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

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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-1, 4-dihydro-4-oxocinoline-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-alkyl-6, 8-difluoro- and 6-fluoro-1, 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.