Piperidineacetic acid derivatives useful as fibrinogen antagonis

Details Piperidineacetic acid derivatives useful as fibrinogen antagonis Piperidineacetic acid derivatives useful as fibrinogen antagonis

1997-05-29

1999-01-19

Huang, Evelyn

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546187, 546199, A61K 31445, G07D40104, C07D40114

Patent

active

058614141

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/EP95/05043, filed on Dec. 21, 1995, published as WO 96/20192 on Jul. 4, 1996.
This invention relates to acetic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine.
It is widely accepted that the glycoprotein complex Gp IIb/IIIa is the fibrinogen binding site on platelets that mediates the adhesive function required for platelet aggregation and thrombus formation. We have now found a group of non-peptidic compounds which inhibit fibrinogen-dependent platelet aggregation by blocking the binding of fibrinogen to the putative fibrinogen receptor Gp IIb/IIIa complex.
The invention thus provides the compounds of formula (I) ##STR2## and pharmaceutically acceptable derivatives thereof, in which: X represents either CH.sub.2 --CH.sub.2 or CH.dbd.CH; and group is optionally substituted by one or more halogen atoms (where halogen represents fluorine, chlorine, bromine or iodine).
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates) and inorganic base salts such as alkali metal salts (for example sodium salts).
Other salts of the compounds of formula (I) include salts formed with trifluoroacetic acid.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds. Of particular interest as such derivatives are compounds modified at the carboxyl function.
Thus compounds of interest include carboxylic acid esters of the compounds of formula (I). Examples of such esters include C.sub.1-6 alkyl esters.
It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position
It will be further appreciated by those skilled in the art that carboxylic acid ester derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (I), or both.
The term `alkyl` as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
Preferably X represents CH.dbd.CH.
Preferably Y represents a hydrogen atom.
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Compounds in which X represents CH.dbd.CH in the (E) configuration are particularly preferred.
Preferred compounds of the invention are: eridin-1-yl}-acetic acid, and pharmaceutically acceptable derivatives thereof; acid, and pharmaceutically acceptable derivatives thereof.
A particularly preferred compound of the invention is: acid hydrochloride, and hydrates thereof.
Compounds of formula (I) inhibit blood pl

REFERENCES:
patent: 3681382 (1972-08-01), Gschwend
patent: 5219867 (1993-06-01), Gollamudi
Cox D et al. Medicinal Research Reviews, 14(2), pp. 195-228, 1994.

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