Fluorocinnoline Derivatives. II. Synthesis and Antibacterial Activity of Fluorinated l-Alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic Acids

Abstract

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-l,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alky 1-6,8-difluoro-and 6-fluoro-l,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17—35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin. floxacin; antibacterial agent fluorinated 4-oxocinnoline-3-carboxylate; alkylation; 7-amino-4-oxocinnoline-3-carboxylic acid; cinoxacin. © 1989, The Pharmaceutical Society of Japan. All rights reserved.