Prodrugs as drug delivery systems. 77. Phthalidyl derivatives as prodrug forms for amides, sulfonamides, carbamates and other NH-acidic compounds

Abstract

A series of N-phthalidyl derivatives of various carboxamides, sulfonamides, a carbamate and a urea has been prepared with the aim of assessing their potential as prodrug forms for NH-acidic compounds. The hydrolysis of the compounds was studied in aqueous solution at various pH values and in the presence of human plasma. The degradation was shown to take place by hydrolytic opening of the lactone ring with the formation of an N-hydroxyalkyl intermediate which quickly decomposed to the parent NH-acidic compound and phthalaldehydic acid. This hydrolysis was catalyzed by plasma enzymes. The phthalidyl derivative of a primary sulfonamide behaved differently as it was extremely unstable in aqueous solution, the decomposition proceeding via an elimination-addition mechanism. It is concluded that in contrast to unstable linear N-acyloxyalkyl derivatives, phthalidyl derivatives in which the ester function is incorporated in a lactone group may be useful as prodrug forms for primary as well as secondary amides and other similar NH-acidic compounds, the exception being primary sulfonamides.