Pyridone-carboxylic acids as antibacterial agents. I. Synthesis and antibacterial activity of 1-alkyl-1,4-dihydro-4-oxo-1,8- and 1,6-naphthyridine-3-carboxylic acids.

Abstract

Condensation of 2-amino-6-chloropyridine (1) with diethyl ethoxymethylenemalonate gave the aminomethylenemalonate 2, which upon thermal cyclization (Gould-Jacobs reaction) afforded ethyl 7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (3). Alkylation of 3 produced the 1-alkyl derivative 4. Substitution of 4 with a cyclic amine gave ethyl 7-substituted 1-alkyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (5). The ester 5 was hydrolyzed to the corresponding carboxylic acid 6. 7-Substituted 1-alkyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acids (20) were also synthesized from 4-amino-2-chloropyridine (13) in a similar manner. The in vitro antibacterial activity was enhanced by the presence of a cyclic amine at position 7 on 6 and 20. In general, the 1,8-naphthyridine 6 was more active than the 1,6-naphthyridine counterpart 20. 1-Ethyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (6e) (an analog of pipemidic and nalidixic acid) was comparable to pipemidic acid but superior to nalidixic acid in terms of activity in vitro against Pseudomonas aeruginosa.