Piperidine derivatives

Details Piperidine derivatives Piperidine derivatives

1996-03-21

1997-12-30

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514326, C07D40110, A61K 31445

Patent

active

057032408

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to piperidine derivatives, to process 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) ##STR3## wherein R.sup.1 is a C.sub.1-4 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;
R.sup.6 is a hydrogen atom, a C.sub.1-4 alkyl, (CH.sub.2).sub.m cyclopropyl, --S(O).sub.n C.sub.1-4 alkyl, phenyl, NR.sup.7 R.sup.8, CH.sub.2 C(O)CF.sub.3 or trifluoromethyl group; 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 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.
Referring to the general formula (I), R.sup.1 is suitably a methoxy, ethoxy or prop-2-oxy group.
Referring to the general formula (I), R.sup.2 is suitably a group ##STR6##
Referring to the general formula (I), when R.sup.3 represents a halogen atom, this is suitably chlorine, or more preferably fluorine.
Referring to the general formula (I), when R.sup.4 or R.sup.5 represents a C.sub.1-4 alkyl group this is suitably a methyl group, or when R.sup.4 or R.sup.5 represents a C.sub.1-4 alkoxy group this is suitably a methoxy group. Suitable values for R.sup.4 include hydrogen, methyl, methoxy, fluorine or trifluoromethyl. Suitable values for R.sup.5 include hydrogen, fluorine, chlorine or bromine. R.sup.4

REFERENCES:
patent: 5232929 (1993-08-01), Desai et al.
patent: 5332817 (1994-07-01), Desai et al.
Maggi, C.A. et al.: Tachykinin Receptors and tachykinin receptor antagonists. J. Auton. Pharmacal. (1993) vol. 13, pp. 60-66.

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