PREPARATION OF l-ACYLOXYETHYL FSTERS OF 7[2-(2-AMINOTHIAZOL-4-YL)ACETAMIDO}3-[[ [1-(2-DIMETHYLAMINOETHYL)-1H-TETRAZOL5-YL]THIO]- METHYL]CEPH-3-EM-4-CARBOXYLIC ACID(CEFOTIAM) AND THEIR ORAL ABSORPTION IN MICE

In a separate study on the orally active acyloxymethyl esters(1)of 7{2一(2-aminothiazol4-yl)acetamido}3一[[[1一(2-dimethylaminoethy1)一1H-tetrazol-5-y1】thio]methyl]ceph-3-em-4-carboxylic acid(cefotiam, CTM), we have shown, by quantitative structure-oral bioavailability (BA)relation analysis, that the R2 group in the acyl group R2CO must have both an adequate lipophilicity(HANscH's lipophilic parameter,π)and steric hindrance(TAFT's Es value). However, to satisfy these requirements, a complex alkyl group R2 must be employed, the ester of which is difficult to synthesize and has unique metabolic fate. In this study, we selected and prepared the 1-acyloxyethyl esters(2)of CTM instead of l to avoid R2 groups that are too comphcated. We found that the esters(2)gave improved oral BAs over 1:the I一(3-methylvalerylOxy)ethyl eSter(2h)showed the highest peak plaSma CTM level(Cm。 。)COmparable tO that obtained after subcutaneous injection of CTM. The 1一(cyclohexylacetoxy)ethyl ester (2t), the I一(2-ethylbutyryloxy)ethyl ester(21), and 2h showed BAs near 100%. For these esters(2), good correlations were also observed among theπ, the Es values of R2, and the log Cm。x and log BA in the analysis of the quantitative structure-oral bioavailability relation: an ester having an alkyl group as R2 with a π value of 3.070r 3.08 and a Es value of-1.04 0r-1.29 gave the highest Cmax or BA, respectively. As expected, the optimalπvalues are almost the same as those obtained with l but the optimal Es values are larger(Es=一2.07). Thus, it has been confirmed by preparing 1-acyloxyethyl esters(2)of CTM that the oral bioavailability of CTM can further be improved without preparing acyloxymethyl esters(1)with a comphcated acyl group.