Substituted cycloalkylamine derivatives and their use as calcium channel antagonists

A compound of formula (I) selected from the group consisting of

• (.+-.) cis-1-methylamino-2-(4-benzyloxyphenoxy)cyclopentane;
• (.+-.) trans-1-methylamino-2-(4-benzyloxyphenoxy)cyclopentane;
• (.+-.) cis-1-methylamino-2-(4-benzyloxybenzyl)cyclopentane;
• (.+-.) cis-1-amino-2-(4-benzyloxybenzyl)cyclopentane;
• (.+-.) cis-1-amino-2-(4-benzoylphenoxymethyl)cyclopentane;
• (.+-.) cis-1-amino-2-(4-benzylphenoxymethyl)cyclopentane;
• (.+-.) cis-1-methylamino-2-(4-benzylphenoxymethyl)cyclopentane;
• (.+-.) cis-1-amino-2-(3,4-dichlorophenoxymethyl)cyclopentane;
• (.+-.) cis-1-Amino-2-›4-(4-fluorophenoxy)phenoxymethyl!cyclopentane;
• (.+-.) cis-1-Amino-2-›4-(1-methyl-1-phenylethyl)phenoxymethyl!cyclopentane;
• (.+-.) cis-1-Methylamino-2-›4-(1-methyl-1-phenylethyl)phenoxymethyl!cyclopentane;
• (.+-.) cis-1-Amino-2-›4-(1-(4-fluorophenyl)-1-methylethyl)phenoxymethyl!cyclopent ane;
• (.+-.) cis-1-Methylamino-2-›4-(1-(4-fluorophenyl)-1-methylethyl)phenoxymethyl!-cy clopentane;
• or a salt thereof.

A process for the preparation of a novel compound of formula (I) which comprises:

• (a) when X is 0 and p and q are both 0, reaction of a compound of formula (II):
• ##STR11## wherein n and Ar are as hereinbefore defined with a compound R.sup.1 R.sup.2 NH wherein R.sup.1 and R.sup.2 are as hereinbefore defined;
• (b) when R.sup.1 and R.sup.2 are both hydrogen, reduction of a compound of formula (III):
• ##STR12## wherein n, p, q, X and Ar are as hereinbefore defined and R.sup.3 is C.sub.1-4 alkyl or phenylC.sub.1-4 alkyl;
• (c) when X is 0 or S reaction of a compound of formula (IV):
• ##STR13## wherein R.sup.1, R.sup.2, p and n are as hereinbefore defined and X.sup.1 is O or S, with a compound of formula L(CH.sub.2).sub.q Ar wherein L is a leaving group and q and Ar are as hereinbefore defined;
• (d) reaction of a compound formula (V):
• ##STR14## wherein R.sup.1, R.sup.2, p and n are as hereinbefore defined and L.sup.1 is a group displaceable by a nucleophile, with a compound HX(CH.sub.2).sub.q Ar wherein X, q and Ar are as hereinbefore defined;
• (e) interconversion of a compound of formula (I) to a different compound of formula (I),
• and optionally after any of the above processes, forming a salt of formula (I).

A pharmaceutical comprising a compound of formula (IB) ##STR15## wherein X is O, S, C.dbd.O or a bond;

• p and q are independently 0-4;
• R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkylC.sub.1-4 alkyl;
• n is 1, 2, 3 or 4;
• and
• Ar is phenyl optionally substituted by 1 to 3 substituents selected from:
• halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylenedioxy, trifluoromethyl, trifluoromethoxy;
• CN, No.sub.2, amino, mono-and di-alkylamino and Ph(Alk.sup.1).sub.r Y(Alk.sup.2).sub.s - where Ph is an optionally substituted phenyl;
• Y is a bond, oxygen or a carbonyl group;
• Alk.sup.1 and Alk.sup.2 are independently 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 further provided that:
• when X is O and p and q are 0, Ar is not unsubstituted phenyl or phenyl substituted by fluorophenoxy, chloro or methyl;
• and when X is a bond and the sum of p and q is 1, Ar is not unsubstituted phenyl, or phenyl substituted by amino, methoxy, methyl, dimethylamino, or methylenedioxy;
• or a pharmaceutically acceptable salt thereof;
• and a pharmaceutically acceptable carrier or excipient.

A method of treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need thereof an effective amount of a compound of formula (I):

• ##STR16## wherein X represents 0, S, C.dbd.O or a bond;
• p and q independently represent 0-4;
• R.sup.1 and R.sup.2 each independently represent hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkylC.sub.1-4 alkyl;
• n is 1, 2, 3 or 4;
• and
• Ar represents phenyl optionally substituted by 1 to 3 substituents selected 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;
• or a pharmaceutically acceptable salt thereof.