Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-20
1999-07-06
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514320, 546210, 546223, A61K 31445, C07D21156, C07D40110
Patent
active
059198036
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to piperidine 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, WO-A-9300331, WO-A-9301170, WO-A-9413663 and WO-A-95/08549.
The present invention provides compounds of formula (I) ##STR3##
wherein R.sup.1 is a C.sub.2-4 alkoxy group;
R.sup.2 is ##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 C.sub.1-4 alkyl, C.sub.1-4 alkoxy or trifluoromethyl group;
and pharmaceutically acceptable derivatives thereof.
By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt or solvate of a compound 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 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 formula (I). 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.
Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are pharmaceutically acceptable salts and solvates thereof.
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 derivatives.
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.2-4 alkoxy group may be a straight chain or branched chain alkoxy group, for example, 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.
Referring to the general formula (I), a halogen atom may be a fluorine, chlorine, bromine or iodine atom, such as a fluorine, chlorine or bromine atom.
R.sup.3 is preferably a hydrogen atom.
R.sup.
REFERENCES:
patent: 5703240 (1997-12-01), Armour et al.
Gardner, C.J. et al., 1995, Brit. J. Pharm. 116(8) 3158-63.
Beattie, D.T. et al., 1995, Brit. J. Pharm. 116(8) 3149-57.
Ward, Peter et al., J.Med.Chem., 1995, 38(26), 4985-92.
Giblin Gerard Martin Paul
Sharratt Peter John
Chang Ceila
Glaxo Group Limited
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