Synthesis and Biological Activity of 1-Methyl-2- (5 0 -isoxazoloethenylpyrrolidin-3 0 -ylthio)carbapenems

ÐA new series of 1b-methylcarbapenems 1a±i bearing isoxazoloethenyl groups on the pyrrolidine ring has been prepared and evaluated for in vitro antibacterial activity and stability to DHP-I. Most compounds showed excellent antibacterial activity and high stability to DHP-I superior to that of meropenem. Of these new carbapenems, 1a,b,h exhibited the best combination of antibacterial activity and DHP-I stability. # 2000 Elsevier Science Ltd. All rights reserved. Recently, 1b-methylcarbapenems have received much attention because of their excellent biological and chemical behavior. Meropenem, which has potent antibacterial activity and high stability to dehydropeptidase-I (DHP-I), has been launched on the market and several compounds are currently under clinical or preclinical evaluation.3y6 In a recent paper we described the synthesis, antibacterial activity, and stability to DHP-I of a series of novel 1b-methylcarbapenems containing the isoxazolopyrrolidine moiety. These carbapenems exhibited potent and well-balanced antibacterial activity including P. aeruginosa as well as high stability to DHP-I comparable to that of meropenem. Also, Banyu scientists recently reported carbapenems possessing potent antiMRSA activity, and demonstrated that the increased lipophilicity of the C-2 side chain of carbapenem enhanced anti-MRSA activity.8y10 Taking these results into consideration, we investigated the incorporation of ethenyl group as a hydrophobic spacer between pyrrolidine ring and isoxazole moiety in order to enhance the anti-Gram-positive activity. The resulting new carbapenems were found to exhibit excellent antibacterial activity against both Gram-positive and Gram-negative bacteria and possess high stability to DHP-I. Especially, these carbapenems showed excellent activity against Gram-positive bacteria compared to parent carbapenems containing the isoxazolopyrrolidine moiety. In this paper, we wish to disclose the synthesis and biological evaluation of new 1b-methylcarbapenems 1a±i having a 50-isoxazoloethenylpyrrolidin-30-ylthio group as a C-2 side chain (Fig. 1).