Synthesis and structure-activity relationships of carbapenems related to C-19393 H2.

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Abstract
By applying a previously reported synthetic process new carbapenems having various (substituted) thio and alkoxy groups at the C(3) position and 1-hydroxy-1-methylethyl and analogous groups at the C(6) position with cis- and trans-stereochemistry in activity; the in vitro antibacterial and .beta.-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds showed improved in vitro antibacterial activity especially against Pseudomonas aeruginosa; they showed a strong .beta.-lactamase inhibitory activity as well. Two noteworthy effects of substituent variation at the C(6) position on the activities were observed: the trans-configuration caused a definite loss in activity; and introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem.