Quinolonecarboxylic acids. 2. Synthesis and antibacterial evaluation of 7-oxo-2,3 dihydro-7H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acids

• Published in: Journal of medicinal chemistry Vol. 30; no. 3; pp. 465 - 473
• Main Authors: Cecchetti, Violetta, Fravolini, Arnaldo, Fringuelli, Renata, Mascellani, Giuseppe, Pagella, Piergiuseppe, Palmioli, Maurizio, Segre, Giorgio, Terni, Patrizia
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.1987
• Subjects: Anti-Bacterial Agents - chemical synthesis; Chromatography, High Pressure Liquid; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Indicators and Reagents; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Pyridones - chemical synthesis; Pyridones - pharmacology; Spectrophotometry, Infrared; Thiazines - chemical synthesis; Thiazines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00386a005

A series of pyridobenzothiazine acid derivatives was synthesized and their in vitro antibacterial activity was evaluated. The 1,4-benzothiazine intermediates, which by Gould-Jacobs quinoline synthesis produced pyridobenzothiazine acids, were prepared by hydrolytic basic cleavage of substituted 2-aminobenzothiazoles and successive cyclocondensation with 1-bromo-2-chloroethane or alternatively with monochloroacetic acid, hence reduction by LiAlH4. The pyridobenzothiazine acids 10c, 30, and 31 show potent antibacterial activities against Gram-positive and Gram-negative pathogens. Structure-activity relationships are discussed. The compound 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d e] [1,4]benzothiazine-6-carboxylic acid (31) (MF-934) has been found to possess, together with the antibacterial activity, a weak acute toxicity and interesting pharmacokinetic characteristics in several animal species (rat, dog, monkey, man).