Patent GB-1176348-A (GB)
Title: Indole Derivatives
IPC: C30B19/04
Filed: 1967-05-08
Abstract: 1,176,348. 1 - Acyl - 3 - indolyl aliphatic acids and derivatives thereof. SUMITOMO CHEMICAL CO. Ltd. 8 May, 1967 [12 May, 1966; 27 June, 1966; 30 June, 1966 (2); 8 July, 1966 (2); 1 Aug., 1966; 19 Aug., 1966 (2); 15 Dec., 1966; 16 Dec., 1966 (2); 20 Dec., 1966; 6 Jan., 1967 (2); 7 Jan., 1967; 16 Jan., 1967 (2); 17 Jan., 1967 (3); 20 Jan., 1967], No. 21268(67. Heading C2C. Novel 1-acyl-3-indolyl aliphatic acids and derivatives thereof of the formula wherein R<SP>1</SP> is an unsubstituted or C 1-4  alkyl,- C 1-4  alkoxy-, C 1-4  alkylthionitro-, cyano- or halogen-substituted aromatic carbocyclic ring, or an unsubstituted or a methyl-, ethyl- or halogen-substituted 5- or 6-membered heterocyclic ring containing an oxygen, sulphur or nitrogen atom; R<SP>2</SP> and R<SP>3</SP> are independently hydrogen or C 1-3  alkyl; R<SP>4</SP> is hydrogen, or C 2-4  alkoxycarbonyl; R<SP>5</SP> is C 1-4  alkoxy, benzyloxy, tetrahydropyranyloxy, amino, or hydroxy; R<SP>6</SP> is C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, nitro, C 2-4  alkenyl, C 2-4  alkenyloxy, halogen or hydrogen; A is an unsubstituted or phenyl- or halogen-substituted, saturated or unsaturated, straight or branched hydrocarbon chain having up to 5 carbon atoms; m and p each are 0 or 1 and n is 0 to 3, are prepared by any of the following methods: (a) by heating a keto-aliphatic acid of the formula R<SP>2</SP>COCH 2 (CHR<SP>3</SP>)m.(CH 2 ) n .(CHR<SP>4</SP>)p- COR<SP>5</SP> with a phenylhydrazine of the p. formula R<SP>6</SP>.C 6 H 4 .N(C=NH-A-R<SP>1</SP>).NH 2  or a N<SP>1</SP>- acylated phenylhydrazine of the formula R<SP>6</SP>.- C 6 H 4 .N(CO.A-R<SP>1</SP>).NH 2  or a N<SP>1</SP>-acylatedphenylhydrazone of the formula R<SP>6</SP>C 6 H 4 .N (CO.A-R<SP>1</SP>)N=B wherein B is an aldehyde or a ketone residue; (b) Compounds wherein R<SP>5</SP> is hydroxy may be prepared by the hydrolysis of the corresponding esters, by thermal decomposition of the corresponding tertiary butyl ester, by hydrogenalysis of the corresponding benzyl ester, or by treating the corresponding amide with nitrous acid in an inert solvent; (c) Compounds wherein m=1, n=1, p=0 and R<SP>5</SP> = hydroxy may be made by: (1) heating the corresponding N<SP>1</SP>-acylated phenylhydrazine or N<SP>1</SP>-acylated phenylhydrazone with an acid of the formula R<SP>2</SP>COCH 2 (CHR<SP>3</SP>) m CH(COOH) 2 ; (2) oxidation of the corresponding indole-3- aldehyde or indole-3-alcohol; (3) dehydrogenation of the corresponding 2,3-dihydroindole derivative; (4) ring closure of R<SP>6</SP>C 6 H 4 .- N(CO-A-R<SP>1</SP>).CH(R<SP>2</SP>).CO.CH(R<SP>3</SP>)COOH, and (d) Compounds wherein m=0, p=0, n=1 and R<SP>5</SP> = OH may be made by: (1) ring closure of the appropriately substituted 3-(2<SP>1</SP>-acylaminophenyl)-levulinic acid; (2) heating the corresponding N<SP>1</SP>-acylated-phenylhydrazine or N<SP>1</SP>- acylate phenyl-hydrazone with either acetosuccinic acid or 2-ketoadipic acid; and (3) dehydration of the corresponding 2-hydro-3- hydroxy-indolylacetic acid or derivative thereof, followed by hydrolysis if required. N<SP>1</SP>-acylated-phenylhydrazines are prepared by reacting the corresponding phenylhydrazines or phenylhydrazones in an inert solvent in the presence of a hydrogen halide with a compound Y-CO-A-R<SP>1</SP> wherein Y is halogen, or by acid hydrolysis of the corresponding N<SP>1</SP>- acylated-phenylhydrazones obtained by reacting the phenylhydrazone in a basic solvent or an inert solvent in the presence of a hydrogen halide accepter with Y-CO-A-R<SP>1</SP>. 1 - Phenylacetyl - 2 - methyl - 5 - methoxy - 3 - indolylacetaldehyde is prepared by hydrolysis of the diethyl-acetal obtained by heating N<SP>1</SP>- phenylacetyl - N<SP>1</SP> - (p - methoxyphenyl)- hydrazinehydrochloride with levulinic aldehyde diethylacetal. 2 - (1<SP>1</SP> - Cinnamayl  -  2<SP>1</SP>- methyl - 5<SP>1</SP> -  methoxy- 3<SP>1</SP> - indolyl) - ethanol and 2 - (1<SP>1</SP> -phenylacetyl- 2<SP>1</SP> - methyl - 5<SP>1</SP>- methoxy - 3<SP>1</SP> - indolyl) - ethanol are made by heating the corresponding N<SP>1</SP>- acylated-phenlhydrazine hydrochloride with 4- oxo-n-pentanol. 4 - {N - (p - methoxyphenyl) - N - cinnamayl}- amino-3-oxovaleric acid is obtained by the hydrolysis of the corresponding t.-butyl ester resulting from the reaction of tert.-butyl-γ- bromo-#-keto-valeriate with N-cinnamoyl-panisidine which is, in turn, prepared from panisidine and cinnamoyl chloride. t. - Butyl - 1 - cinnamoyl - 2 - methyl - 3 - hydroxy - 5 - methoxy - 2,3 - dihydro - 3 - indolyl acetate is made by reacting the corresponding 3-oxo-2,3-dihydro-indole with t.-butyl bromoacetate. Therapeutic compositions having anti-inflammatory, anti-pyretic, and analgesic properties, contain the above novel 1-acetyl-3-indolyl aliphatic acids or derivatives thereof as the active ingredient and at least one or more pharmaceutically acceptable carriers.