Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogs related to latamoxef (moxalactam)

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Abstract
Relationships between intrinsic antibacterial activity and .beta.-lactam reactivity of 7.beta.-[(4-hydroxyphenyl)acetyl]amino- and 7.beta.-[(4-hydroxyphenyl)malonyl]amino derivaties of 1-oxa- and 1-thiacephems, with or without the 7.alpha.-methoxy group (1-8), were investigated to clarify the enhanced antibacterial activity of latamoxef disodium. Substituent effects of a C atom at the 1- and 7.alpha.-positions were also investigated by using racemic 1-carbacephem and 7.alpha.-methyl-1-oxacephem (10). Syntheses of 2-8 and 10 are also described. Acid chlorides derived from the O-benzyloxycarbonyl derivative of (4-hydroxyphenyl)acetic acid and the p-methoxybenzyl derivative of (4-hydroxyphenyl) malonic acid smoothly effected the introduction of these side chains. Conjugate addition of lithium dimethylcuprate to a quinoid system proceeded stereospecifically, furnishing the 7.alpha.-methyl group for the synthesis of 10. Values of log (1/concentration) averaged for the sensitive gram-negative strains (Escherichia coli NIHJ JC-2 and Klebsiella pneumoniae SRL-1) were taken as an estimation of the intrinsic antibacterial activity. The chemical reactivity of the .beta.-lactam ring was estimated by pseudo-1st-order rate constants (k) of alkaline hydrolysis measured at pH 9.20.degree. and 35.0.degree. C or by IR stretching frequencies of the .beta.-lactam carbonyl measured in dimethyl sulfoxide. Substitution of an O atom at the 1-position increased the hydrolysis rates and the antibacterial activity by a factor of .apprx. 6.3; substitution of a 7.alpha.-methoxy group increased the antibacterial activity by a factor of .apprx. 3.2 without significant change in the hydrolysis rates. The effect of the 7.alpha.-methoxy group on the transition state in alkaline hydrolysis is discussed. Substitutions at the 1-position with a methylene group and, especially, at the 7.alpha.-position with a methyl group greatly diminished the antibacterial activity; the hydrolysis rate remained high with the substitution of a methylene group. Substitution of an O atom for the S atom at the 1-position of 1-thiacephems increased the .beta.-lactam carbonyl frequencies by .apprx. 6 cm-1; introduction of a 7.alpha.-methoxy group in 1-thia- and 1-oxacephems reduced the frequencies by .apprx. 5 cm-1.

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