Studies on FK482. II. Synthesis and Structure-Activity Relationships of 7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic Acid Derivatives

Abstract

Various 7β-[2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives (Ia-e, IIa-g) were synthesized in order to find a new orally active cephalosporin improving the antibacterial activity of cefixime (CFIX) against Staphylococcus aureus. These derivatives include three types of α-substituted 2-(2-aminothiazol-4-yl) acetyl side chain ; i) mono or non substituted acetyl moiety, ii) carboxyalkoxyimino acetyl moiety, iii) phosphonomethoxyimino and hydroxyimino acetyl moiety. Their structure-activity relationships and urinary recoversies in rats were studied. As a result, the compound with a hydroxyimino acetyl side chain (IIg, FK482) showed good oral absorption and excellent antibacterial activity against both gram-positive and gram-negative bacteria and was selected as a candidate for clinical trial.