GB1476087A — 5-aryl-1,2,3,4-tetrahydro-y-carbolines

USPTO Abstract

1476087 5 - Phenyl - 1,2,3,4 - tetrahydro- γ-carbolines PFIZER Inc 26 March 1975 [1 April 1974] 12773/75 Heading C2C Novel 5 - phenyl - 1,2,3,4 - tetrahydro - γ- carbolines of the general Formula I wherein X is a hydrogen, fluorine, chlorine or bromine atom or a methyl group, Z is a hydrogen, fluorine or chlorine atom or a methoxy or trifluoromethyl group and R is a hydrogen atom, a C 1-6 alkyl or benzyl group, or a group of the Formula X in which A is a C 1-5 alkylene group, M is -CH = CH-, -CH 2 -, -CO-, -CH(OR 1 )- or -C(CH 3 )(OR 1 )-, where R 1 is a hydrogen atom or C 2-6 alkanoyl group, and K is a hydrogen, fluorine or chlorine atom or a methyl or trifluoromethyl group, with the proviso that when Z is a hydrogen atom, X is a fluorine, chlorine or bromine atom or a methyl group, and pharmaceutically acceptable acid addition salts thereof are prepared (a) when R is a hydrogen atom, by heating the corresponding ester of the general Formula III with ethanolic KOH; (b) when R is a C 1-6 alkyl or benzyl group or a group of the Formula X in which M is -CH 2 - or -CO-, by reacting the product of (a) with R-hal, wherein hal is a halogen atom or a sulphonate ester group; (c) when R is a C 1-6 alkyl group, by reacting a 1,2,3,4-tetrahydro-γ-carboline of the general formula with a Z-substituted bromobenzene in the presence of Cu 2 Br 2 and Na 2 CO 3 ; (d) when R is a C 2-6 alkyl group, by reducing the corresponding compound in which R is a C 2-6 alkanoyl group with a metal hydride; (e) when R is a methyl group, by reducing the ester of the general Formula III with LiAlH 4 or aluminium hydride; (f) when R is a group of the Formula X, by reacting a nitrile of the general formula with a Y-substituted phenyl magnesium halide; (g) when R is a group of the Formula X and M is -CH(OH)-, by reducing the corresponding compound in which M is -CO- with NaBH 4 ; (h) when R is a group of the Formula X and M is -C(OH)(CH 3 )-, by reacting the corresponding compound in which M is -CO- with CH 3 MgI; (i) when R is a group of the Formula X and M is -CH(OR 1 )- or -C(CH 3 )(OR 1 )-, in which R 1 is a C 2-6 alkanoyl group, by esterifying the corresponding compound in which M is -CH(OH)- or -C(CH 3 )(OH)-; and (j) when R is a group of the Formula X in which M is -CH = CH-, by dehydrating the corresponding compound M is -CH(OH)- and A is an alkylene group containing one more C atom than in the desired product, followed optionally by salification. Esters of the general Formula III are prepared by reacting a p-X-phenylhydrazine with N- ethoxycarbonyl-4-piperidone and reacting the resulting 2 - ethoxycarhonyl - 8 - W - 1,2,3,4- tetrahydro - γ - carboline with a Z - substituted bromobenzene in the presence of Cu 2 Br 2 and Na 2 CO 3 . Ketones of the general Formula I wherein R is a C 2-6 alkanoyl group are prepared by acylation of the corresponding compound in which R is a hydrogen atom. 1,2,3,4 - Tetrahydro - γ - carbolines of the general Formula IV are prepared by reacting a p-X-phenylhydrazine with a N-R-4-piperidone. Nitriles of the general Formula VI are prepared by reacting the corresponding compound I wherein R is a hydrogen atom with halogen- A-CN. Pharmaceutical compositions having tranquillizing activity comprise, as active ingredient, a novel 5-phenyl-1,2,3,4-tetrahydro-γ-carboline (I), wherein R is other than a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmacologically acceptable carrier.