Patent GB-1063383-A (GB)
Title: -a-halomethyl 3-indolylacetic acids and their derivatives
IPC: C07D403/06
Filed: 1963-08-26
Abstract: 1,063,383. α-Halomethyl-3-indolylacetic acid derivatives. MERCK & CO. Inc. Aug. 26, 1963 [Sept. 7, 1962], No. 33704/63. Heading C2C. Novel compounds of formula in which R 1  is an aromatic radical having one ring or two fused rings and containing 5 or 6 atoms, any hetero atoms being oxygen, nitrogen, and/or sulphur, and there being no more than three hetero atoms in no more than one of said rings, which may be substituted by halogen, hydroxy, C 1-5  alkoxy, phenoxy, nitro, C 1-6  alkanoylamino, di-(C 1-5  alkyl) amino, mercapto, C 1-5  alkylthio, halo-C 1-5  alkylthio, benzylthio, benzyloxy, phenylthio, halo-C 1-5  alkyl, C 1-8  alkanoyl, halo-C 1-6  alkanoyl, halo- C 1-5  alkoxy, cyano, di-(C 1-5  alkyl)-sulphamido, C 2-6  carboalkoxy, aldehydo, di-(C 1-5  alkyl) carbamoyl, allyloxy, benzoyl, phenylacetyl, benzylthiomethyl, or sulphonamido; R 2  is hydrogen, C 1-5  alkyl, C 2-5  alkenyl, phenyl, tolyl, methoxybenzoyl, p-halobenzyl, or benzyl; R 3  is a radical of formula CXYZ where X is chlorine, bromine or fluorine, and each of Y and Z are hydrogen, chlorine, bromine or fluorine; R 4  is hydroxy, C 1-5  alkoxy, p-halobenzyloxy, amino, C 1-5  alkylamino, di-(C 1-5  alkyl) amino, (C 1-6  alkanoyl) amino, phenylamino, tolylamino, dialkylaminoalkoxy, benzylamino, halobenzylamino, phenylethylamino, C 7-9  aralkoxy, diphenylamino, monoalkylanilino, #-methoxyethylamino, p-methoxyanilino, C 1-5  alkanolamino, dialkanolamino, morpholino, halo-C 1-5  alkylamino, haloanilino, or an -OM radical, M being an ammonium, C 1-5  alkylammonium, morpholinium, cholinium, glucosammonium, methylcyclohexylammonium, trimethylammonium, triethylammonium, n-butylammonium, anilinium, 2,3-xylidinium, piperazinium, or an inorganic cation; and R 5  is hydrogen, C 1-5  alkyl, C 1-5  alkoxy, trifluoromethyl, difluoromethyl, nitro, cyano, aminomethyl, amino, ureido, benzylmercapto, C 1-5  alkylthio, diphenylamino, halo-C 1-5  alkylamino, C 1-5  alkylamino, anilino, C 1-5  alkoxy-C 1-5  alkylamino, C 1-5  alkylanilino, C 1-5  alkoxyanilino, alkanolamino, di- (C 1-5  alkyl) amino, aralkylamino, dialkanolamino, morpholino, haloanilino, haloaralkylamino, or tolylamino, and the acid anhydrides of these acids, are prepared by condensing a 3-α-haloacetylindole with an ester of an α-haloacetic acid to produce a #-(3-indolyl)-#-halomethyl-glycidic acid ester, converting the ester to an acid and decarboxylating the acid to form an α - (3 - indolyl) - α - halomethyl - acetaldehyde, treating the aldehyde with hydroxylamine to form an oxime, dehydrating the oxime, e.g. by treatment with a mild dehydrating agent or by treatment with an alkyl or aryl chloroformate in the presence of a base, to give an alkyl or aryl carbonate ester, the ester then being pyrolysed, to yield an α-(3-indolyl-α-halomethylacetonitrile, treating the nitrile with an alkanol and a hydrogen halide to form an imino-alkyl-ester hydrohalide and hydrolysing this compound to form an alkyl α-halomethyl-α-(3-indolyl) acetate which may be hydrolysed under mild conditions to the corresponding acid, which may then, if desired, (1) be converted to its symmetrical or mixed anhydride, and the anhydride reacted (a) with an alcohol of formula Q<SP>1</SP>OH where Q<SP>1</SP> is an alkyl or aralkyl radical, in the presence of a non-hydroxylic base to give an ester, or (b) with ammonia or a primary or secondary amine to produce an amide. The amides of the invention may also be prepared by mild acid hydrolysis of the corresponding nitrile. The synthesis of various compounds having a 5-substituent which has a nitrogen atom attached to the ring is generally based on the 5-nitro substituent, the nitro group being transformed by various methods. The preparation of the 3-α-haloacetylindole starting material is disclosed in Specification 1,063,384. Therapeutic compositions, which have antiinflammatory and antipyretic activity and are effective in the prevention and inhibition of granuloma tissue formation, and which may be administered, e.g. orally, contain as active ingredients compounds of Formula I above.