Patent GB-1237008-A (GB)
Title: Novel indoline derivatives
Inventor: CANAS-RODRIGUEZ ANTONIO
IPC: A61P25/26
Filed: 1968-12-18
Abstract: 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 NR<SP>1</SP>R<SP>2</SP> group, in which R<SP>1</SP> and R<SP>2</SP> 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 R<SP>4</SP> 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 R<SP>1</SP>, R<SP>2</SP> or R<SP>4</SP> 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 NR<SP>1</SP>R<SP>2</SP> group in which neither R<SP>1</SP> nor R<SP>2</SP> 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 - NR<SP>1</SP>R<SP>2</SP> wherein hal is a halogen atom; (b) by reaction of a 1-phenyl-2-indolinone with an aldehyde or ketone of the general formula R<SP>3</SP>COC n-1 H 2n-2 NR<SP>1</SP>R<SP>2</SP>, R<SP>3</SP>COC m-1 H 2m-2 R<SP>5</SP> or O=C=R<SP>6</SP>, 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 CHR<SP>3</SP> group has been abstracted, R<SP>1</SP> and R<SP>2</SP> are as defined above or, when they form a heterocyclic ring, the ring may be unsaturated, R<SP>3</SP> is a hydrogen atom or an alkyl group of not more than 8-n or 4-m carbon atoms, R<SP>5</SP> is a group of the formula -CH=R<SP>4</SP> as defined above or an unsaturated derivative thereof and R<SP>6</SP> is as R<SP>4</SP> or an unsaturated derivative thereof, with the proviso that neither R<SP>1</SP> nor R<SP>2</SP> is hydrogen and any secondary nitrogen atom in R<SP>5</SP> or R<SP>6</SP>, or in R<SP>1</SP> and R<SP>2</SP> 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 NR<SP>1</SP>R<SP>2</SP> 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 R<SP>1</SP>R<SP>2</SP>NH and reduction of the resulting amide; (d) when X is two hydrogen atoms and R is a C n H 2n NR<SP>1</SP>R<SP>2</SP> group, by reaction of a reactive derivative of an alcohol of the general formula with ammonia or an amine of the general formula R<SP>1</SP>R<SP>2</SP>NH; and (e) when X is two hydrogen atoms and R is a C n H 2n NR<SP>1</SP>R<SP>2</SP> 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.