Rehse K, Lüdtke E
Institut für Pharmazie der Freien Universität Berlin.
Arch Pharm (Weinheim). 1994 Sep;327(9):581-9. doi: 10.1002/ardp.19943270906.
24 new thiazole-2-nitrosimines were prepared and described by means of spectroscopical methods (NMR, IR, MS, UV). At pH 7 in cell free systems as well as in platelet rich plasma the compounds are stable against hydrolysis and do not react with the platelet glutathione. The chemical stability is underlined by the mass spectra: M+. is of high intensity and sometimes even forms the base peak (e.g. 8a). Thermal elimination of N2 is of minor importance. The =N-NO bond in solution is susceptible to cleavage by visible light. The metabolite so formed is able to inhibit the platelet aggregation induced by collagen (Born-test). Five compounds exhibit this activity in concentrations below 10 mumol/L (IC50). This is due to the release of a NO species, as could be demonstrated by the stimulation of soluble guanylate cyclase in a cell free system (e.g. 8a, KM = 72 mumol/L). In vivo the nitrosimines show antithrombotic properties. Two h after a single oral dose of 8g (60 mg/kg) a 57% inhibition of the laser induced thrombus formation in the mesenteric arterioles of rats is observed. After 8 h a 43% inhibition still is seen.
通过光谱方法（核磁共振、红外光谱、质谱、紫外光谱）制备并描述了24种新型噻唑 - 2 - 亚硝基胺。在无细胞体系以及富含血小板血浆中，pH值为7时，这些化合物对水解稳定，且不与血小板谷胱甘肽发生反应。质谱表明其化学稳定性：M⁺具有高强度，有时甚至形成基峰（例如8a）。N₂的热消除不太重要。溶液中的=N - NO键易被可见光裂解。如此形成的代谢产物能够抑制胶原蛋白诱导的血小板聚集（博恩试验）。五种化合物在浓度低于10 μmol/L（IC₅₀）时表现出这种活性。这是由于一氧化氮的释放，如在无细胞体系中对可溶性鸟苷酸环化酶的刺激所证明的那样（例如8a，KM = 72 μmol/L）。在体内，亚硝基胺显示出抗血栓特性。单次口服剂量8g（60 mg/kg）后两小时，观察到大鼠肠系膜小动脉中激光诱导血栓形成受到57%的抑制。八小时后，仍可见43%的抑制率。
