瑞马唑仑衍生物的设计合成及其生物活性研究

发布时间：2018-03-03 13:35

本文选题：麻醉　切入点：静脉麻醉药　出处：《重庆医科大学》2016年博士论文　论文类型：学位论文

【摘要】：随着医学技术的不断发展、医疗水平的日益提升,人类的许多疾病已逐步得到了有效的控制。现代麻醉学的发展使得许多原来的手术禁区能够成功地进行,但能够满足各种手术,不同人群的要求,使人们达到满意的镇静、镇痛及肌松效果,仍然是研发麻醉药物的热点和难点。本论文介绍了镇静麻醉药物,尤其是苯二氮卓类药物的研发历程和最新动态。具有镇静催眠功能的苯二氮卓类药物具有明显优于巴比妥类药物的特性,但其水溶性差,临床只能口服给药。咪达唑仑是第一个用于临床的苯二氮卓类镇静性麻醉药,其缺点在于其代谢物具有药理活性,使病人恢复苏醒的时间延长,因而限制了其用途。为了寻找代谢更为迅速的药物,药物化学家受到依托咪酯和瑞芬太尼的启发,摒弃此前仅从主环修饰苯二氮卓类药物的传统观念,按照软药原理,在苯二氮卓母环上引入侧链,导致了瑞马唑仑的出现,为苯二氮卓类药物的研发开创了新的思路。本论文首先对瑞马唑仑代谢特性进行了深入的研究,发现瑞马唑仑侧链易代谢,生成唑仑丙酸和甲醇。代谢实验证实甲醇的次生代谢的产物甲酸可能是造成ICU镇静中瑞马唑仑血药浓度偏高的重要原因。基于以上发现,以瑞马唑仑为先导化合物,对其侧链进行优化改造。通过碱解,成酯,成盐等方法,制备得到7个不同侧链取代的衍生化合物,经红外,质谱,核磁等确证结构。然后对目标化合物进行了活性筛选,优选得到化合物EL-001。在多种动物模型上进行的活性评估结果显示,EL-001活性明显优于瑞马唑仑。代谢实验结果表明,EL-001比瑞马唑仑代谢快且无残留,进一步验证了瑞马唑仑代谢出的甲醇及其次生代谢物甲酸,造成ICU镇静中瑞马唑仑血药浓度偏高的主要原因,可能是Ono公司退出瑞马唑仑继续开发的主要原因。总之,本论文优选得到了成药性更优的化合物EL-001,全面系统的临床前研究正在进行之中。通过本课题对瑞马唑仑及其衍生物的研究,评估了瑞马唑仑及EL-001药效及代谢物对羧酸酯酶活性的影响,为苯二氮卓类药物的研发提供新的思路。
[Abstract]:With the development of medical technology and the improvement of medical level, many diseases of human being have been controlled effectively. The development of modern anesthesiology has enabled many of the original surgical exclusion zones to be successfully carried out. However, it is still a hot and difficult point in the research and development of anesthetic drugs to meet the requirements of various operations and different populations, and to make people achieve satisfactory sedation, analgesia and muscle relaxation effects. In particular, the research and development of benzodiazepines and the latest developments. The benzodiazepines with sedative and hypnotic properties are obviously superior to barbiturates, but their water solubility is poor. Midazolam is the first benzodiazepine sedative anesthetic to be used clinically. Its disadvantage is that its metabolites have pharmacological activities and prolong the recovery time of patients. In order to find drugs that metabolize more quickly, pharmacists, inspired by etomidate and remifentanil, abandoned the traditional idea that benzodiazepines were modified only from the main ring, according to the principle of soft drugs. The introduction of side chain into benzodiazepine ring led to the emergence of ramazolam, which opened up a new idea for the research and development of benzodiazepines. It was found that the side chain of ramazolam was easy to metabolize, resulting in the formation of propionic acid and methanol. The metabolic experiments confirmed that formic acid, the secondary metabolite of methanol, may be an important reason for the high concentration of remiprazolam in ICU sedation. Seven derivatives with different side chains were prepared by alkaline hydrolysis, esterification and salt formation, and the derivatives were synthesized by IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, IR, MS, etc. The structure of the target compound was confirmed by nuclear magnetic field, and then the target compound was screened for activity. The activity evaluation of EL-001 in various animal models showed that the activity of EL-001 was significantly superior to that of ramazolam. The metabolic results showed that EL-001 was metabolized faster than that of ramazolam and had no residue. It is further verified that the methanol and its secondary metabolite formic acid metabolized by Rimazolam lead to the high concentration of remiazolam in ICU sedation, which may be the main reason for Ono to withdraw from the further development of Rimazolam. In this paper, we have obtained a more drug-forming compound EL-001, and a comprehensive and systematic preclinical study is under way. Through this study, we have studied ramazolam and its derivatives. The effects of ramazolam, EL-001 and metabolites on the activity of carboxylate esterase were evaluated, which provided a new idea for the research and development of benzodiazepines.
【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914;R96

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