| Abstrakt: |
The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-β-methylcarbapenems containing a variety of cationic heteroaromatic substituents is described. As a result of these studies, we uncovered a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 (1c)Scheme 3Synthetic route to novel carbapenems. Reagents and conditions:(i) NaOMe, MeOH, (or TFA, Et3SiH), then 24, iPr2EtN, DMAC, MeCN; (ii) MeI, Me2CO or THF; (iii) ICH2CONH2, Me2CO; (iv) I(CH2)3NHAoc, DMF; (v) MeOTf, CH2Cl2; (vi) FSO3Me, CH2Cl2; (vii) Pd(PPh3)4, PPh3, THF–EtOH, nBu3SnH or morpholine; (viii) Pd(OH)2-C, H2, THF–phosphate buffer (pH 6.5)., containing a two methylene spacer moiety and an imidazolio group, which possesses a balanced spectrum of antibacterial activity, including Pseudomonas aeruginosaand Methicillin-resistant Staphylococcus aureus(MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydropeptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by introduction of a substituent on to the imidazole ring. |
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