Kahns A H, Bundgaard H
Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
Acta Pharm Nord. 1991;3(1):45-50.
The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were found to hydrolyze quantitatively to the parent salicylamide. The pH-rate profiles obtained at pH 1-11 were accounted for by a spontaneous or water-catalyzed reaction which predominated at pH 1-4 and a hydroxide ion-catalyzed reaction. The rates of hydrolysis were catalyzed slightly in the presence of human plasma and rat liver homogenate, the exception being the N-benzoyl derivative which was hydrolyzed very fast in plasma solutions to N-benzoylsalicylamide. The aqueous solubility and lipophilicity characteristics of 1,3-benzoxazine-2,4-dione were determined. The results obtained suggest that the latter may function as a prodrug for salicylamide with the potential of depressing the extensive first-pass metabolism of salicylamide following oral or rectal administration.
在水溶液中研究了1,3 - 苯并恶嗪 - 2,4 - 二酮及其N - 甲基和N - 苯甲酰基衍生物的水解动力学和机理，以提供有关苯并恶嗪二酮结构反应性的基本信息，并评估未取代的1,3 - 苯并恶嗪 - 2,4 - 二酮作为水杨酰胺前药的潜力。发现这些化合物定量水解为母体水杨酰胺。在pH 1 - 11获得的pH - 速率曲线由在pH 1 - 4占主导的自发或水催化反应以及氢氧根离子催化反应来解释。在人血浆和大鼠肝匀浆存在下，水解速率略有催化，例外的是N - 苯甲酰基衍生物，它在血浆溶液中非常快速地水解为N - 苯甲酰基水杨酰胺。测定了1,3 - 苯并恶嗪 - 2,4 - 二酮的水溶性和亲脂性特征。所得结果表明，后者可能作为水杨酰胺的前药发挥作用，具有降低口服或直肠给药后水杨酰胺广泛首过代谢的潜力。
