Aspirin prodrugs: synthesis and hydrolysis of 2-benzyloxy-2-methyl-4H-1,3-benzodioxin-4-ones

Aspirin is widely used for its analgesic, antiinflammatory and antipyretic properties. Among its disadvantages are the relatively narrow therapeutic margin, its irritancy towards the gastric mucosa, and occasionally patient hypersensitivity towards aspirin. As part of our effort to develop prodrugs without these liabilities eleven new title compounds have been isolated and characterized. These 'superaspirin' candidates were subjected to non-enzymatic hydrolysis for a first rapid screening in vitro. Only 2-(2,6-dimethoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4c) was observed to act as an exclusive aspirin prodrug, while 2-(2-methoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4b) and 2-(2-ethoxybenzyloxy)-2-methyl-4H-1,3- benzodioxin-4-one (4d) were shown to release both aspirin 6 and salicylic acid 7. Subsequently, these three candidates were further characterized by investigation of the pH profile of their hydrolysis rates.