非甾体抗炎药昔康类化合物衍生物的合成研究

发布时间：2018-01-19 03:03

本文关键词： 昔康类衍生物苯并异噻唑啉酮 1 3-苯并噻嗪-4-酮溴化钾磷酸三钾　出处：《兰州大学》2017年硕士论文　论文类型：学位论文

【摘要】：炎症是一种非常常见的疾病,据报道,全世界有约一亿的人口服用非甾体抗炎药,其中有50%以上的患者是老年人,非甾体抗炎药在临床用药中是仅次于抗感染药的第二大类药物。纵观非甾体抗炎的发展历史,自1898年阿司匹林问世以来,相继出现了保泰松、吲哚美辛、布洛芬等非甾体抗炎药,但是由于这类药物酸性较大,容易引起消化不良、胃痛、溃疡、出血、穿孔等副作用。直到20世纪80年代美罗昔康问世,非甾体抗炎药的这些副作用才得到较好的缓解。后来又发现了对Cox-2的抑制剂昔布类物,但由于2004年的罗非昔布事件,这类药物的安全性值得检验。因此,昔康类药物在抗炎领域依旧发挥着重要的作用。昔康类药物是一类在临床中有着重要应用的非甾体抗炎药,有关昔康的合成研究一直以来都是药物及化学等各个领域研究的热点和难点,目前已有很多合成此类化合物的方法,但是它们均具有反应条件苛刻,使用的试剂价格昂贵且毒性过大对环境不友好,反应难控制,反应产率低的缺点。因此我们对昔康类化合物及其衍生物的合成新方法展开了研究,一方面,我们发展了合成苯并异噻唑啉酮结构的新方法,之后仅需利用已成熟的三步反应,即可合成昔康类药物的关键中间体。另一方面,我们通过对昔康类药物的构效关系研究,打算以生物电子等排体原理合成苯并噻嗪酮类化合物,得到更多昔康类药物的衍生物。在以上思路的指导下,我们发展了合成苯并异噻唑啉酮类化合物和苯并噻嗪酮类化合物的新方法。具体而言,我们使用溴化钾为催化剂,空气为氧化剂可以合成苯并异噻唑类化合物;使用磷酸三钾为碱,双1,4-加成反应合成了苯并噻嗪酮类化合物。这两个新方法均具有廉价、高效、低毒、高产、环境友好的特点,这将为昔康类化合物及衍生物合成提供重要的研究思路。
[Abstract]:Inflammation is a very common disease. About 100 million of the world's population are reported to be taking NSAIDs, more than 50% of whom are elderly. Non-steroidal anti-inflammatory drugs (NSAIDs) are the second largest class of drugs in clinical use after anti-infective drugs. Throughout the history of non-steroidal anti-inflammatory drugs, since the advent of aspirin in 1898, there has been a series of oxetaxone and indomethacin. Ibuprofen and other non-steroidal anti-inflammatory drugs, but because these drugs are acidic, prone to indigestion, stomach pain, ulcers, bleeding, perforation and other side effects. Until 1980s, meroxicam came out. These side effects of non-steroidal anti-inflammatory drugs were better alleviated. The inhibitor of Cox-2 was later discovered, but due to the rofecoxib event in 2004. The safety of these drugs is worth testing. Therefore, Xikang drugs still play an important role in the field of anti-inflammatory. Xikang drugs are a kind of non-steroidal anti-inflammatory drugs that have important clinical application. The research on the synthesis of Xikang has always been a hot and difficult point in the field of medicine and chemistry. There are many methods to synthesize this kind of compounds, but they all have harsh reaction conditions. The reagents used are expensive and toxic to the environment, the reaction is difficult to control and the reaction yield is low. Therefore, we have studied the new method of synthesis of Xikang compounds and their derivatives, on the one hand. We have developed a new method for the synthesis of benzoisothiazolinone, and then we can synthesize the key intermediates of Xikang drugs by using only the mature three-step reaction. On the other hand, we have developed a new method for the synthesis of benzoisothiazolinone. By studying the structure-activity relationship of Xikang drugs, we intend to synthesize benzothiazinone compounds by the principle of bioelectron isoexclusion, and get more derivatives of Xikang drugs. Under the guidance of the above ideas. We have developed a new method for the synthesis of benzoisothiazolinones and benzothiazones. In particular, we use potassium bromide as catalyst and air as oxidant to synthesize benzoisothiazoles. Benzothiazinone compounds were synthesized by using tripotassium phosphate as base and bis (1n) 4-addition reaction. These two new methods have the advantages of low cost, high efficiency, low toxicity, high yield and friendly environment. This will provide important research ideas for the synthesis of Xikang compounds and derivatives.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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