DERIVATIVES OF BENZIMIDAZOLYLALKANOIC ACIDS

• Main Authors: TSUNG-YING SHEN, HARVEY SCHWAM, ALEXANDER RICHARD MATZUK
• Format: Patent
• Language: English
• Published: 05.08.1970
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; METALLURGY; ORGANIC CHEMISTRY

1,200,907. Derivatives of benzimidazolylalkanoic acids. MERCK & CO. Inc. 27 Nov., 1967 [2 Dec., 1966], No. 53872/67. Heading C2C. Novel compounds of formulµ Ia and Ib in which A is an aryl, aralkyl, heteroaryl, heteroaralkyl, aroyl, aralkanoyl, heteroaroyl or heteroaralkanoyl radical of fewer than three fused rings, either unsubstituted or having one or more hydrocarbon, hydroxy, alkoxy, C 1-6 alkanoyloxy, aryloxy, aralkoxy, alkoxyaryloxy, alkoxyaralkoxy, nitro, halogen, amino, amine oxide, C 1-6 alkylamino, di-(C 1-6 alkyl)-amino, C 1-6 alkanoylamino, amidino, hydrazino, alkoxyamino, sulfonylamino, mercapto, alkylthio, aralkylthio, arylthio, trifluoromethylthio, methylbenzylthio, halogenated alkyl, acyl, haloalkoxy, haloalkylthio, sulfamoyl, benzylthiomethyl, cyano, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, di-(C 1 _ 6 alkyl)-sulfamoyl, C 1-6 aminoalkyl, di-(C 1-6 alkyl)-amino-(C 1 _ 6 alkyl), carboxy, COOM0, where M‹ is an alkali metal, di- (C 1-6 alkyl)-carbamoyl, amido, azido or (C 1-6 alkoxy)-carbonyl substituents or a methylenedioxy group attached to adjacent carbon atoms of the aromatic radical; R 1 is methylene, ethylene or ethylidene; R 2 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, nitro, amino, C 1-6 alkylamino, di-(C 1-6 alkyl)-amino, C 1 _ 6 alkanoylamino, C 1-6 alkanoyl, bis-(C 1-6 hydroxyalkyl)-amino, 1-pyrrolidino, 4-methyl-1- piperazinyl, 4-morpholinyl, cyano, trifluoromethyl, halogen, di - (C 1-6 alkyl)-sulfamoyl, benzylthio, C 1-6 aminoalkyl, di-(C 1-6 alkyl). amino - (C 1-6 alkyl), trifluoromethylthio, benzyloxy, (C 1-6 alkyl) - benzyloxy, (C 1 _ 6 alkoxy) - benzyloxy, C 2-6 alkenyl, C 2-6 alkenyloxy, 1-azacyclopropyl, cyclopropyl, cyclopropyl - (C 1-6 alkoxy) or cyclobutyl - (C 1-6 alkoxy) and R 3 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or trifluoromethyl, with the proviso that when A is attached to the carbon atom of the imidazole ring, at least one of R 2 and R 3 is other than hydrogen, halogen and hydroxy; and M is hydroxyl, esterified hydroxy, OZ (where Z is a cation), OY (where Y is acyl), amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methylethylamino, methylbutylamino, dibutylamino, glucosamino, glycosylamino, allylamino, phenethylamino, N- ethylphenethylamino, #-hydroxyethylamino, 1 - ethyl - 2 - aminomethyl piperidino, tetrahydrofurfurylamino, 1,2,5,6 - tetrahydropyridino, morpholino, N-methyl piperazino, piperazino, N-phenyl piperazino, piperidino, benzylamino, anilino, cyclohexylamino, pyrrolidino, N-hydroxyethyl piperazino, sodium #- sulfoethylamino, N,N - dimethylcarboxamidomethylamino, N,N - dimethylaminoethylamino, p - methoxyanilino, 1 - methyl - 2 - aminomethyl pyrrolidino, or N-carbobenzyloxymethylamino, are prepared by one of the following methods: (a) when A is an acyl radical in the 1-position by reacting an appropriate o-phenylenediamine with an ester of α-cyanoacetic acid or α- or #-cyanopropionic acid to form the corresponding 2-benzimidazolyl alkyl nitrile which is converted into the corresponding acid or ester and acylated in the unsubstituted 1-position; (b) when A is an acyl radical in the 2-position, an appropriate ophenylenediamine is reacted with an acid of formula A-CH(OH)COOH to produce an 2 - [A - CH(OH)] - benzimidazole which is oxidized to the corresponding 2-acyl compound which is treated with an ester of α-haloacetic or α- or #-halopropionic acid; (c) when A is not acyl and is in the 2-position, an appropriate o-phenylenediamine is reacted with an acid of formula A-COOH to give a 2-A-benzimidazole which is reacted with an ester of α-haloacetic or α- or #-halopropionic acid; (d) when A is not acyl and is in the 1-position, an appropriate o-nitraniline is reacted with a halide of formula A-halogen or an aldehyde of formula ACHO to give an N-substituted nitraniline which is reduced to give the corresponding N-substituted o-phenylenediamine which is reacted with succinic anhydride an α-cyanopropionate or α-cyanoacetate; (e) an acid or ester is converted into a compound where M is other than OH or esterified hydroxy by standard methods; and (f) a group R 2 or R 3 is converted into a different group R 2 or R 3 . Pharmaceutical compositions in conventional forms for oral and parenteral administration and having anti-inflammatory, anti-pyretic and analgeric activity comprise an above novel compound and a carrier, coating or exipient.