In a separate study on the orally active acyloxymethyl esters (
1) of 7[2-(2-aminothiazol-4-yl)acetamido]3-[[[1-(2-dimethylaminoethyl)-1
H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (cefotiam, CTM), we have shown, by quantitative structure-oral bioavailability (BA) relation analysis, that the R
2 group in the acyl group R
2CO 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 R
2 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
1 to avoid R
2 groups that are too complicated. We found that the esters (
2) gave improved oral BAs over
1: the 1-(3-methylvaleryloxy) ethyl ester (
2h) showed the highest peak plasma CTM level(C
max) comparable to that obtained after subcutaneous injection of CTM. The 1-(cyclohexylacetoxy)ethyl ester (
2t), the 1-(2-ethylbutyryloxy)ethyl ester(
2j), and
2h showed BAs near 100%. For these esters (
2), good correlations were also observed among the π, the Es values of R
2, and the
log C
max and log BA in the analysis of the quantitative structure-oral bioavailability relation: an ester having an alkyl group as R
2 with a π value of 3.07 or 3.08 and a Es value of-1.04 or -1.29 gave the highest C
max or BA, respectively. As expected, the optimalπvalues are almost the same as those obtained with
1 but the optimal Es values are larger (Es=-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 complicated acyl group.
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