The synthesis and biological activity of (l i?,5S,6S)-2-[(3SV5S)-5-substituted pyrrolidin-3-ylthio]-6-[(l i?)-l-hydroxyethyl]-l-methylcarbapen-2-em-3-carboxylic acids are described. These compounds exhibit potent antibacterial activity against a wide range of both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. Of these new carbapenems, (lR,5S,6S)-2-[(3S,5S)-5sulfamoylammomethyl pyrrolidin-3-ylthio]-6-[(l i?)-l-hydroxyethyl]-l-methylcarbapen-2-em-3-carboxylic acid (S-4661) showed the most potent and well balanced activity and was selected as a candidate for further evaluation. The carbapenem compounds which have a (3S)pyrrolidin-3-ylthio group at the C-2 position in the carbapenem skeleton are noted for their broad and potent antibacterial activityJ), and a large numberof derivatives have been synthesized and investigated with enthusiasm. Amongthose compounds, panipenem2) was the first to be successfully launched in the market and clinical evaluations are in progress for meropenem3), BO-27274) and DX-87395) which have enhanced metabolic stability to renal dehydropeptidase-1 (DHP-1) because of the introduction of a l/?-methyl group to the carbapenem
Wedescribe an efficient method for introducing a sulfamoylamino group into the C-2' position of pyrrolidine using the Mitsunobu reaction. S-4661, its JV-methyl analogues and stereoisomers were synthesized using this method and their structure-activity relationships were investigated.
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