A series of novel 7-substituted 1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids have been prepared and tested for antibacterial activities and for convulsive activities in combination with nonsteroidal antiinflammatory drug. Structure-activity relationships revealed that 7-(2-(aminomethyl)morpholino) derivative 28 had a better Gram-positive activity than the reference quinolones, such as ciprofloxacin, norfloxacin, and ofloxacin. Its Gram-negative activity was equipotent with those of norfloxacin and ofloxacin but was inferior to that of ciprofloxacin. In mouse systemic infection models, 28 showed an excellent therapeutic efficacy which might result from the potent antibacterial activity and suitable physicochemical properties. Convulsive activities of 7-morpholino derivatives in combination with nonsteroidal antiinflammatory drug fenbufen or its metabolite biphenylacetic acid markedly diminished as compared to those of 7-piperazino derivatives in the electrophysiological, biochemical, and behavioral experiments. These results suggest that 28 (Y-26611) is a novel quinolone with reduced neurotoxic excitatory adverse reaction.

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Synthesis and antibacterial activities of 7-[2-(2-amino-1,3,4-thiadiazol-5-yl)acetamido]-cephalosporins and their derivatives having the methoxyimino group at the 2-position of the 7-acyl moiety are described. These compounds are of interest as structural analogues of potent antibiotics,showed comparable activity with cefazolin. Introduction of methoxyimino group to the 7-side chain resulted in a lowering of activity. Chemistry 2-Amino-1,3,4-thiadiazol-5-ylacetic acid (4a) has been prepared by alkaline hydrolysis of the corresponding ester 3a'>. When the N-trityl derivative (3b) was hydrolyzed with aqueous potassium hydroxide and the reaction mixture was then acidified by hydrochloric acid at 0'C, spontaneous evolution of gaseous carbon dioxide occurred to give quantitatively 5b (mp 197-198'C). In contrast to easy decarboxylation of the N-trityl acid (4b), the N-formyl derivative (3c) gave the desired acid 4c in 71yield by a similar treatment. The N-chloroacetyl derivative (3d) also afforded 4d in 56% yield together with 5d. The acid 4d was more conveniently obtained in 85 % yield by chloroacetylation of 4a.

The title compounds have been synthesized from N-protected l-aspartic acid via Curtius rearrangement.