Synthesis and biological properties of some 3-((N-subtstituted-amino)pyridinium-4-thiomethyl)-7-((2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido)ceph-3-em-4-carboxylates.

Abstract

The synthesis and antibacterial activity of a series of /Mactamase stable, broad spectrum 7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido] -cephalosporins, characterised by a C-3-[Af-(substituted-amino)pyridinium-4-thiomethyl] group, is described.Gram-positive and Gramnegative bacteria including extended spectrum /?-lactamase-producing strains were most susceptible to the A^-amino-and iV-methylamino derivatives (3a) and (3b); with the exception of Pseudomonas aeruginosa, (3b) was more active in vitro and in vivo than cefpirome or ceftazidime.The development of the C-7 (2-aminothiazolyloxyimino)cephalosporins with their inherent good stability to /Mactamases has led to established antibacterial agents such as cefotaxime,1* ceftazidime2) and ceftriaxone3) and the newly marketed cefpirome.4) A primary concern in the search for new /Mactam antibiotics remains their stability to /Mactamases since these enzymes are still a major cause of treatment failure. The recent emergence of extended spectrum /Mactamase-producing bacteria has further highlighted the need for new potent broad spectrum agents with enhanced /Mactamasestability. Good activity against Gram-positive and Gram-negative bacteria including /Mactamase producing strains has been reported for 2-aminothiazolyloxyimino cephalosporins with a C-3[N-alkylpyridinium-4-thiomethyl]-or [J/V-alkylcyclopenteno[Z7]pyridinium-4-thiomethyl] group.5~7) Within these series, poor aqueous solubility and relatively high acute toxicity has been found for some derivatives lacking an additional carboxy group. Introduction of such an acidic moiety often improved solubility and toxicity but at the expense of someGram-positive potency. A recent report from these laboratories describes a series of 7a-formamido cephalosporins, characterised by a novel C-3 [A^-(substituted-amino)pyridinium-4-thiomethyl] group. 8) Although these compounds were highly /Mactamase stable agents with potent Gram-negative activity, including Pseudomonas aeruginosa, the Gram-positive activity was of borderline clinical utility. It was of interest therefore to investigate the effect of this particular C-3 substitution on the biological properties of conventional cephalosporins, where improved anti-staphylococcal potency might be anticipated. Our initial studies focused on 3-[(iV-substituted-amino)pyridinium-4-thiomethyl] -7-[2-(2-amino-thiazol-4-yl)-2-(Z)-(methoxyimino)acetamido] -ceph-3-em-4-carboxylates (3) which form the subject of this paper.Chemistry