セフェム系経口剤「セフィキシム」及び「セフジニル」の研究開発

スポンサーリンク

概要

• 論文の詳細を見る

• This article reviews the structure-activity relationships, biological properties and synthesis of two new oral cephalosporin antibiotics, cefixime (CFIX) and cefdinir (CFDN). Our research into new oral cephalosporin antibiotics began in the late 1970's. The first goal of our research was to discover a new oral cephem possessing similar antibacterial activity and resistance to β-lactamase as the 3 rd generation injectable cephalosporins. We focused our attention on searching for a non-prodrug type cephem, that is, a new parent structure with high intrinsic absorption. We selected ceftizoxime (CZX) as a seed compound due to its relatively high excretion rate (8.5%) in the urine after oral administration to rats. We concentrated our research on the chemical modification of the oxime moiety in CZX based on our hypothesis for oral absorption, and discovered a lead compound with a carboxymethoxyimino group which displayed better urinary excretion (41.0%). Optimization studies led to a new oral cephem, CFIX. However, CFIX shows only low to moderate antibacterial activity against gram-positive bacteria such as S. aureus. Hence, the second goal of our research was to discover a new oral cephem with enhanced activity against gram-positive bacteria. From a consideration of structure-absorption relationships, we studied the activity and absorbability of cephems bearing other acidic functional groups at the oxime moiety of CFIX. As a result, we found a new oral cephem, CFDN with a hydroxyimino group at the 7-position. CFIX has excellent biological properties, displaying potent antibacterial activity against a wide range of gram-positive bacteria except S. aureus and gram-negative bacteria including opportunistic pathogens, high stability towards β-lactamases and long acting efficacy. CFDN exhibits excellent and well balanced antibacterial activities against gram-positive and gram-negative bacteria. The pharmacokinetic of CFDN in healthy volunteers showed that serum levels were high enough to make CFDN as an effective antibacterial agent. The proposed mechanisms of intestinal absorption of CFIX and CFDN are briefly described. The efficient synthetic methods to CFIX and CFDN were achieved via a common intermediate, 7-amino-3-vinylcephalosporanic acid diphenylmethyl ester from 7-ACA.

• 公益社団法人日本薬学会の論文
• 1993-09-25

著者

• 川端 浩二

  藤沢薬品工業

• 川端 浩二

  藤沢薬品工業(株)新薬研究所

• 高谷 隆男

  藤沢薬品工業

• 坂根 和夫

  藤沢薬品工業(株)新薬研究所

• 稲本 美子

  藤沢薬品工業(株)新薬研究所

• 山中 秀昭

  藤沢薬品工業(株)新薬研究所

関連論文

• セフェム系経口剤「セフィキシム」及び「セフジニル」の研究開発
• FK482(Cefdinir)に関する研究(第4報)7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-substituted Cephalosporin誘導体の合成並びに構造活性相関
• FK482(Cefdinir)に関する研究(第3報)7β-[(Z)-2-Aryl-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic Acid誘導体の合成並びに構造活性相関
• FK482に関する研究(第2報)7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic Acid誘導体の合成並びに構造活性相関

スポンサーリンク