二取代咪唑啉的合成和NO清除活性研究

具有清除NO能力使得咪唑啉成为治疗NO引起的各种疾病的有前途的药物。为了确定优秀咪唑啉类NO清除剂的结构 ,合成了 2 烷基、2 杂环基和 2 取代苯基咪唑啉 ,评价了它们的NO清除活性。在Br2 和NaOH存在下 2 硝基丙烷顺利地转化为二叔丁基双羟胺 ( 1 ) ,总收率 40 %。 1和对应的醛缩合得到2 取代 1 ,3 二羟基 4,4,5 ,5 四甲基咪唑啉 2a h ,收率分别为 5 3%、69%、83%、73%、69%、85 %、5 1 %和63%。用PbO2 作为氧化剂 2a h转化为对应的咪唑啉 3a h ,收率分别为 99%、38%、88%、83%、79%、80 %、5 2 %和 73%。在ESR实验中 3a h给出典型的NO自由基谱 ,表明它们是化学稳定的NO自由基。在血管条实验中 3a h剂量依赖性和 2位取代基依赖性地抑制乙酰胆碱诱导的血管舒张作用。依据在本文合成的化合物中 2 取代苯基咪唑啉具有最好的NO清除活性和最高的化学稳定性 ,认为 2 取代苯基咪唑啉可以作为咪唑啉类NO清除剂的先导结构。

Synthesis and NO Scavenging Activity of 2-Substituteanitronyl Nitroxides

The ability scavenging nitric oxide makes nitronyl nitroxides to be promising dr ugs for the treatments of various diseases caused by excess production of NO. Id entifying the preferential structure for the NO scavenger in the present paper the 2-alkyl, 2-heterocycle and 2-substitutedphenylnitronyl nitroxides were syn thesized and their in vitro NO scavenging activities were assayed. In the presen ce of Br 2 and NaOH 2-nitropropane was smoothly converted into di-tert-butyl bishydroxylamine (1) in 40% total yield. The condensatio n of 1 and corresponding a ldehydes provided the corresponding 2-substituted-1,3-dihydroxy-4,4,5,5-tet ramethylimidazolindine 2a-h in 5 3%, 69%, 83%, 73%, 69%, 85%, 51%, and 63% yield, respectively. With PbO 2 as oxidation agent 2a-h were converted into the cor responding nitronyl nitroxides 3a-h in 99%, 38%, 88%, 83%, 79%, 80%, 52% and 7 3% yield, respectively. In the ESR measurements 3a-h gave typical NO spectra, d emonstrating they were chemically stable free radicals. In the aortic strip expe riments 3a-h dose-dependently an d 2-substituent-dependently inhibited Ach-i nduced vasorelaxation. 100 μmol/L and 10 μmol/L of 3a-h exhibited obvious NO scavenging activity(compare to vehicle, P<0.001). At the concentration of 1 μmol/L however only 4-hydroxyphenylnitronyl nitroxide (3g) exhibited obvious NO scavenging effect (compare to ve hicle, P<0.001). The activities of the hig h dose were higher than that of moderate dose (P<0.001) and the activities o f the moderate dose were higher than that of low dose (P< 0.001). Based on the observations it is concluded that nitronyl nitroxides are useful NO scavenger and 2-substitutednitronyl nitroxide may be selected as the desirable lead compo und in the development of NO scavenger.Based on the observations that 2-substit utedphenylnitronyl nitroxides were chemically most stable and bioactive it is co ncluded that nitronyl nitroxides are useful NO scavenger and 2-substitutedpheny lnitronyl nitroxide may be selected as the desirable lead compound in the development of NO scavenger.