N-芳基取代异硫脲类H～+/K～+-ATP酶抑制剂的合成及活性研究

【作者】 吴安辉；

【导师】 程卯生；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2002， 硕士

【摘要】 H⁺／K⁺-ATP酶抑制剂是继组胺H₂-受体拮抗剂之后一种新型的抑酸类抗溃疡药物。本文简述了H⁺／K⁺-ATP酶抑制剂的作用机制和发展概况。在前期工作的基础上，设计、合成了吡啶和喹啉取代的两类异硫脲化合物，研究其对H⁺／K⁺-ATP酶抑制作用的构效关系。本文共合成了20个未见文献报道的目标化合物，并经¹H-NMR，¹³C-NMR和MS确证其结构。 采用大鼠游离胃灌注方法考察目标化合物对胃酸分泌的影响，结果表明：其中有12个目标化合物的抑酸活性强于或相当于阳性对照药泮妥拉唑钠，化合物BTU-08的抑酸作用最强，为阳性对照药的1.7倍。喹啉环取代的目标化合物的活性优于吡啶环取代的目标化合物。 根据测定的药理活性数据，应用CoMFA技术研究了该类化合物的QSAR，得到了电性效应及场效应对该类化合物活性的影响规律，在此规律基础上对能够增强活性的化合物结构给予预测，为进一步结构修饰以获得更好活性的H⁺／K⁺-ATP酶抑制剂提供了指导。更多还原

【Abstract】 H+/K+-ATPase inhibitor has become novel type of antiulcer drug with inhibition of gastric acid secretion after the appearance of histamine H2-receptor antagonist. In this thesis we briefly summarized the mechanism and the progress of the H+/K+-ATPase inhibitors. On the base of our former research work, we designed and synthesized pyridine and quinoline derivatives as new types isothioureas to study the QSAR of the H+/K+-ATPase inhibitor. We totally synthesized 20 new N-arylisothiourea derivatives and indentified their structures by 1H-NMR, 13C-NMR and MS.The method of affusing the dissociated stomach of the big rat was used to study the changing of the gastric acid secretion effected by the target compounds. The result shows that 12 of the target compounds have comparable or strong gastric acid inhibitory activities with the positive control sodium pantoprazolc. Especially, compound BTU-08 gave the most powerful activity which was nearly two times higher than the control. And the bioactivity of the quinoline derivatives is better than the pyridine derivatives.Using the compound bioactivities we studied the QSAR of the N-arylisothioureas by CoMFA computation. And we got the regular how the steric factor and electrostatic factor effect on the bioactivity. And we also predicted the model structure which will have more powerful bioactivity based on the regular. This regular will benefit the work of modifying the molecular to find the better H+/K+-ATPase inhibitor in the future.更多还原