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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 Brönsted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa-3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa-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 k1) to departure of the leaving group ROH (step k2) 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.

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The alkaline hydrolysis of propham, chlorpropham, and swep to carbanilic acids was investigated for sodium hydroxide concentrations ranging from 0.01 to 4.0 N. The dependence of the observed pseudo-first-order rate constants on the hydroxide ion concentration was in agreement with the rate laws of the two reaction mechanisms-ElcB and Bh2-that can be involved in the hydrolysis of carbamates. The values of the ionization constants of propham (pKa = 15.0), chlorpropham (pKa = 14.45), and swep (pKa = 13.9) account for their behavior in aqueous media. The Hammett p value of 0.98 obtained for the hydrolysis of a series of isopropyl carbanilates, the activation entropy of swep and the changeover in reaction mechanism, from ElcB to BA,2, observed in the hydrolysis of alkyl and aryl 3,4-dichlorocarbanilates are decisive arguments supporting the involvement of a B&2 reaction scheme in the hydrolysis of propham, chlorpropham, and swep. The formation of phenyl isocyanate during the degradation of these herbicidal carbanilates can therefore be ruled out.