GB1102762A - Phthalane, isochromane and isochromene derivatives - Google Patents

Abstract

The invention comprises compounds of formula <FORM:1102762/C2/1> wherein A is -CR1R2-, -CR1R2-CH2-, -CHR1-CHR2 or -CR1=CH-, wherein each or R1 and R2 is a hydrogen atom or a C1- 8 alkyl group, -NR3R4 is a mono-or di-C1- 8 alkylamino group or is the radical of a 5- or 6-ring membered heterocyclic amine, R5 is a hydrogen atom or a cyclohexyl, phenyl or thienyl group optionally substituted by a halogen atom or a C1- 8 alkyl, C1- 8 alkoxy or trihalomethyl group, "alkylene" is a C2- 8 alkylene group having at least two carbon atoms in the chain between the ring carbon atom and the nitrogen atom, and X is a hydrogen or halogen atom or a C1- 8 alkyl, C1- 8 alkoxy or trihalomethyl group, pharmaceutically acceptable acid addition salts thereof, and their preparation by (a) dehydration of a compound of formula <FORM:1102762/C2/2> wherein -NR3R4 is a dialkylamino group, the alkylene group has three carbon atoms in the linking chain, and the group A is saturated, followed if desired by N-demethylation by reaction with a compound of formula ClCOOR6, wherein R6 is a C1- 8 alkyl or benzyl group, to form the corresponding carbamate, followed by hydrolysis, (b) reaction of a compound of formula <FORM:1102762/C2/3> wherein the group A is saturated, with a compound of formula Hal-alkylene -NR3R4 or Hal-alkylene-Hal, in the presence of an alkali metal amide, alkyl or phenyl, followed in the latter case by reaction with an amine HNR3R4, or (c) where A is unsaturated, treatment of a saturated group A with N-bromo-succinimide and dehydrobrominating with an alkali metal alcoholate. 4 - Dimethylamino - 1 - phenyl - 1 - [2 - (2- hydroxy - 2 - propyl) - 5 - chloro - phenyl]-butanol-1 is prepared from 6-nitro-3,3-dimethyl-phthalide by treatment with stannous chloride, diazotization and reaction with cuprous chloride to form 6-chloro-3,3-dimethyl-phthalide, treating this with phenyl magnesium bromide to form o - benzoyl - p - chlorophenyl - dimethylcarbinol, and treating this with dimethylaminopropyl magnesium bromide. 1 - (Phenyl or o - tolyl) - 3,3 - di - (methyl or ethyl) phthalanes are prepared by reaction of 1-(phenyl or o-tolyl)-3,3-di-(methyl or ethyl)-phthalene with lithium aluminium hydride to form 3 - [2 - (a - hydroxy - 2 - methylbenzyl)-phenyl - pentanol - 3 or 2 - [2 - (a - hydroxybenzyl) phenyl-propanol-2, followed by treatment with glacial acetic acid and concentrated hydrochloric acid. 4 - Dimethylamino - 1 - [2 - (2 - hydroxy - 2-propyl) phenyl]-butanol-1 is prepared by reaction of 3,3-dimethylphthalide with dimethylaminopropylmagnesium bromide to form 1-(3-dimethylaminopropyl) - 3,3 - dimethyl - phthalane-1-ol, and treating this with lithium aluminium hydride. The compounds of the invention have anti-depressant activity and may be used in pharmaceutical compositions in combination with a carrier, for example in forms suitable for oral or parenteral administration.