【作者】 王绯；

【导师】 张守芳；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2004， 博士

【摘要】 本论文是关于一类新型非甾体抗炎剂—吡咯并[1，2-a]吡嗪-1-酮(下称吡嗪酮)类化合物的合成和抗炎镇痛作用的构效关系研究。 非甾体抗炎药(NSAIDs)是目前临床应用最为广泛的一类药物，主要用于治疗各种急、慢性炎症及中、轻度疼痛。然而，传统的非甾体抗炎药普遍都具有导致胃肠道、肾以及肝损伤等毒副作用。因此，寻找高效低毒的抗炎药一直是该类药物的主要研究方向。 近年来，随着对炎症发生机制以及抗炎药物作用机理研究的深入，非甾体抗炎药的研究也取得了很大的进展，新型非甾体抗炎药，如选择性COX-2抑制剂、5-LOX抑制剂、COX/5-LOX双重抑制剂和NO释放型非甾体抗炎药等无论在理论研究上，还是在开发实践上，都取得了令人瞩目的成果，为新抗炎镇痛剂的开发研究增添了新的活力。 沈阳药科大学有机合成研究室在对吡咯里嗪酮类抗炎镇痛剂的研究过程中发现，吡里酮的结构类似物吡嗪酮具有显著的抗炎镇痛作用。以吡嗪酮为先导化合物，先期已合成了少量的吡嗪酮衍生物。其中，一些化合物具有明显的抗炎镇痛活性，显示该类化合物的深入研究前景。本课题是在吡嗪酮类化合物已有的研究基础上，开拓新的化合物类型，设计合成新型吡嗪酮类化合物，进行深入的抗炎镇痛构效关系研究。 设计合成了三类53个未见文献报道的新型吡嗪酮类化合物，即，21个3-芳基-2-甲基吡嗪酮，11个3，4-二氢-3-芳基-2-甲基吡嗪酮和21个3，4-二芳基-2-甲基吡嗪酮类化合物。 创造了一条以芳基乙酮和吡咯甲酸甲酯为原料，制备3-芳基-2-甲基吡嗪酮类化合物的新路线，利用该路线，成功地制备了系列的3-芳基-2-甲基吡嗪酮类化合物。掇妻 改变上述合成路线的反应条件，以H3PO4为环合催化剂，成功地制得了目标化合物3，4一二芳基一2一甲基一1一毗咯并[1，2一a]毗嗦酮。路线简捷易行。 以二甲苯致小鼠耳肿胀法和醋酸致小鼠扭体法对所合成的目标化合物分别进行了抗炎和镇痛活性试验。结果表明，以200mg/kg的剂量灌胃给药，多数目标化合物具有不同程度的抗炎和/或镇痛活性。其中，ZWF一506、zwF一516、ZwF一518、ZWF一5 19、ZWF一526、ZWF一529、ZWF一539、ZWF一545和ZWF一552的抗炎和镇痛活性与布洛芬相近或稍强，值得深入研究。 初步总结了一些构效关系，如:在所合成的3一芳基。2。甲基毗嚓酮类化合物中，抗炎镇痛作用活性与3一苯基上的取代基密切相关。其中ZWF一516和ZWF一5 19，活性最高，作用最强。3，4一二芳基一2一甲基毗嗦酮类化合物的抗炎活性比相应的3一芳基一2一甲基毗嚓酮类化合物的抗炎活性低，说明4一位苯基取代基不利于抗炎作用。 进一步运用比较分子力场分析(C。M队)方法，对所合成的毗嗦酮类衍生物的结构与抗炎和镇痛活性进行了三维构效关系分析。 本课题的研究结果表明，所设计合成的三类毗嗦酮化合物大部分具有不同程度的抗炎镇痛活性，具有良好研究前景，值得进行深入研究。更多还原

【Abstract】 The synthesis and structure-activity relationship (SAR) of the novel nonsteroidal anti-inflammatory agents, pyrrolo[l,2-a]pyrazine-1-one derivatives were reported in this dissertation.Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of acute and chronic inflammation, and moderate pain in clinic. However, most of traditional NSAIDs could lead to the gastrointestinal damage, nephrotoxicity and hepatotoxicity. Therefore, it has been the interest in this research field to develop novel anti-inflammatory and analgesic agents with low toxicity.Since the study of the inflammatory mechanism has made great achievements in last century, great progresses on the research of NSAIDs have also been achieved recent years. Many novel anti-inflammatory agents with new anti-inflammatory mechanism have been developed, such as selective inhibitors of cyclooxygenase-2 (COX-2), dual inhibitors of cyclooxygenase and 5-lipoxygenase (COX/5-LOX) and nitric oxide-releasing NSAIDs (NO-NSAIDs), and so on. Some of them have been applied in clinic.It has been found that some pyrazinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR of pyrazinones and their analogues reported in our laboratory, three types of pyrazinones were designed and synthesized for further study of the SAR. Fifty-three new pyrazinone derivatives were prepared, including twenty-one 3-aryl-2-methyl-l-pyrrolo[l,2-a]pyrazinones, eleven 3-aryl-3,4-dihydro-2-methyl-l-pyrrolo[l,2-a]pyrazinones and twenty-one 3,4-diaryl-2-methyl-l-pyr-rolo[l,2-a]pyrazinones. Among them, fifty-three compounds have not been found inliteratures.With arylethanones and methyl pyrrole-2-carboxylate as starting materials, a new synthetic scheme was designed for the preparation of 3-aryl-2-methyl-1-pyrrolo[l,2-a] pyrazinones. An improved scheme was also found for the synthesis of 3,4-diaryl-2-me-thyl-l-pyrrolo[l,2-a]pyrazinones, in which phosphoric acid was found to be a powerful catalyst for the cyclization.Anti-inflammatory and analgesic activities were evaluated with xylene-induced ear edema and acetic acid-induced writhing in mice, respectively. The results show that most of the prepared compounds have notable anti-inflammatory and/or analgesic activities at a dose of 200mg/kg. The activities of compounds ZWF-506, ZWF-516, ZWF-518, ZWF-519, ZWF-526, ZWF-529, ZWF-539, ZWF-545 and ZWF-552 are comparable to ibuprofen, the positive control. Therefore, they could be regarded as valuable compounds for further study to develop novel anti-inflammatory and analgesic agents.Some new SAR is found from the results of pharmacological tests above. For 3-aryl-2-methyl-l-pyrrolo[l,2-a] pyrazinones, the substitutes of the benzene ring take an important part in anti-inflammatory and analgesic activities. ZWF-516 and ZWF-519 showed the most remarkable activities among all the compounds. Anti-inflammatory activities of 3,4-diaryl-2-methyl-l-pyrrolo[l,2-a]pyrazinones were lower than those of 3-aryl-2-methyl-l-pyrrolo[l,2-a] pyrazinones. This indicates that the aryl substitutes at 4 position of the pyrazinone ring make unfavourable contribution to anti-inflammatory activities.Three dimensional quantitative structure-activity relationship (3D-QSAR) was studied with Comparative Molecular Field Analysis (CoMFA).In conclusion, some new structure-activity relationship of anti-inflammatory and analgesic activities of pyrazinones is found, and these would be helpful for further studies in this field.更多还原