Krise J P, Zygmunt J, Georg G I, Stella V J
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
J Med Chem. 1999 Aug 12;42(16):3094-100. doi: 10.1021/jm980539w.
The synthesis and preliminary evaluation of a novel prodrug approach for improving the water solubility of drugs containing a tertiary amine group are reported. The prodrug synthesis involves a nucleophilic substitution reaction between the parent tertiary amine and a novel derivatizing reagent, di-tert-butyl chloromethyl phosphate, resulting in formation of the quaternary salt. The tertiary butyl groups are easily removed under acidic conditions with trifluoroacetic acid giving the N-phosphonooxymethyl prodrug in the free phosphoric acid form, which can subsequently be converted to the desired salt form. The synthesis was successfully applied to a model compound (quinuclidine) and to three tertiary amine-containing drugs (cinnarizine, loxapine, and amiodarone). The prodrugs were designed to undergo a two-step bioreversion process. The first step was an enzyme-catalyzed rate-determining dephosphorylation followed by spontaneous chemical breakdown of the N-hydroxymethyl intermediate to give the parent drug. Selected prodrugs were shown to be substrates for alkaline phosphatase in vitro. A preliminary in vivo study confirmed the ability of the cinnarizine prodrug to be rapidly and completely converted to cinnarizine in a beagle dog following iv administration.
报道了一种用于提高含叔胺基团药物水溶性的新型前药方法的合成及初步评价。前药合成涉及母体叔胺与新型衍生化试剂二叔丁基氯甲基磷酸酯之间的亲核取代反应，生成季盐。叔丁基在酸性条件下用三氟乙酸很容易除去，得到游离磷酸形式的N-膦酰氧基甲基前药，随后可转化为所需的盐形式。该合成方法成功应用于模型化合物（奎宁环）和三种含叔胺的药物（桂利嗪、洛沙平、胺碘酮）。前药设计为经历两步生物转化过程。第一步是酶催化的限速去磷酸化反应，然后N-羟甲基中间体自发化学分解生成母体药物。所选前药在体外显示为碱性磷酸酶的底物。一项初步体内研究证实，静脉给药后，桂利嗪前药在比格犬体内能够迅速且完全转化为桂利嗪。
