DESIGN OF A WATER-SOLUBLE, SOLUTION-STABLE AND BIOLABILE PRODRUG OF METRONIDAZOLE FOR PARENTERAL ADMINISTRATION - N-SUBSTITUTED AMINOMETHYLBENZOATE ESTERS

Various N-substituted aminomethylbenzoate esters of metronidazole were synthesized and evaluated as water-soluble prodrugs with the aim of developing preparations suitable for intravenous injection. The esters showed all a high solubility in weakly acidic solutions and were further characterized by possessing a high stability in such solutions allowing long-term storage combined with a high susceptibility to undergo enzymatic hydrolysis in plasma. Half-lives of hydrolysis in 80% human plasma were found to be less than l min for some esters. These compounds (the 4-(morpholinomethyl)benzoate and 3-[(4-methylpiperazin-1-yl)methyl]benzoate esters) were predicted to possess shelf-lives of more than 10 years in aqueous solution of pH 4.0 and at 25°C. These properties regarding solubility, chemical stability and enzymatic lability make N-substituted aminomethylbenzoate esters a promising new prodrug type for metronidazole as well as for other slightly soluble drugs containing an esterifiable hydroxyl group. © 1990.