INVESTIGATION OF (OXODIOXOLENYL)METHYL CARBAMATES AS NONCHIRAL BIOREVERSIBLE PRODRUG MOIETIES FOR CHIRAL AMINES

The preparation of (oxodioxolenyl)methyl carbamates and their evaluati on as novel nonchiral prodrug moieties for chiral primary and secondar y amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3- dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5- phenyl, and 5-anisyl substitution (5a, 5b, and 5c) on the dioxolenone ring were prepared as model amine prodrugs by a one step process invol ving displacement of p-nitrophenol from appropriately substituted (oxo dioxolenyl)methyl p-nitrophenyl carbonates. Plasma enzyme-catalyzed di oxolenone ring opening of these carbamates led to a cascade reaction r esulting in the rapid and quantitative regeneration of the parent amin e drug. Aryl substitution did not significantly alter the hydrolysis r ates of these dioxolenone carbamates in buffers at pH 1 and 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b) and 5-anis yl-4-methyl-1,3-dioxol-4-en-2-one (1c) in pH 7.4 phosphate buffer were 2-3-fold faster than that of the 5-methyl-substituted analog (1a). Ap plication of this prodrug strategy to the chiral fibrinogen receptor a ntagonist L-734,217 resulted in a prodrug that gave quantitative recon version in rat and dog plasma in vitro and oral bioavailability of 23 +/- 6% in dogs for the parent drug.