Heteroaryliumthio substituted carbapenem derivatives: synthesis and in vitro activity of 1 beta-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems.

The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.