PT98767A - Process for the preparation of spiro[cycloalkylbenzene- 1,1'(1',2',3',4'-tetrahydroisoquinolines)] and pharmaceutical compositions - Google Patents

Abstract

This invention relates to a process for the preparation of compounds of formula I <IMAGE> in which: R1 and R2, which may be the same or different, represent hydrogen or C1-6 alkyl, R3 and R4 independently of each other represent one or more radicals selected from hydrogen, OH, NH2, NO2, halogen, C1-6 alkyl or C1-6 alkoxy, n is a whole number from 1-2 inclusive, in addition to this, one or both spiro rings can contain a double unsaturated bond, and their pharmaceutically acceptable derivatives, provided that when n is 1 and R3 represents disubstitution with a hydroxy radical and a methoxy radical or disubstitution with two methoxy radicals then R4 does not represent disubstitution with two methoxy radicals or trisubstitution with three methoxy radicals, characterized in that it comprises: a) preparing a compound of formula I in which R2 is hydrogen for cyclizing the corresponding compound of formula III: <IMAGE> in which R1, R3, R4 and n are defined as above, and X is a group which is suitably lost, or b) preparation of a compound of formula I in which R2 is C1-6 alkyl by reaction of the corresponding compound of formula I in which R2 is hydrogen with an alkylation agent of alkyl C1-6-Y formula in which Y is a group which is lost, or c) preparation of a compound of formula I in which R2 is C1-6 alkyl by reducing the corresponding compound of formula I in which R2 represents a C1-6 alkanoyl group or a urethane group, or d) preparation of a compound of formula I in which R2 is methyl by reaction of the corresponding compound of formula I in which R2 represents hydrogen with formaldehyde and formic acid, or e) preparation of a compound of formula I with an additional double bond in one or both spiro rings by halogenation-dehydrohalogenation of the corresponding compound of formula I, or f) preparation of a compound of formula I containing an amine or hydroxy group by the removal of a protector group from a compound of formula I in which one or more of the amine or hydroxy groups are protected, and, when desired or necessary, conversion of the corresponding compound of formula I into its pharmaceutically acceptable derivative, or vice versa. The compounds are useful as pharmaceutical products; in particular they have N-methyl-(d)-aspartate (NMDA) blocking properties and are useful in the treatment and/or prevention of neurodegenerative conditions.