N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems. A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared. These are open drugs of the skeletal muscle relaxant chlorzoxazone. The corresponding 4-acetamidophenyl ester named chlorzacetamol is a mutual prodrug of chlorzoxazone and acetaminophen. Chlorzacetamol,and two other mutual prodrugs of active benzoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropriate anilines. Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropriate amines. All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media. The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 degrees C shows a change in the Bransted-type relationship log t(1/2) vs pK(a) of the leaving groups ROH: lag t(1/2) = 0.46pK(a)- 3.55 for aryl and trihalogenoethyl esters and log t(1/2) = 1.46pK(a) - 16.03 for alkyl esters. This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k(1)) to departure of the leaving group ROH (step k(2)) when the leaving group ability decreases. This mechanism occurs for all the prodrugs related to model A. Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism). This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs. As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma. It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates. In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction. This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.
