Piperidine derivatives having tachykinin antagonist activity

Details Piperidine derivatives having tachykinin antagonist activity Piperidine derivatives having tachykinin antagonist activity

1997-07-08

2000-02-01

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514329, 546210, 546223, A61K 31445, C07D 4010

Patent

active

060203463

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to piperidine derivatives, to processes for their preparation, pharmaceutical compositions containing them and their medical use.
3-Aminopiperidine derivatives described as having substance P antagonist activity are disclosed in, for example, PCT Patent Applications WO93/00331, WO93/01170 and WO94/13663.
In particular the invention relates to novel compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins.
The present invention provides compounds of formula (I) ##STR3## wherein R.sup.1 is --O--(CH.sub.2).sub.p C.sub.3-7 cycloalkyl, --O--C.sub.1-7 fluoroalkyl, or --O--(CH.sub.2).sub.n X; ##STR4## R.sup.3 is a hydrogen or halogen atom; R.sup.4 and R.sup.5 may each independently represent a hydrogen or halogen atom, or a SO.sub.2 NR.sup.7 R.sup.8, NHSO.sub.2 R.sup.9, S(O).sub.s R.sup.9, OC.sub.1-4 alkyl, NO.sub.2, CO.sub.2 H, CO.sub.2 C.sub.1-4 alkyl, CN or, when n is 2, X may also represent OH, SH or NH.sub.2 ; cyclopropyl, --S(O).sub.s C.sub.1-4 alkyl, phenyl, NR.sup.10 R.sup.11, CH.sub.2 C(O)CF.sub.3, trifluoromethyl, difluoromethyl or cyano group; C.sub.1-4 alkyl group; a C.sub.1-4 alkyl or acyl group;
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. Dihydrochloride salts are particularly suitable.
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 centres (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. ##STR5##
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.
Referring to the general formula (I), a C.sub.1-4 alkoxy group may be a straight chain or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or 2-methylprop-2-oxy. A C.sub.1-4 alkyl group may be a straight chain or branched chain alkyl group and may be, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-1-yl or 2-methylprop-2-yl. An --O--(CH.sub.2).sub.p C.sub.3-7 -cycloalkyl group may be, for example cyclopropyloxy, cyclopropylmethyloxy, cyclobutyloxy, cyclobutylmethyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.
Referring to the general formula (I), an --O--C.sub.1-7 fluoroalkyl group may contain 1, 2 or 3 fluorine atoms and the C.sub.1-7 alkyl chain may be straight or branched. Examples of suitable groups include fluoromethyloxy, difluoromethyloxy, trifluoromethyloxy and 2,2,2-trifluoroethyloxy.
Referring to the general formula (I), when R.sup.7, R.sup.8, or R.sup.9 represents a C.sub.1-4 alkyl group, this is suitably methyl.
Referring to the general fo

REFERENCES:
patent: 5703240 (1997-12-01), Armour et al.
patent: 5773450 (1998-06-01), Lowe et al.
Maggie "Tachykinin receptors and tachykinin receptor antagonists" J. Auton. Pharm. v. 13, p. 23-39, 1993.
Ward et al., J. Med. Chem., vol. 38, No. 26, pp. 4985-4992, (1995).

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