托伐普坦类似物的合成及其利尿活性

Synthesis and Diuretic Activities of Tolvaptan Analogues

以2-氨基-5-氯苯甲酸甲酯为原料,经五步反应制得7-氯-5-氧代-2,3,4,5-四氢-1H-苯氮杂卓艹(2);2与5-硝基吡啶-2-甲酰氯(或对硝基苯甲酰氯)发生N-酰化反应,再经SnCl2还原制得关键中间体4a(或4b);在4的氨基上引入取代苯甲酰基或苯磺酰基合成了15个具有潜在AVP-V2受体抑制作用的新型托伐普坦类似物(5a～5k,6b,6i,7b和8d),其结构经1H NMR,IR和MS表征。SD大鼠利尿活性试验表明,5～8均有一定的利尿活性,且部分化合物活性较高。

7-Chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine（2） was prepared by a five-step reaction from methyl 2-amino-5-chlorobenzoate.Two key intermediates,4a and 4b,was prepared by N-acetylation of 2 with 5-nitrylpyridine-2-carbamoyl chloride or p-nitrylbenzoyl chlorid,then reduction in the presence of SnCl2.Fifteen novel potential inhibition of the AVP-V2 receptors,tolvaptan derivatives（5a～5k,6b,6i,7b and 8d） were synthesized by introducing substituted-benzoyl or substituted-phenyl-sulfonyl at amino of 4.The structures were characterized by 1H NMR,IR and MS.The SD rats diuretic test showed that some of them exhibited better diuretic activities.