STUDIES ON CONDENSED-HETEROCYCLIC AZOLIUM CEPHALOSPORINS .1. SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF 7-BETA-[2-(2-AMINOTHIAZOL-4-YL)-2(Z)-ALKOXYIMINOACETAMIDO]-3-(IMIDAZO[1,2-A]PYRIDINIUM-1-YL)METHYL-3-CEPHEM-4-CARBOXYLATES

In our study of the structure-activity relationships of cephalosporins bearing quaternary ammonium groups at the 3 position, we postulated that delocalization of the azolium positive charge would lead to an expanded antibacterial spectrum and increased activity. Since quaternization of condensed-heterocyclic compounds such as imidazo[1,2-a]pyridine gives positive charge delocalization, 7-beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]cephalosporin derivatives (1 approximately 53) bearing various (imidazo[1,2-a]pyridinium-1-yl)methyl moieties at the 3 position were prepared and their antibacterial activity was determined. As expected, these cephalosporins exhibited potent activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. These results imply that imidazo[ 1,2-a]pyridine is a quite useful substituent for improving antibacterial activity and spectrum. The structure-activity studies revealed that a favorable substituent on the imidazo[1,2-a]pyridine is the cyano radical at the 6 position of the ring, and ethoxyimino or 1-carboxy-1-methylethoxyimino groups are suitable for the alkoxyimino substituent. Among the cephalosporins tested, 7-beta-[2-(2-aminothiazol-4-yl)-2(Z)-ethoxyiminoacetamido]-3-(6-cyanoimidazo [1,2-a]pyridinium-1-yl)methyl-3-cephem-4-carboxylate (45) and 7-beta-[2-(2-aminothiazol-4-yl)-2(Z) -(1-carboxy-1-methylethoxyiminoacetamido]-3-(6-cyanoimidazo[1,2-a]pyridinium-l-yl)methyl-3-cephem-4-carboxylate (49) showed good antibacterial activity.