Patent IE-32083-B1 (IE)
Title: Indoles
IPC: C07D209/18
Filed: 1968-04-24
Abstract: 1,218,570. Substituted indole derivatives. JOHN WYETH & BRO. Ltd. 9 May, 1968 [24 May, 1967; 1 March, 1968], Nos. 24256/67 and 10096/68. Heading C2C. Novel substituted indole derivatives of the Formula I wherein R<SP>1</SP> is H, C 1-6 alkyl, C 7-10 aralkyl, or aroyl; R<SP>2</SP> is H, C 1-6 alkyl or aryl; R<SP>3</SP> is H, halogen, C 1-6 alkoxy, OH or C 1-6 alkyl; R<SP>4</SP> is H, halogen or C 1-6 alkyl; R<SP>5</SP> is aryl (including heterocyclic aryl), C 1-6 alkoxy, aryloxy, C 7-10 aralkyl, C 7-10 aralkyloxy, or diaryl-C 1-6 alkyl; A is alkylene or mono- or diketo alkylene containing up to 4 carbon atoms, Z is an oxo ( = O) group and the formula is a pyridinium, tetrahydropyridine or pipendine ring system, substituted by NHCZR<SP>5</SP> and R<SP>4</SP> with the proviso that Z may also be two hydrogen atoms when A is alkylene, R<SP>5</SP> is aryl and the ring is piperidine and acid addition and quaternary ammonium salts of the tetrahydros pyridine compounds and piperidine compoundare prepared (a) by reacting a compound of the general formula wherein Y is a halogen atom or an equivalent radical, for example, tosyl, with the appropriate amidopyridine, amidotetrahydropyridine, amidopiperidine or arylaminopiperidine derivative; (b) acylating a compound of general Formula I above in which the NHCZR<SP>5</SP> is replaced by NH 2 with a reactive derivative of an acid of the formula R<SP>5</SP>COOH; (c) selectively reducing the corresponding pyridinium compounds with an alkali metal borohydride to the tetrahydropyridine derivatives, or hydrogenating or carefully reducing them with a hydride transfer agent, such as LiAlH 4 , to or the corresponding piperidine compounds, or reducing with LiAl 4 under more drastic conditions tetrahydropyridine compounds to the corresponding piperidine compounds, in which any doubly bonded oxygen groups are also reduced; (d) carrying out a Fischer indole synthesis on a compound of the general formula where the broken line indicates that a double bond is optionally present in the 3, 4 position of the ring; or (e) akylating, aralkylating, and aroylating a compound in which R<SP>1</SP> is H. 4 - Benzamidopyridine is prepared by adding benzyol chloride to 4 - aminopyridine. In a similar manner 3 - benzamidopyridine, 4- (benzyloxycarbonylamino)pyridine, 4 - (4 - chloro)- benzamidopyridine and 4 - (2,2 - diphenylacetamido)pyridine are prepared. 3 - [2 - (4 - Amino - 1 - piperidyl)ethyl]indole is prepared either by catalytically hydrogenating 4 - amino - 1 - [2 - (3 - indolyl)ethyl]pyridinium bromide resulting from the reaction of 4 - aminopyridine on 3 - (2 - bromoethyl)indole or by hydrolysing 3 - [2 - (4 - acetamido -1 - piperidyl)- ethyl]indole, which is in turn made by the catalytic hydrogenation of 4 - acetamido - 1 - [2 - (3- indolyl)ethyl]pyridinium bromide obtained by refluxing a solution of 4-acetamidopyridine and 3 - (2 - bromoethyl)indole. By a similar process 3 - [2 - (3 - (or 2) - amino - 1 - piperidyl)ethyl]- indole, 3 - (or 2) - amino - 1 - [2 - (3 - indolyl) ethyl]pyridinium bromide, 3 - [2 - (4 - amino - 1- piperidyl)ethyl] - 2 - methylindole, 3 - [2 - (4 - acefamido - 1 - piperidyl)ethyl] - 2 - methylindole, 4- acetamido - 1 - [2 - (2 - methylindol - 3 - yl)ethyl]- pyridinium bromide, 3 - [2 - (4 - amino 1 - piperidyl - 1 - oxoethyl]indole and 4 - amino - 1 - [2- (3 - indolyl) - 2 - oxoethyl]pyridinium bromide are obtained. 3 - [2 - (4 - Amino - 1 - piperidyl)ethyl] - 1- methylindole is made by the sodium derivative of the 1-unsubstituted indole with methyl iodide. By a similar method used benzyl chloride 3 - [2- (4 - amino 1 - piperidyl)ethyl] - 1 - benzylindole is obtained. 4-Benzamidopiperidine is prepared by hydrogenolysing N - benzyl - 4 - benzamidopiperidine resulting from the benzoylation of N - benzyl - 4- aminopiperidine which is in turn obtained by reducing the oxime of N - benzyl - 4 - perididone, made by N-benzylation of 4-piperidone. 3 - [2 - (4 - Amino - 1 - piperidyl)ethyl] - 5- methoxy - 2 - methylindole is prepared by hydrolysing the corresponding 4 - acetamido compound resulting from the hydrogenation of 3-[2- (4 - acetamido - 1,2,5,6 - tetrahydropyrid - 1 - yl) ethyl ] - 5 - methoxy - 2 - methylindole, which is in turn made by reducing with NaBH4 4 - acetamido - 1 - [2 - (5 - methoxy - 2 - melhylindol - 3- yl) - ethyl]pyridinium bromide obtained by reacting 4 - acetamido - pyridine with 3 - (2- bromo)ethyl - 5 - methoxy - 2 - methylindole resulting from the treatment with 48% hydrobromic acid of the alcohol produced by reducing 5 - methoxy - 2 - methylindole - 3 - acetic acid with LiAlH 4 . Pharmaceutical compositions suitable for oral or parenteral administration contain the above novel indole derivatives or a non-toxic acid addition 4 quaternary ammonium salts, thereof as the active ingredient. The above compositions exhibit anti-inflammatory activity, and/or action on the cardiovascular system and sometimes central nervous system activity.
[GB1218570A]