PRO-DRUGS AS DRUG DELIVERY SYSTEMS .3. ESTERS OF MALONURIC ACIDS AS NOVEL PRO-DRUG TYPES FOR BARBITURIC-ACIDS

A series of malonuric acid esters were synthesized and evaluated as potential pro-drugs of barbituric acids. The esters were found to undergo a rapid and quantitative cyclization in neutral and alkaline aqueous solution to the corresponding barbituric acids by an intramolecular nucleoplulic attack of the terminal ureido nitrogen anion on the ester carbonyl moiety. At pH 7.4 and 37°C the half-time of conversion is from 8 to 63 min for various methyl malonurates, suggessting that malonuric acid esters are possible candidates as pro-drugs of their respective barbituric acids. Besides the kinetics of the cyclization, the L-octanol- water partition coefficients and aqueous solubilities of the esters were determined. It is proposed that by appropriate selection of the alcohol moiety of malonuric acid esters it may be feasible to obtain pro-drugs of barbiturates with varying physicochemical properties, such as lipophilicity and rate of cyclization, and hence to control and modify the delivery and overall activity characteristics of the parent drugs. © 1979.