formula (I) is an optionally substituted ethenyl group there can exist cis(Z) and (E) trans isomers and the invention includes all such isomers and a mixture 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 include 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).
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 include 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. The types of ester grouping that may be used as metabolically labile esters are those widely used in pharmaceutical chemistry and are well known to those skilled in the art.
The term alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom examples of such groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
The term substituted alkyl refers to alkyl substituted by one or more hydroxy, aminocarbonyl, carboxyl or amino groups.
The term optionally substituted ethenyl means an ethenyl group
REFERENCES:
patent: 5145845 (1992-09-01), Johnson et al.
patent: 5373018 (1994-12-01), Cugola et al.
patent: 5374648 (1994-12-01), Cugola et al.
patent: 5374649 (1994-12-01), Cugola et al.
patent: 5519048 (1996-05-01), Salituro et al.
Conti Nadia
De Magistris Elisabetta
Di Fabio Romano
Feriani Aldo
Glaxo Wellcome S.p.A.
Kifle Bruck
Shah Mukund J.
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