Chemical feasibility studies concerning potential prodrugs of acetylsalicylic acid.

Abstract

A rationale is developed for aspirin prodrugs based on non-acidic latentiated derivatives. Knowledge of the gastro-intestinal liabilities and pharmacological profile is required for this approach whereby aspirin is built into a common ortho ester function of the type 2-substituted 2-methyl-4H-1,3-benzodioxin-4-one with latentiated carboxyl and acetoxy groups. Twelve compounds of this type, ten substituted with various alkoxy and aryloxy groups and two with arylthio groups, have been isolated and characterized. A new synthetic route, comprising the reaction of 2-acetoxybenzoyl chloride with TMS derivatives of the corresponding alcohols and phenols, has been devised for the preparation of some of the compounds while others were prepared according to known methods. Subsequently, the prodrug candidates have been subjected to non-enzymatic hydrolysis for a first rapid screening in vitro. Only 2-tert-butoxy-2-methyl-4H-1,3-benzodioxin-4-one is observed to act as a true proaspirin, releasing aspirin, under these conditions, but analogous compounds with tertiary substituents may display the same behavior, and this chemical approach to aspirin modification may offer a viable rationale for aspirin prodrugs with reduced gastric irritancy or for making "superaspirins".