CYCLIZATION-ACTIVATED PRODRUGS - N-(SUBSTITUTED 2-HYDROXYPHENYL AND ALPHA-HYDROXYPROPYL)CARBAMATES BASED ON RING-OPENED DERIVATIVES OF ACTIVE BENZOXAZOLONES AND OXAZOLIDINONES AS MUTUAL PRODRUGS OF ACETAMINOPHEN

N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)ca rbamates based on masked active benzoxazolones (model A) and oxazolidi nones (model B), respectively, were synthesized and evaluated as poten tial drug delivery systems. A series of alkyl and aryl N-(5-chloro-2-h ydroxyphenyl)carbamates 1 related to model A was prepared. These are o pen drugs of the skeletal muscle relaxant chlorzoxazone. The correspon ding 4-acetamidophenyl ester named chlorzacetamol is a mutual prodrug of chlorzoxazone and acetaminophen. Chlorzacetamol,and two other mutua l prodrugs of active benzoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetr achloroethyl carbonate with the appropriate anilines. Based on model B , two mutual prodrugs of acetaminophen and active oxazolidinones (meta xalone and mephenoxalone) were similarly obtained using the appropriat e amines. All the carbamate prodrugs prepared were found to release th e parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media. The det ailed 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 f or aryl and trihalogenoethyl esters and log t(1/2) = 1.46pK(a) - 16.03 for alkyl esters. This change is consistent with a cyclization mechan ism involving a change in the rate-limiting step from formation of a c yclic 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 pla ce by means of a rate-limiting elimination-addition reaction (E1cB mec hanism). This affords acetaminophen and the corresponding 2-hydroxypro pyl isocyanate intermediates which cyclize at any pH to the correspond ing oxazolidinone drugs. As opposed to model A, the rates of hydrolysi s of mutual prodrugs of model B clearly exhibit a catalytic role of th e plasma. It is concluded from the plasma studies that the carbamate s ubstrates 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 mechani stic particularity precludes their potential toxicity in terms of pote nt electrophiles capable of modifying critical macromolecules.