Studies on β-Lactam Antibiotics for Medicinal Purpose. XIII. Synthesis and Structure-Activity Relationships of 7β-[α-(4-Alkyl-2, 3-dioxo-1-piperazinecarboxamido)-α-substituted acetamido]-7α-methoxycephalosporanic Acids

Abstract

7β-[α-(4-Alkyl-2, 3-dioxo-1-piperazinecarboxamido)-α-substituted acetamido]-7α-methoxycephalosporanic acids (Ia-q) were prepared and tested for antibacterial activity. Ia-q showed potent activities to gram-negative bacilli, particularly to Escherichia coli, Klebsiella pneumoniae and Serratia marcescens. Three of these compounds, 7β-[D-(-)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-propanamido]-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (Ia), 7β-[D (+)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-β-[(S)-hydroxy]-butanamido]-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (Ic) and 7β-[D (+)-α-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-β-[(S)-methoxy]butanamido]-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (II) were selected and evaluated for antibacterial activity against clinical isolates, stability against β-lactamases, acute toxity, serum level, urinary and biliary excretions and protective effect against experimental infection compared with cefmetazole (CMZ). These evaluations suggest that Ic will be a useful antibiotic for clinical applications.