GB1230534A - - Google Patents

Abstract

1,230,534. 1 - Acyl - 5 - aminoindole - 3 - alkanoic acid derivatives. MERCK & CO. Inc. 21 Aug., 1969 [26 Aug., 1968], No. 41838/69. Heading C2C. Novel compounds of formula in which R 1 is a C 1-5 alkyl radical, an aryl radical, optionally having a halo, nitro, C 1-5 alkyl, C 1-5 alkoxy, or C 1-5 alkylthio substituent, or a heteroaryl radical; R 2 is a hydrogen atom or a C 1-5 alkyl radical; R 3 is a hydrogen atom or a C 1-5 alkyl radical; R 4 is a hydrogen atom or an alkyl, aryl, alkenyl radical that is unsubstituted or has inert substituent(s); each of R 5 and R 6 is an alkyl or hydroxyalkyl radical; and X is an alkylene or alkenylene radical may be prepared by the following multistage process showing the preparation of the starting materials and their conversion to the above novel compounds illustrated in the following reaction scheme in which R 1 , R 2 , R 3 , R 5 , R 6 and X are as defined above, each of R y and R z is a hydrogen atom or an alkyl, aryl, aralkyl, carboxyalkyl or carbalkoxyalkyl radical; R<SP>1</SP> 4 is an acidlabile group, such as t-alkyl, tetrahydropyranyl or trialkyl silyl or a group as defined above for R 4 , and R is a hydrogen atom or a saltforming group such as a sulphonate. Compound III may be converted directly to compound VI by heating with levulinic acid or its esters in the presence of a strong acid. Alternatively, compound III may be cleaved in the presence of an aqueous acid to form compound IV, which compound in turn may be converted directly to compound VI by reaction with levulinic acid in the presence of an acid catalyst; or compound IV may first be converted to the corresponding hydrazone compound (compound V) by reaction with levulinic acid or its esters under known conditions, and subsequently converted to compound VI as described above. When R<SP>1</SP> 4 is a group of the type defined for R 4 there is obtained an above novel ester instead of compound VI. Alternatively, compound V may be prepared by acylating compound II in which R y is methyl and R z a propionic ester or acid radical. Compound III may be prepared by reacting compound I with an aldehyde or ketone to form compound II which, in turn, is acylated in the presence of a base to form compound III. The novel compounds of the invention may also be prepared by acylation with an appropriate aralkenoyl halide of the t.-butyl ester of a 1 - unsubstituted - 5 - dialkylaminoindole alkanoic acid optionally with acid catalysed hydrolysis to the acid. t. - Butyl 2 - methyl - 5 - dimethylaminoindole- 3-acetate is prepared by reduction in presence of formaldehyde of the t.-buty-2-methyl-5-nitroindole-3-acetate prepared by reaction of t.- butanol and 2 - methyl - 5 - nitroindole - 3 - acetic acid anhydride obtained by dehydration of the acid with dicyclohexylcarbodiimide. Pharmaceutical compositions in conventional forms for oral and topical administration and having anti-inflammatory activity comprise an above novel compound and an inert carrier, diluent, excipient or coating.