SYNTHESES OF 14C LABELED NITRONE SPIN TRAPS

一些常用的硝酮自旋陷阱，包括α-苯基-N-t- 丁基硝酮（PBN）、5，5-二甲基-1-吡咯啉-N-氧化物（DMPO）和α-（4- 吡啶-1-氧化物）-N-叔丁基硝酮（4-POBN），具有许多潜在的 有用的治疗和预防活性如降低脓毒性 休克死亡率，逆转衰老的影响，心脏保护和 心肌梗死缺血/再灌注模型中的血管舒张。 需要它们的14 C标记的类似物来促进处置， 代谢研究，进一步药理学评价的硝酮。 在冷运行中使用未标记的材料和试剂， 证明了所有的合成步骤，导致商业上可行的 制备 .和4-POBN-α-14 C。 第一阶段的努力还 在现有的DMPO路线中引入了两个新的替代步骤， 一种更方便、更有效的方法， 丙烯醛的爆炸和急性毒性。 第二阶段申请 建议完成综合开发，包括：（a）实际 上述14 C标记的自旋陷阱的“热”合成;（B）冷运行 然后热合成MeO 3-PBN-alpha 14 C;（c）测定 这些放射性标记硝酮的稳定性，以推荐适当的储存 及处理方法：及（d）为老化的废物再净化程序 硝酮以恢复大于或等于98%的纯度。

Some commonly used nitrone spin traps, including alpha-phenyl-N-t- butylnitrone (PBN), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and alpha-(4- pyridyl-1-oxide)-N-t-butylnitrone (4-POBN), possess many potentially useful therapeutic and prophylactic activities such as lowering septic shock fatality, reversing the effects of aging, cardioprotection and vasodilation in ischemia/reperfusion models of myocardial infarction. Their 14C-labeled analogs are needed to facilitate disposition and metabolism studies in further pharmacological evaluation of the nitrones. Using unlabeled materials and reagents in cold runs, Phase I has demonstrated all the synthetic steps leading to a commercially viable preparation of . and 4-POBN-alpha-14C. Efforts in Phase I have also introduced two new alternate steps in th existing route to DMPO to provide a much more convenient and productive approach without the hazards of explosion and acute toxicity of acrolein. This Phase II application proposes to complete the synthetic development, including: (a) the actual "hot" synthesis of the 14C-labeled spin traps named above; (b) cold runs and then hot synthesis of MeO3-PBN-alpha14C; (c) determination of the stability of these radiolabeled nitrones to recommend appropriate storage and handling methods: and (d) repurification procedures for the aged nitrones to regain greater than or equal to 98% purity.