喹喔啉酮并杂环类衍生物的设计合成及其抗抑郁、抗炎活性的研究

发布时间：2019-04-28 10:47

【摘要】：喹喔啉类是一种氮原子取代萘环的两个碳原子的重要的杂环类化合物,由于其广泛的生物活性,在药物化学和药理行业引起很大的关注。实验部分一,抗抑郁化合物的设计。抑郁症是一种常见的精神疾病,给人的身体健康造成伤害,严重影响患者的生活质量,增加患者的自杀风险,也给医疗带来负担。实验中设计并通过缩合,氯代,肼代和烷基化反应等合成一系列5-烷基-四唑并[1,5-a]喹喔啉-4(5H)-酮(5a-5t)和与不同杂环拼接的化合物7,9,13-17,共27个化合物。通过抗抑郁经典实验的强迫游泳和悬尾实验模型初步评价其抗抑郁活性,以氟西汀为阳性对照药,旷场实验测定小鼠自主活动会产生的假阳性影响。抗抑郁活性药理实验结果显示,在5a-5t系列中大多数化合物在50 mg/kg剂量下表现出一定的抗抑郁活性。其中化合物5d最为显著,在50 mg/kg剂量与阳性对照药氟西汀(缩短不动时间59.71%)相比,缩短小鼠不动时间64.27%。化合物5d与不同杂环化合物进行药理活性对比,结果显示以四氮唑为杂环的化合物抗抑郁活性最为显著。在量效关系研究中,化合物5d在50,25和10 mg/kg不同剂量的强迫游泳实验结果中表现出剂量依赖性。旷场实验中空白组作对照结果显示化合物5d对小鼠的自主运动无明显影响,表明强迫游泳和悬尾实验药理结果与中枢神经系统无关,进一步证明化合物5d的抗抑郁作用。实验部分二,抗炎化合物的设计。非甾体抗炎药是目前全球治疗炎症最常规的用药,主要用于治疗各种临床病症,缓解与炎症相关的症状,但非甾体抗炎药的长期使用会潜在增加胃肠道和上消化道并发症等不良反应发生的风险。当前广泛使用的非甾体抗炎药物副作用较大,为了寻找安全性高,药效更好的抗炎药物,在实验室前人研究的IV系列化合物基础上,进行结构修改,以邻苯二胺为起始原料,设计合成5-烷基-4-氧代-4,5-二氢-[1,2,4]三唑并[4,3-a]喹喔啉-1-甲酰胺衍生物(14a-14t)系列化合物共20个。化合物14a-14t的抗炎活性研究正在进行中。两实验部分共合成化合物47个,化学结构经过红外光谱,核磁共振和质谱确证。
[Abstract]:Quinoquinoline is an important heterocyclic compound which replaces two carbon atoms of naphthalene ring by nitrogen atom. Because of its extensive biological activity, quinoquinolines have attracted much attention in pharmaceutical chemistry and pharmacology. The first part of the experiment is the design of antidepressant compounds. Depression is a common mental illness, causing harm to people's physical health, seriously affecting the quality of life of the patients, increasing the risk of suicide of the patients, and also bringing a burden to the medical treatment. In the experiment, a series of 5-alkyl-tetrazolium [1,5a] quinoxaline-4 (5H)-one (5a-5t) were synthesized by condensation, chloro, hydrazine and alkylation reactions, and the compounds 7,9,13, 17,17, which were spliced with different heterocycles, were designed and synthesized by condensation, chloro, hydrazine and alkylation. There are 27 compounds in total. The antidepressant activity was evaluated by forced swimming and tail suspension test models of classic antidepressant experiments. Fluoxetine was used as a positive control drug and the false positive effect of spontaneous activity in mice was determined by open-field test. The results of pharmacological experiments on antidepressant activity showed that most of the compounds in the 5a-5t series showed antidepressant activity at the dose of 50 mg/kg. The compound was the most significant in 5 days. Compared with fluoxetine (59.71%), the immobility time of mice was shortened by 64.27% at 50 mg/kg dose compared with that of fluoxetine (59. 71%). The pharmacological activity of the compound was compared with that of different heterocyclic compounds for 5 days. The results showed that the antidepressant activity of the compound with tetrazolium as heterocyclic ring was the most significant. In the study of dose-effect relationship, the compound showed a dose-dependent effect on the results of 50, 25 and 10 mg/kg forced swimming at different doses for 5 days. In the open-field experiment, the blank control group showed that compound 5 days had no obvious effect on the autonomic movement of mice, indicating that the pharmacological results of forced swimming and tail suspension test had nothing to do with the central nervous system, and further proved the antidepressant effect of the compound for 5 days. The second part is the design of anti-inflammatory compounds. Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the most conventional drug used in the treatment of inflammation worldwide, which is mainly used to treat various clinical symptoms and relieve inflammation-related symptoms. However, long-term use of NSAIDs can potentially increase the risk of adverse reactions such as gastrointestinal and upper gastrointestinal complications. At present, the widely used non-steroidal anti-inflammatory drugs have great side effects. In order to find the anti-inflammatory drugs with high safety and better efficacy, the structure was modified on the basis of the series of IV compounds studied in the laboratory, and o-phenylenediamine was used as the starting material. A series of 20 compounds of 5-alkyl-4-oxo-4,5-dihydro-[1,2,4] triazo [4,3a] quinoxaline-1-formamide derivatives (14a-14t) were designed and synthesized. Studies on the anti-inflammatory activity of compound 14a-14t are under way. A total of 47 compounds were synthesized in the two experiments, and their chemical structures were confirmed by IR, NMR and MS.
【学位授予单位】：延边大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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