Meropenem derivatives

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

Meropenem (Merrem IV) is a dimethylcarbamoyl pyro-lidinyl derivative of thienamycin. It does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures (0.5% of meropenem- and 1.5% of imipenem-treated patients seized). Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa but less activity against Gram-positive cocci. Chnical experience with meropenem demonstrates therapeutic equivalence with imipenem. 

MEROPENEM Meropenem (merrem iv) is a derivative of thienamycin that does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity and clinical efficacy are similar to imipenem, except that it may be less likely to cause seizures. 

It was discovered that the A -formimidoyl derivative both stabilised the molecular and enhanced the antipseudomonal activity [7]. The basic starting material for both imipenem and meropenem is 4-acetoxy-2-azetidinone (4-AA) (8), a well known heterocycle synthon which can readily be converted to 9 [8]. 

The MALDI-TOF MS assay described above was able to detect the presence of an approximately 39,850-w/z peak, which can be used as an indicator for the presence of the C. ew c(//-derived CMY-2-like group of the acquired AmpC P-lactamases (Papagiannitsis et al. 2014). In addition, the observation of the 39,670 and 38,900-w/z peaks for ACC-4 and DHA-1 enzymes, respectively, indicated that MALDI-TOF MS may discriminate the diverse groups of acquired AmpC-type cephalosporinases (see Fig. 12.4). In addition, the latter method revealed a peak at mIz 383, representing the putative acyl-enzyme complex (complex of CMY-2 P-lactamase with the meropenem molecule). 

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