THE SYNTHESIS AND BIOLOGICAL CHARACTERISTICS OF NEW ORALLY ACTIVE CEPHEMS

The chemotherapeutic significance of oral antibacterial agents is evidenced by their ability to generate annual sales of several billion dollars. Although many useful agents are currently available, the search for new, more potent compounds with broader spectra of activity continues. Our own efforts in this area have been influenced by the activity and pharmacokinetic properties of FK-482 (1). FK-482 is characterized by a (Z)-2-(2-aminothiazol-4-yl) 2-hydroxyiminoacetamido group at C-7 of a 3-vinyl cephalosporin nucleus. The 3-vinyl nucleus has previously been shown to support oral bioavailability with other side chains attached to the C-7 nitrogen. Thus, we chose to append the (Z)-2-(2-aminothiazol-4-yl) 2-hydroxyiminoacetyl group to the 3-chlorocephalosporin and 3-chloro-1-carba-1-dethiacephalosporin nuclei since they serve as the foundation for the well known oral agent Ceclor (cefaclor) and the recently introduced Lorabid (loracarbef).