オキサセフェム系抗生物質の開発研究

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A pioneering work in the field of oxacephem antibiotics which had been carried out in our research laboratories is reviewed. Our research of β-lactam antibiotics was started in 1974 with the policy to make chemical modification at the nuclei but not the side chain of the existing β-lactam antibiotics, with an expectation to discover a new type of antibiotics. After the success in establishing an efficient synthetic method for 3'-nor-cephalosporin, we started oxacephem research in 1975. We succeeded in developing three synthetic methods starting from penicillins which efficiently served to prepare numerous oxacephem (1-oxa-1-dethia-cephalosporin) derivatives. It turned out that the oxacephem nucleus was much more distorted with an increased ring strain, resulting in reduction of the β-lactam amide resonance to a greater extent than the cephalosporin nucleus. This physicochemical properties conferred an increased chemical reactivity on the nucleus as evidenced by an increased hydrolysis rate as compared with the corresponding 1-thia counterpart. This increased chemical reactivity coupled with the reduced hydrophobicity of the oxacephem nucleus as evidenced by the lower distribution constant in a water-octanol system, characterized unique biological properties of oxacephem derivatives. These include (1) 2-16 times increase in antibacterial activity with emphasis against gram-negative bacteria ; (2) increased protecting effect in vivo parallel to the increased in vitro activity ; (3) reduction of the stability to β-lactamases leading to decreased antibacterial activity against the β-lactamase producing strains ; (4) 1.6-3.2 times increase in penetrability through the outer membrane of certain gram-negative bacteria, the increase being due to the increased hydrophilicity of the oxacephem nucleus ; (5) remarkably reduced binding to human serum albumin improving the efficacy of the oxacephems in the blood ; (6) a remarkable change in the excretion pattern, i.e. recovery in the bile reduced and that in the urine increased. These biological characteristics are generally favorable for antibacterial agents against pathogenic diseases except for the reduced stability to β-lactamases. This unfavorable property of the oxacephem nucleus was the only barrier for developing a new agent of the oxacephem nucleus. However, this problem was relatively easily solved by introduction of (1) the methoxy group at 7α and (2) appropriately α-substituted acyl amide side chain at 7β ; the former and the latter substituent effectively stabilized the oxacephems to various kinds of penicillinases and cephalosporinases, respectively. It turned out that both effects were complementary and, thus, combination of both substituents produced perfect stabilization of the oxacephems to β-lactamases, and brought about the complete recovery of the activity against resistant strains. Extensive studies were performed to obtain deep and broad knowledge in structureactivity relationships in the field of the newly explored oxacephems. As the results of these efforts we succeeded in obtaining two important and useful oxacephem compounds, i.e. latamoxef 18 and flomoxef 19. Latamoxef 18 is a very potent and broadly active third generation β-lactam antibiotic, and perfectly stable to various kinds of β-lactamases showing efficacy against most of the resistant bacteria. Moreover, it has very favorable pharmacological properties, such as a high blood level and a long half-life, which are essential for efficacy in human body. One of the drawback of this antibiotic, as commonly observed in the third generation antibiotics, was the rather weak activity against grampositive bacteria, especially against Staphylococcus aureus. This weak point was basically improved by introducing a new 7β-acylamido side chain and by a minor structural change in the N-methyl-tetrazol part, as seen in structure 19. Flomoxef can be characterized by its potent activity against S. aureus with ke
社団法人日本薬学会の論文
1991-02-25

オキサセフェム系抗生物質の開発研究

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