Allopurinol prodrugs. II. Synthesis, hydrolysis kinetics and physicochemical properties of various N-acyloxymethyl allopurinol derivatives

Abstract

Fourteen novel N-acyloxymethyl derivatives of allopurinol were synthesized and evaluated as potential prodrugs with the aim of enhancing the rectal delivery characteristics of the parent drug. The hydrolysis of the compounds (1- or 2- acyloxymethyl and 1,5- or 2,5-bis(acyloxymethyl) derivatives) was subject to specific base catalysis as well as enzymatic catalysis by plasma enzymes. In 80% human plasma solutions all the compounds were converted quantitatively to allopurinol, passing through an unstable N-(hydroxymethyl)allopurinol intermediate. The derivatives were more lipophilic than allopurinol as expressed by octanol-water partition coefficients and reversed-phase liquid Chromatographic capacity factors but the water-solubility was only slightly reduced or, for some derivatives, even greater than that of allopurinol. This behaviour was attributed to differences in the crystal lattice energy and a relationship between melting points, partition coefficients and water-solubilities for these and four previously studied N 1-acyl allopurinol prodrug derivatives was established. The results suggested, that N-acyloxymethylation may be a promising means of obtaining prodrug forms of allopurinol with improved physicochemical properties with regard to drug delivery.