Patent GB-1063385-A (GB)
Title: Substituted -a-halogenated methylenyl 3-indolyl acetic acids
IPC: C07D407/06
Filed: 1963-08-26
Abstract: 1,063,385. α - Halogenated - methylenyl - 3 - indolyl-acetic acid derivatives. MERCK & CO. Inc. Aug. 26, 1963 [Sept. 7, 1962], No. 43066/65. Divided out of 1,063,383. Heading C2C. Novel compounds of formula in which R 1  is an aromatic radical having one ring or 2 fused rings containing 5 or 6 atoms, any hetero atoms being oxygen, nitrogen and/or sulphur, and there being no more than 3 hetero atoms in no more than one of said rings, which may be substituted by halogen, hydroxy, C 1-5  alkoxy, phenoxy, allyloxy, nitro, C 1-6  alkanoyl amino, 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 1-6  alkanoyl, halo-C 1-6  alkanoyl, halo-C 1-5  alkoxy, cyano, di-(C 1-5  alkyl) sulphonamido, C 2-6  carboalkoxy, aldehydo, di-(C 1-5  alkyl) carbamoyl, benzoyl, phenylacetyl, benzylthiomethyl, or sulphonamido; R 2  is hydrogen, C 1-5  alkyl, C 2-5  alkenyl, phenyl, tolyl, methoxybenzoyl, phalobenzyl, or benzyl; R<SP>1</SP> 3  is a halomethylene radical of formula = CXY, where X is chlorine, bromine or fluorine and Y is hydrogen, chlorine, bromine or fluorine; R 4  is hydroxy, C 1-5  alkoxy, dialkylaminoalkoxy, amino, C 1-5  alkylamino, di-(C 1-5  alkyl) amino, C 1-6  alkanoylamino, phenylamino, tolylamino, benzylamino, halobenzylamino, phenylethylamino, C 1-5  alkoxyalkylamino, C 7-9  aralkoxy, diphenylamino, monoalkylanilino, #-methoxyethylamino, pmethoxyanilino, C 1-5  alkanolamino, dialkanolamino, halo-C 1-5  alkylamino, haloanilino or morpholino, or an -OM radical M being ammonium, alkylammonium, morpholinium, cholinium, glycosammonium, methylcyclohexylammonium, trimethylammonium, triethylammonium, n-butylammonium, anilinium, 2,3- xylindinium, piperazinium or an inorganic cation; and R 5  is hydrogen, C 1-5  alkyl, C 1-5  alkoxy, trifluoromethyl, difluoromethyl, nitro, cyano, amino, ureido, benzylmercapto, C 1-5  alkylthio, diphenylamino, halo-C 1-5  alkylamino, C 1-5  alkylamino, C 1-5  alkoxyanilino, C 1-5  alkanolamino, anilino, di-(C 1-5  alkyl)-amino, aralkylamino, dialkanolamino, morpholino, alkylanilino, haloanilino, haloaralkylamino, alkoxyalkylamino or tolylamino, are prepared by reacting a 3-indoleglyoxalate with a halogenated alkylidene triphenylphosphorane of formula (C 6 H 5 ) 3 P = CXY to form an ester which is hydrolysed under mild conditions, this hydrolysis optionally being omitted if a benzyl or C 1-5  alkyl ester is produced, followed, if desired, by converting the acid obtained to a symmetrical or mixed anhydride and reacting the anhydride with ammonia or a primary or secondary amine to form an amide. The esters of the invention may be prepared from the corresponding acids, e.g. by converting the acid to its symmetrical or mixed anhydride which is then reacted with the desired alcohol in the presence of a non- hydroxylic base. The t-alkyl esters may be converted to the acid by direct pyrolysis or by treatment with a catalytic amount of an arylsulphonic acid. 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 compound which may be transformed in various ways. The 3-indoleglyoxalate starting material may be prepared by reacting an N-1 unsubstitutedindole, appropriately substituted in the 2- and 5-positions except that R 5  is not an amino or alkylamino group, with an oxalyl halide and then an alcohol to give an N-1-unsubstituted 3-indoleglyoxate which is then acylated, or by acylating the N-1 unsubstituted indole and reacting the 1-acyl-indole with oxalyl halide an alcohol, and, after the acylation reaction, if desired, converting any 5-nitro substituent into an amino or alkylamino group. Therapeutic compositions having anti-inflammatory and antipyretic activity, and which are effective in the prevention and inhibition of granuloma tissue formation, which may be administered, e.g. orally, contain as active ingredient compounds of Formula I above.