NOVEL INDOLINE DERIVATIVES

摘要

1,237,008. 1-Phenyl-indoline derivatives. PFIZER Ltd. 17 Dec., 1969 [18 Dec., 1968], No. 60083/68. Heading C2C. Novel 1-phenyl-indoline derivatives of the general formula wherein R is either a -C n H 2n NR1R2 group, in which R1 and R2 are each a hydrogen atom or a C 1-8 alkyl or benzyl group or, together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring containing at least 4 carbon atoms which, if it contains a further nitrogen atom, may be substituted at said nitrogen atom by a C 1-8 alkyl, C 1-8 hydroxyalkyl or benzyl group and C n H 2n is a C 2-8 alkylene group separating the nitrogen atom from the indoline ring by at least 2 carbon atoms, or a group of the formula wherein m is 0-4 and R4 is a bivalent group of (7-m) carbon atoms forming, with the carbon atom to which it is attached, a saturated heterocyclic ring of at least 4 carbon atoms and at least one nitrogen atom, any such nitrogen atom being separated from the indoline ring by at least two carbon atoms and optionally carrying a C 1-5 alkyl, C 1-8 hydroxyalkyl or benzyl group; X is an oxygen atom or two hydrogen atoms; and any benzene ring (including the fused benzene ring) in the structural formula or in R1, R2 or R4 is optionally substituted by one or more halogen atoms or C 1-8 alkyl, C 1-8 alkoxy, trifluoromethyl, nitro, hydroxyl or optionally N-substituted sulphamoyl groups, and pharmaceutically acceptable acid addition salts thereof are prepared (a) when X is an oxygen atom and R is a -C n H 2n NR1R2 group in which neither R1 nor R2 is a hydrogen atom, by reaction of a 1- phenyl-2-indolinone with thallium metal or thallium ethoxide, followed by a haloalkylamine of the general formula hal-C n H 2n - NR1R2 wherein hal is a halogen atom; (b) by reaction of a 1-phenyl-2-indolinone with an aldehyde or ketone of the general formula R3COC n-1 H 2n-2 NR1R2, R3COC m-1 H 2m-2 R5 or O=C=R6, wherein C n-1 H 2n-2 and C m-1 H 2m-2 are, respectively, the groups C n H 2n and C m H 2m (m is at least 1) from which a terminal CHR3 group has been abstracted, R1 and R2 are as defined above or, when they form a heterocyclic ring, the ring may be unsaturated, R3 is a hydrogen atom or an alkyl group of not more than 8-n or 4-m carbon atoms, R5 is a group of the formula -CH=R4 as defined above or an unsaturated derivative thereof and R6 is as R4 or an unsaturated derivative thereof, with the proviso that neither R1 nor R2 is hydrogen and any secondary nitrogen atom in R5 or R6, or in R1 and R2 together, is substituted by a C 1-8 alkyl, C 1-8 hydroxyalkyl or benzyl group, and reducing the resulting unsaturated derivative; (c) when X is two hydrogen atoms and R is a -C n H 2n NR1R2 group, by reaction of a carboxylic acid of the general formula wherein C n-1 H 2n-2 is the group C n H 2n from which a terminal CH 2 group has been abstracted, or an ester thereof with ammonia or an amine of the general formula R1R2NH and reduction of the resulting amide; (d) when X is two hydrogen atoms and R is a C n H 2n NR1R2 group, by reaction of a reactive derivative of an alcohol of the general formula with ammonia or an amine of the general formula R1R2NH; and (e) when X is two hydrogen atoms and R is a C n H 2n NR1R2 group, by reduction of a 1-phenyl-indole derivative of the general formula with sodium in liquid ammonia; followed optionally by salification of the product. 1 - Phenyl - 3 - (3 - indolinyl) - propanol is prepared by hydrogenation of ethyl 3-(3-indolyl)- propionate with a platinum oxide catalyst, reduction of the resulting ethyl 3-(3-indolinyl). propionate with lithium aluminium hydride and treatment of the resulting 3-(3-indolinyl)- propanol with bromobenzene in the presence of cuprous bromide and anhydrous potassium carbonate. Pharmaceutical compositions having antidepressant and antihypertensive activity comprise, as active ingredient, a 1-phenyl-indoline derivative of the first general formula above or a pharmaceutically acceptable acid addition salt thereof, together with a suitable carrier, and may be administered orally or parenterally.