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

By applying the synthetic process reported in our previous paper, we synthesized 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; the in vitro antibacterial and beta-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds (e.g., 11A-a-3 approximately 5) 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: 1) the trans-configuration caused a definite loss; and 2) introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem (13A-a-2) with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem (11A-a-12).