title: Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.
abstract: Orally active 1-(alkyl substituted cyclohexyloxycarbonyloxy)alkyl ester prodrugs (9b-h) of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-3- [[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]-methyl]ceph+ ++-3- em-4-carboxylic acid (cefotiam, CTM) have been studied as well as the thia (9i) and aza (9j) analogs. These represent derivatives of the 1-(cyclohexylacetoxy)ethyl ester (2) of CTM. The syntheses and oral bioavailability (BA) in mice are described. Among them, the 1-(cyclohexyloxycarbonyloxy)butyl ester (9h) gave the highest BA, 93.5%; the esters having a cyclohexyloxy group in the ester moiety gave BAs of more than 75%, although the BA of the 1-(ethoxycarbonyloxy)ethyl ester (9a) was only 23.9%. The thia analog showed a moderate BA, 46%, but the aza analog, 9j, did not show a BA of CTM. These results indicate that the 1-(substituted cyclohexyloxycarbonyloxy)alkyl group was the suitable promoiety to improve the oral BA of CTM. Chiral 1-(alkoxycarbonyloxy)alkyl groups used as the ester moiety, gave an almost 1: 1 mixture of diastereoisomeric esters. These were tested as such. However, an experiment in which the separated isomers of the 1-(cyclohexyloxycarbonyloxy)ethyl ester (9d) were administered orally confirmed that both diastereoisomers gave identical BAs.
authors.forename: T
authors.initials: T
authors.lastname: Nishimura
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: A
authors.initials: A
authors.lastname: Miyake
authors.forename: M
authors.initials: M
authors.lastname: Yamaoka
authors.forename: K
authors.initials: K
authors.lastname: Takanohashi
authors.forename: N
authors.initials: N
authors.lastname: Hamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Hirai
authors.forename: T
authors.initials: T
authors.lastname: Yashiki
authors.forename: M
authors.initials: M
authors.lastname: Numata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002439:Cefotaxime / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D015310:Cefotiam; D007202:Indicators and Reagents; D007421:Intestine, Small / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D015310:Cefotiam; D002439:Cefotaxime