Substituted cycloalkylamine derivatives and their use as calcium

Details Substituted cycloalkylamine derivatives and their use as calcium Substituted cycloalkylamine derivatives and their use as calcium

1996-09-20

1998-10-06

Burn, Brian M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

514659, 564397, 564443, 564446, 564454, A61K 31135

Patent

active

058176985

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of International Application No. PCT/EP95/00964, filed Mar. 14, 1995.
The present invention relates to carbocyclic derivatives, processes for their reparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists, e.g. for the treatment of ischaemic stroke.
Stroke is reportedly the third most common cause of death in the developed world. Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
DE 3231912 describes aminocyclohexylmethylaniline derivatives; no pharmaceutical activity is ascribed to the compounds. DE 4010325 discloses phenoxycarbocyclic derivatives which are said to have insecticidal activity and intermediates therefor. Teller and Jarboe (J. Med. Chem. (1982) 25 (3) 227) describe cis-and trans-2-(3,4-dimethoxybenzyl)cyclopentylamine, said to be transient hypotensive agents.
EPA 200101 describes therapeutic compositions comprising as active ingredient one of a very broad class of compounds of the formula: --Y--Z.sub.3 --R.sub.4) oxygen or sulphur ring; R.sub.1, R.sub.2 and R.sub.3 are selected from a wide range of substituents; R.sub.4 is also selected from a wide range of acyclic and cyclic substituents, including saturated and unsaturated carbocyclic and heterocyclic rings, which include inter alia cyclopentane and cyclohexane, substituted by (XR.sub.6).sub.n where X is O, S or NR.sub.8 (R.sub.8 is H or lower alkyl), R.sub.6 is inter alia H or lower alkyl and n is 0 or 1; Z, Z.sub.1, Z.sub.2 and Z.sub.3 are independently a bond or an alkylene chain; Y is inter alia a bond, O, S or CO; and M is inter alia O. The more preferred compounds are said to be those wherein Ar is quinoline and in the substituent (XR.sub.6).sub.n X is O. The specification contains only a few examples or named compounds wherein R.sub.4 is cyclohexyl or cyclopentyl and in each of them the ring is substituted by either a hydroxy or methoxy group. No compounds containing an amino-substituted, saturated, 4-7-membered carbocyclic ring are specifically named or exemplified. The compounds described in EPA 200101 are said to be lipoxygenase inhibitors possessing anti-inflammatory and anti-allergic properties.
We have now found a distinct class of amino-substituted carbocyclic derivatives which represent a novel selection with respect to the compounds described in EPA 200101 and which surprisingly exhibit activity as calcium channel antagonists.
The present invention therefore provides in a first aspect the use of compounds of formula (I): ##STR2## wherein X represents O, S, C.dbd.O or a bond; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; from: halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 alkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO.sub.2, amino, mono- or di- alkylamino and Ph(Alk.sup.1).sub.r Y(Alk.sup.2).sub.s - where Ph is optionally substituted phenyl, Y is a bond, oxygen or a carbonyl group, Alk.sup.1 and Alk.sup.2 independently represent C.sub.1-4 alkyl which may be straight or branched and r and s are independently 0 or 1, provided that the length of (Alk.sup.1).sub.r Y(Alk.sup.2).sub.s does not exceed 5 atoms; and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disorder wherein a calcium channel antagonist is indicated.
As indicated above certain compounds of formula (I) are believed to represent a novel selection with respect to EPA 200101. In a further aspect therefore the invention provides compounds of formula (IA): ##STR3## wherein X represents O, S, C.dbd.O or a bond; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkylC.sub.1-4 alkyl; from: halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-2 alkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO.sub.2, amino, mono- or di- alkylamino and Ph(Alk.sup.1).sub.r Y(Alk.sup.2).sub.s - where Ph is optionally substituted phenyl, Y is a bond, oxygen or a carb

REFERENCES:
Belleu, et al., "Conformation of N-(.beta.Chloroethyl)-2-phenoxyethylamines in Relation to Adrenergic Blocking Activity", Journal of Medicinal Chemistry, 6 pp. 579-583 (1963).
Anchisi, et al., "An Investigation into the Electron-ionization induced Mass Spectrometric Behaviour of some trans-and cis-Substituted Cycloalkylamines of Pharmaceutical Interest", Rapid Communications in Mass Spectrometry, 7 pp. 1-5 (1993).

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