【作者】 于红；

【导师】 张守芳；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2003， 博士

【摘要】 本课题是关于新型非甾体抗炎剂—1H-1，2-二氢-1-吡咯里嗪酮(下称吡里酮)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)是目前临床上应用最广泛的一类药物，主要用于治疗各种急、慢性炎症及疼痛等常见病。然而，传统的非甾体抗炎药都具有引起胃肠道溃疡及肾功能损伤等毒副作用，因此，寻找疗效高、毒副作用低的抗炎药一直是该类药物研究的一个重要方向。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发展，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，如选择性环氧化酶-2抑制剂、环氧化酶／5-脂氧酶双重抑制剂和一氧化氮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进展，为新抗炎镇痛剂的研究注入了新的活力。 沈阳药科大学有机合成研究室在对吡咯里嗪类抗炎镇痛剂的研究过程中发现，吡里酮具有较强的镇痛作用和明显的抗炎作用，现已合成了其一系列结构新颖的衍生物，发现了大量具有显著抗炎镇痛作用的活性化合物。本课题以吡里酮为母体，依据已有的吡里酮类化合物构效关系研究结果，参照计算机辅助药物设计比较分子力场分析(CoMFA)方法所建立的三维定量构效关系(3D-QSAR)方程，设计合成了三类56个吡里酮衍生物，其中包括25个5-芳基吡里酮，15个5-芳酰基吡里酮和16个5-芳烷基吡里酮。其中，51个化合物未见于文献报道。 设计了一条以芳基乙酮为原料，合成5-芳基吡里酮类化合物的新路线，利用该路线成功地合成了各类取代苯基吡里酮。设计了一条以吡咯为原料，经酰化、还原、Michael加成、Hoesch反应合成5-芳烷基吡里酮类化合物简捷可行的合成路线，成功地制得了目标化合物。 用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进行了抗炎和镇痛活性试验。试验结果表明，以200 mg／kg的剂量灌胃给药，多数目标化砚冤涅演哪大学犀里学应老‘之卿要合物具有一定的抗炎镇痛作用，其中化合物ZY-302、ZY-3Og、ZY-3 19、Z丫337·ZY-340和ZY一351的抗炎和镇痛活性与阳性对照药布洛芬相似或更强，值得深入研究。 总结了一些初步构效关系，5一芳基毗里酮类化合物取代苯环对位带有烷烃或含硫取代基，有利于增强抗炎和镇痛活性;而氨基、经基、烃氧基和酞氨基则使活性降低。5一芳烷基毗里酮类化合物普遍具有较强的镇痛活性，多数5一芳甲基毗里酮类化合物的抗炎活性不及相应的芳乙基类化合物，而镇痛活性却明显强于芳乙基类化合物。进一步运用比较分子力场分析方法对所合成毗里酮衍生物的结构与抗炎活性和镇痛活性进行了三维定量构效关系分析。 本课题研究结果证明，所设计合成的各类毗里酮衍生物绝大部分具有不同程度的抗炎镇痛活性，是有研究前途的化合物，值得继续深入研究。更多还原

【Abstract】 The synthesis and structure-activity relationship(SAR) of the novel nonsteroidal anti-inflammatory agents, 1H-1, 2-dihydro-l-pyrrolizinone derivatives were reported in this paper.Nonsteroidal anti-inflammatory drugs(NSAIDs) are widely used in the treatment of arthritis and pain in clinic. However, most of the NSAIDs used in clinic now cause serious side effects on the gastrointestinal tract and kidney. Therefore, developing new anti-inflammatory agents with lower toxicity have been the interest of this research field. Since the study of mechanism of inflammation has made great achievements in the late last century, the research on NSAIDs has also made great progresses in recent years. Many new 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 pyrrolizinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR reported in our laboratory, and with computer-aided drug design, three types of pyrrolizinones were designed for further study of the SAR. Fifty-six new pyrrolizinone derivatives were synthesized with some new synthetic schemes, including twenty-five 5-arylpyrrolizinones, fifteen 5-aroyl-pyrrolizinones and sixteen 5-aralkylpyrrolizinones, and among them, fifty-one compounds have not been found in literature.With acetophenones as starting materials, a new synthetic scheme was developed for the synthesis of 5-arylpyrrolizinones, and it worked well. Also a facilescheme was designed for synthesis of 5-aralkylpyrrolizinones from pyrrole through acylation, reduction, Michael addition and Hoesch reaction.The anti-inflammatory activity was evaluated with xylene-induced ear swelling in mice, and the analgesic activity was evaluated with writhing induced by acetic acid in mice. Most of the prepared compounds showed remarkably anti-inflammatory and/or analgesic activities at a dose of 200 mg/kg. The activities of compounds ZY-302, ZY-309, ZY-319, ZY-337, ZY-340 and ZY-351 are comparable to ibuprofen, the positive control. Therefore, they are regarded as valuable compounds for further study to develop new anti-inflammatory drugs.Some SAR could be found from the results of pharmacological tests above. For 5-arylpyrrolizinones, the alkyl and sulfur-containing groups at 4 position of the benzene ring make great contribution to the anti-inflammatory and analgesic activities; while amino, hydroxy, alkoxy and amido might decrease the activities. Most of 5-aralkylpyrrolizinones have remarkable analgesic activity. The 3D-QSAR of the compounds has been studied with the computer-aided drug design CoMFA. The results show that the nature of a variety of substituents on the phenyl moiety play an important role for the anti-inflammatory and analgesic activities. These would be very helpful for new designs of the compounds of the kind.In conclusion, most of the synthesized compounds have definite anti-inflammatory and analgesic activities and they are promising for developing new potent anti-inflammatory and analgesic agents.更多还原