Studies on the Synthesis and Antibacterial Activity of New Carbamoylpyrrolidinylthio-carbapenems.

Abstract

In the preceding paper1*, we reported the synthesis and biological properties of carbapenem compounds having a 5'-aromatic heterocyclic carbamoyl pyrrolidin-3'-yl thio group as the C-2 side chain and their extended antibacterial spectrum. In order to obtain good antibacterial activities against Pseudomonasaeruginosa and high stability to renal dehydropeptidase-I (DHP-I), we studied the modification of substituents on the pyrrolidine ring. Some new carbapenem derivatives having a 5'-(substituted or unsubstituted carbamoylalkylthioalkyl)pyrroridin-3'-ylthio group at the carbapenem C-2 position were synthesized. It is well known that functionalized alkyl pyrrolidine carbapenems show both good antipseudomonal activity and improved stability against DHP-I2 3). Synthesis of Carbapenem la, 2c, 4a and 4bTreatment of enolphosphate3) with freshly prepared thiol compound(6) afforded 2-substituted carbapenem (7). Deprotection of (la) by hydrogenolysis over 10% Pd-C in the presence of 3-morpholinopropanesulfonic acid (MOPS) buffer (0.1 m, pH = 7.0) provided the target (l^,55f,65')-2-[(25r,45)-2-((carbamoylethyl)mercaptomethyl)pyrrolidin-4-y1]thio-6-\_(R)-1 -hydroxyethyl] -1 -methylcarbapen-2-em-3-carboxylic acid (la). After purification of the crude product by column chromatography on diaion HP-20, the carbamoylpyrrolidinyl carbapenem derivative (la)1" was obtained as an amorphorous solid. N-Methylimidoylation of compound t AH NMR (D2O) 3 1.26 (3H, d,.7=8Hz

Meropenem Exists in Equilibrium with a Carbon Dioxide Adduct in Bicarbonate Solution

“…1 In addition to the carbapenem pharmacophore, the 3′-pyrrolidinylthio group on C-2 is shared by a handful of compounds currently in clinical development and in the published literature. [2][3][4][5] Meropenem is marketed as a powder blend of crystalline drug and sodium carbonate (MERREM) for reconstitution and injection. 6 We report that meropenem exists partially as a covalent, reversible carbon dioxide adduct in solutions of MERREM that are representative of clinical concentrations.…”