A series of 5-substituted-6-fluoro-7-(cycloalkylamino)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acids have been prepared and tested for their in vitro and in vivo antibacterial activities. The 5-methyl group gave better in vitro activity with the 1-cyclopropyl appendage, but poorer activity with the 1-tert-butyl moiety. With the 1-(2,4-difluorophenyl) substitution, the influence of the 7-cycloalkylamino group was determinant: a (3S)-3-amino-pyrrolidine was shown to enhance greatly the in vitro and in vivo activity of the 5-methyl derivative. Compound 33 (BMY 43748) was selected as a promising candidate for an improved therapeutic agent.

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A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3- carboxylic acids has been prepared. These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position. In this paper we report the full details of the asymmetric synthesis of this series of compounds. Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity. Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.

A series of novel 7-piperazinyl-1-substituted-6-fluoroquinolones and naphthyridines have been prepared and their antibacterial activities evaluated. These derivatives are characterized by having alkyl, alkenyl, arylalkyl, cycloalkyl, and cycloalkenyl groups at the 1-position. As a result of this study, derivatives 7 and 26, which are substituted with tert-butyl groups at N-1, were found to possess excellent in vitro and in vivo potency, particularly against Staphylococcus aureus, comparable to that of norfloxacin or ciprofloxacin. Structure-activity relationships of N-1 substituted alkyls and cycloalkyls are also discussed.

A number of 7-substituted-1-tert-butyl-6-fluoroquinolone-3-carboxylic acids and 7-substituted-1-tert-butyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids have been prepared and tested for antibacterial activities. Among those the 7-aminopyrrolidinyl 20b and the 7-diazabicyclo naphthyridine 18b are the most potent compounds in vitro and in vivo. Physicochemical data and acute toxicity are also discussed. Compound 18b, BMY 40062, exhibits the most favorable overall properties, considering in vitro and in vivo microbiological activity, its low toxicity, and pharmacokinetic profile, and was selected for clinical evaluation.