Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.

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.