title: Orally active cephalosporins: synthesis, structure-activity relationships and oral absorption of 3-[(E) and (Z)-2-substituted vinyl]-cephalosporins.
abstract: A series of 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamid o]-3-[(E)- and (Z)-2-substituted vinyl]-3-cephem-4-carboxylic acids was designed and synthesized using palladium-catalyzed coupling reactions of a 3-methanesulfonyloxy-3-cephem and an E substituted vinyl stannane or Wittig reaction of a 3-triphenylphosphoniummethyl cephem and an aldehyde as a key step. These compounds were evaluated for in vitro antibacterial activity and oral absorption in rats. A number of them exhibited excellent antibacterial activity against both gram-positive and gram-negative bacteria including Haemophilus 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.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Kashima, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Terasawa
authors.forename: A
authors.initials: A
authors.lastname: Ohki
authors.forename: F
authors.initials: F
authors.lastname: Shirai
authors.forename: K
authors.initials: K
authors.lastname: Kawabata
authors.forename: K
authors.initials: K
authors.lastname: Sakane
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Tawara
mesh_terms: D000284:Administration, Oral; D002511:Cephalosporins / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D002511:Cephalosporins