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Orally active l-(alkyl substituted cyclohexyloxycarbonyloxy)alkyl ester prodrugs (9b~h) of 7/S-[2-(2-aminothiazol-4-yl)acetamido]-3- [[[l -(2-dimethylaminoethyl)l iy-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 l-(cyclohexylacetoxy)ethyl ester (2) of CTM. The syntheses and oral bioavailability (BA) in mice are described. Among them, the l-(cyclohexyloxycarbonyloxy)butyl ester (9h) gave the highest BA, 93.5%; the esters having a cyclohexyloxy group in the ester moiety gave BAsof more than 75 %, although the BA of the l-(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 BAof CTM.Chiral l-(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 l-(cyclohexyloxycarbonyloxy)ethyl ester (9d) were administered orally confirmed that both diastereoisomers gave identical BAs.In a series of papers from these laboratories, wehave reported that ester prodrugs of parenteral cephalosporins having both good water solubility^and Iipophilicity2~4) are absorbed well from the gastrointestinal (GI) tract and proved that among the cephalosporins studied, 1-acyloxyalkyl esters of 7/3-[2<2-aminothiazol-4-yl)acetamido]-3 -[3 -em-4-carboxylic acid (cefotiam, CTM) showed rather high oral bioavailability (BA(s)) in terms of CTM. Optimization of the 1-acyloxyalkyl promoiety of the CTMesters was then tried,*-3'4* and we found that the esters having a methyl, an ethyl or a propyl group as the alkyl moiety and a cycloalkyl or a branched alkyl group of 5~7 carbon atoms in acyloxy residue showed oral BAs as high as those of the orally active cephalosporins, e.g., cephalexin or cephradine in mice.Onthe other hand, although the l-(ethoxycarbonyloxy)ethyl ester group, an oxa analog of the 1-acyloxyalkyl group, has been used successfully to improve the oral BAof ampicillin5), there has been no report of it being successfully applied to improve the BAof cephalosporins probably because the esters involved have a low solubility in the GI fluid.6)Having been encouraged by finding that the l-(cyclohexylacetoxy)ethyl ester (2) of CTM,having an ester moiety with adequate lipophilicity and steric hindrance at AR2, showed a good water solubility in the vicinity of the physiological pH and a good oral BA, 107.8%,4) we became interested in applying the l-(cyclohexyloxycarbonyloxy)alkyl, cyclohexylthiocarbonyloxymethyl and iV-cyclohexylcarbamoyloxymethyl groups as oxa, thia and aza analogs of the promoiety of 2 to CTMto enhance * Yoshimura, Y. : Unpublish results.

An efficient optical resolution of (±)-(3aα,4α,6aα)-1,3-dibenzyl-3a,4,6,6a-tetrahydro-4-hydroxy-1H-thieno[3,4-d]imidazol-2(3H)-one [(RS)-1] was accomplished by acylation with lipoprotein lipase from Pseudomonas aeruginosa TE3285 in toluene. The lipase acylated (R)-1 enantioselectively, and unreacted (S)-1, which is a chiral d-biotin intermediate, was isolated in excellent chemical and optical yields (&gt;99% e.e.). Effects of acylating agents, water content and molecular sieves were also investigated.

The enzyme-catalyzed kinetic resolution of (±)-(3aα,4α,6aα)-4-acetoxy-1,3-dibenzyl-3a,4,6,6a-tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one [(RS)-(3a)] was examined. Lipase B from Pseudomonas fragi and rabbit liver esterase gave (−)-[3aR-(3aα,4α,6aα)]-1,3-dibenzyl-3a,4,6,6a-tetrahydro-4-hydroxy-1H-thieno[3,4-d]imidazol-2(3H)-one [(R)-(2)], while Streptomyces rochei var. volubilis gave the alcohol (S)-(2), which is a key intermediate in the synthesis of d-biotin, with high enantioselectivity.

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