Orally active cephalosporins: Synthesis, structure-activity relationships and oral absorption of 3-[(E) and (Z)-2-substituted vinyl]-cephalosporins

A series of 7 beta-[(Z)-2-(2-aminothiazol-3-yl)-2-hydroxyiminoacetamido]-3- [(E)- and (Z)-2-substituted vinyl]-3-cephem-4-carboxylic acids was designed and synthesized using palladium-catalyzed coupling reactions of a 3-methan esulfonyloxy-3-cephem and an E substituted vinyl stannane or Wittig reactio n of a 3-triphenylphosphoniummethyl cephem and an aldehyde as a key step. T hese compounds were evaluated for in vitro antibacterial activity and oral absorption in rats. A number of them exhibited excellent antibacterial acti vity against both Gram-positive and Gram-negative bacteria including Haemop hilus influenzae. Among them, FR86524 (2j), having a (Z)-2-(3-pyridyl)vinyl moiety at the C-3 position, had the most well balanced activity. Although FR86254 exhibited low oral absorption, the pivaloyloxymethyl ester (23) of FR86524 showed improved oral absorption. (C) 2000 Elsevier Science Ltd. All rights reserved.