Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-05-14
1999-08-10
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546196, A61K 31445, C07D40514
Patent
active
059359722
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to benzofuran derivatives, to processes for their preparation, pharmaceutical compositions containing them and their medical use.
In particular the invention relates to novel compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins.
3-Aminopiperidine derivatives described as having substance P antagonist activity are disclosed in, for example, PCT Patent Applications WO-A-9109844 and WO-A-9301170.
The present invention provides compounds of formula (I) ##STR2## wherein R represents a hydrogen atom or a C.sub.1-4 alkoxy group; R.sup.1 is selected from phenyl, opitionally substituted by a group --(CH.sub.2).sub.n CONR.sup.3 R.sup.4 or S(O).sub.m R.sup.3 ; or a 5- or 6-membered aromatic heterocycle containing 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by a C.sub.1-4 alkyl, trifluoromethyl or cyano group or a group --(CH.sub.2).sub.n CONR.sup.3 R.sup.4 ;
Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates.
Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of formula (I) and their pharmaceutically acceptable acid addition salts.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention includes both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least two chiral centers (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures.
For example the compounds of formula (I) may be either cis isomers, as represented by figures (a) and (b), or trans isomers, as represented by figures (c) and (d), or mixtures thereof.
All of the isomers of the compounds of formula (I) represented by the figures (a) to (d) and mixtures thereof including racemic mixtures are included within the scope of the invention. ##STR3## The compounds of formula (I) are preferably in the form of their cis isomers (i.e. as represented by figures (a) and (b)). The 2S, 3S isomers (i.e. as represented by figure (b)) are particularly preferred.
According to a further aspect the invention provides compounds of formula (I) wherein R represents a hydrogen atom, R.sup.1 is selected from phenyl, optionally substitued by a group --(CH.sub.2).sub.n CONR.sup.3 R.sup.4 or S(O).sub.m R.sup.3 ; or a 5- or 6-membered aromatic heterocycle containing 1,2,3, or 4 heteroatoms selected form oxygen, nitrogen or sulphur, optionally substituted by a C.sub.1-4 alkyl group; R.sup.2 represents a hydrogen atom; R.sup.3 and R.sup.4 independently represent hydrogen or C.sub.1-4 alkyl; n represents zero, 1 or 2; m represents 1 or 2; and x represents zero.
Referring to the general formula (I), a 5- or 6-membered aromatic heterocycle containing 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen or sulphur may be, for example pyrimidine, furan, pyridine, imidazole, tetrazole, pyrazole, pyrazine, oxazole, thiazole, triazole such as 1,2,4-triazole or 1,2,3-triazole, isoxazole, 1,2,4-oxadiazole or 1,3,4-oxadiazole.
Preferred 5- or 6-membered aromatic heterocycles containing 1,2,3 or 4 heteroatoms selected from oxygen, nitrogen or sulphur include pyrimidine, furan, pyridine, imidazole, tetrazole, pyrazole, pyrazine, oxazole, thiazole, 1,2,4-triazole, 1,2,3-triazole and isoxazole. Further preferred groups include pyrimidine, furan and pyridine, especially pyridine. Even furthe
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Maggi et al. "Tachykinin receptors and tachykinin receptor antagonists" J. Auton. Pharmac. v.13, pp. 23-24, 1993.
Tavorath et al. "Drug treatment of chemotherapy induced delayed emesis" MEDLINE abst. 97-081298, 1997.
Tattersall et al. "Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets" MEDLINE abst 97-165756, 1997.
Evans Brian
Naylor Alan
Chang Ceila
Glaxo Group Limited
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