1,4-Dihydro-4-oxopyridinecarboxylic acids as antibacterial agents. 2. Synthesis and structure-activity relationships of 1,6,7-trisubstituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids, including enoxacin, a new antibacterial agent

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Abstract
The title compounds having nitro, amino, cyano, chloro or fluoro as the C-6 substituent were prepared. Introduction of the chloro and cyano groups at C-6 was accomplished by the Sandmeyer reaction of 6-amino-1,8-naphthyridine derivatives via their 6-diazonium salts. The reaction was extended to the synthesis of the 6-fluoro analogs, involving the Balz-Schiemann reaction of the diazonium tetrafluoroborate. A series of the 1-ethyl, 1-vinyl, 1-(2-fluoroethyl) and 1-(difluoromethyl) analogs of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared. 1-Pyrrolidinyl and, particularly, N-substituted or unsubstituted 1-piperazinyl groups were introduced as the C-7 variants. 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (enoxacin, originally AT-2266) showed that the most broad and potent in vitro antibacterial activity, an excellent in vivo efficacy on systemic infections and a weak acute toxicity. Structure-activity relationships of compounds with variations of substituents at C-1, C-6 and C-7 are also discussed.