Orally active cephalosporins: synthesis, structure-activity relationships and oral absorption of 3-[(E) and (Z)-2-substituted vinyl]-cephalosporins.
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.
Yamamoto
H
H
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Kashima, Osaka, Japan.
Terasawa
T
T
Ohki
A
A
Shirai
F
F
Kawabata
K
K
Sakane
K
K
Matsumoto
S
S
Matsumoto
Y
Y
Tawara
S
S
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
D002511:Cephalosporins