Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2- aminothiazol-4-yl)-3-(substituted)-2-propenoylamino]-3-cephems with C-3 substitutions.
Synthesis and biological activity of a series of 7 beta-[(Z)-2-(2- aminothiazol-4-yl)-3-(substituted)-2-propenoylamino]-3-cephe m-4-carboxylic acids with C-3 substitutions and their pivaloyloxymethyl esters are described. These acid compounds exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Pivaloyloxymethyl esters of selected compounds in this series were found to be well absorbed from small intestine in mice. Pivaloyloxymethyl 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-3- carbamoyloxymethyl-3-cephem-4-carboxylase hydrochloride hydrate (S-1108) was finally selected as the candidate for clinical evaluation.
Ishikura
K
K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Kubota
T
T
Minami
K
K
Hamashima
Y
Y
Nakashimizu
H
H
Motokawa
K
K
Kimura
Y
Y
Miwa
H
H
Yoshida
T
T
D000284:Administration, Oral; D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D002511:Cephalosporins; C076133:S 1108