Prodrugs as drug delivery systems. 43. O-acyloxymethyl salicylamide N-Mannich bases as double prodrug forms for amines

Add time:07/27/2019    Source:sciencedirect.com

Due to their rapid cleavage at physiological pH salicylamide N-Mannich bases have been suggested as prodrug forms for primary and secondary amines. A drawback of the Mannich bases is, on the other hand, their limited stability in vitro, raising some stability-formulation problems. In the present study, blocking of the hydroxyl group of the salicylamide N-Mannich bases by O-acyloxymethylation has been shown to be a potentially useful approach to improve the stability. Various O-acyloxymethylated derivatives of N-(morpholinomethyl)salicylamide were prepared and found to be much more stable in acidic and neutral aqueous solution than the parent salicylamide N-Mannich base and to be readily converted to the latter in the presence of human plasma by enzymatic hydrolysis. In addition to providing an in vitro stabilizing effect the concept of O-acyloxymethylation makes it possible to obtain prodrug derivatives of a given amine drug with varying physicochemical properties of importance for drug delivery such as lipophilicity and water-solubility. This can simply be effected by the selection of an appropriate acyloxymethyl group.

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