Cyclization-Activated Prodrugs: N-(Substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazolidinones as Mutual Prodrugs of Acetaminophen

Abstract

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.

Cyclization-activated Prodrugs

“…In the first case, one of the benzoxazolone precursors prepared was the 4-acetamidophenyl ester chlorzacetamol, which is a mutual prodrug of chlorzoxazone and paracetamol (=ROH). Similarly, the second approach included two mutual prodrugs of paracetamol and active oxazolidinones (metaxalone and mephenoxalone) that were obtained using the appropriate amines [16]. All the carbamate prodrugs thus prepared were found to release the parent drugs in aqueous buffer (pH 6-11) and plasma (pH 7.4) through intramolecular reactions due to a hydroxyl nucleophile.…”

“…Benzoxazolone release occurred by a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (Scheme 3, k 1 ) to departure of the leaving group ROH (Scheme 3, k 2 ) when the leaving group ability decreased. However, oxazolidinones were released from their mutual prodrugs by means of a rate-limiting elimination-addition reaction (Scheme 4) [16].…”

New synthesis of mephenoxalone

“…There are only a few reports in literature about the synthesis of Mephenoxalone. [10][11][12][13] Previously, we reported the synthesis of a bronchodilator blocker Fenspiride (5) 14 and continuing our interest in cyclization reactions using bistrichloromethyl carbonate (BTC or triphosgene) and the addition of trimethylsilyl cyanide to aldehydes, 15 we proposed a new methodology for the synthesis of Mephenoxalone through silanized intermediate.…”

Amino acids as selective sulfonamide acylating agents

“…intramolecular cyclization to a 2,5-diketopiperazine. 18,19 The dipeptide carrier can be linked to the sulfonamide either via the 4-anilino group (N 4 nitrogen atom), i.e. 1, or via the sulfonamido group (N 1 nitrogen atom), i.e.…”