Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.
Orally active 1-(cyclohexyloxycarbonyloxy)alkyl ester prodrugs of cefotiam.
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口服活性头孢替安 1-(环己氧基羰氧基)烷基酯前药。
DOI：
10.7164/antibiotics.40.81
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
M. Numata
中科院分区：
文献类型：
--
作者：
Nishimura Tatsuo;Y. Yoshimura;A. Miyake;M. Yamaoka;K. Takanohashi;N. Hamaguchi;S. Hirai;T. Yashiki;M. Numata
研究了7 β-[2-（2-氨基噻唑-4-基）乙酰氨基]-3- [1-（2-二甲基氨基乙基）-1H-四唑-5-基]硫代]-甲基]头孢替安-3-烯-4-羧酸（头孢替安，CTM）的口服活性1-（烷基取代的环己氧基羰氧基）烷基酯前药（9 b-h）以及硫杂（9 i）和氮杂（9 j）类似物。这些代表CTM的1-（环己基乙酰氧基）乙酯（2）的衍生物。介绍了其合成方法和小鼠口服生物利用度。其中，1-（环己氧基羰基氧基）丁酯（9 h）的BA最高，为93.5%;酯部分具有环己氧基的酯的BA超过75%，尽管1-（乙氧基羰基氧基）乙酯（9a）的BA仅为23.9%。硫杂类似物显示出中等的BA，46%，但氮杂类似物9 j没有显示出CTM的BA。这些结果表明，1-（取代环己氧基羰基氧基）烷基是改善CTM口服BA的合适的引入基团。手性1-（烷氧基羰基氧基）烷基用作酯部分，得到几乎1：1的非对映异构体酯的混合物。这些都是这样测试的。然而，口服给药1-（环己氧基羰基氧基）乙酯（9d）的分离的异构体的实验证实，两种非对映异构体得到相同的BA。
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.