SYNTHESIS/ ACTIVITY OF N-AMINOTETRAHYDROPYRIDINES

本论文的主要目标是设计、合成和药理评价具有重要药用价值的新型N-氨基-1，2，3，6-四氢吡啶衍生物。我们报道了用Tamura的方法合成了新型的N-亚胺基吡啶叶立德，并对其进行了改进。叶立德的硼氢化钠还原得到稳定的N-氨基-1，2，3，6-四氢吡啶，产率较高。我们最近还报道了一些四氢吡啶的初步药理试验结果，这些四氢吡啶具有镇痛和抗炎活性，即使在非常高的剂量水平下也没有观察到毒性。我们以前的工作为新的和令人兴奋的研究提供了基础，以便可以制备一系列与最活跃的类似物相关的化合物，并重新测试并测定辛醇-水分配系数。一旦积累了足够的数据，将对所制备的化合物进行结构活性分析，以研究取代基的电子、空间和亲脂作用。在这项研究中获得的物理和药理数据将被用于设计具有更多有益生物活性的药物。药理研究的主要重点将是开发和轻松合成有效和安全的非类固醇抗炎药，用于治疗风湿性疾病，包括类风湿性关节炎、骨关节炎、痛风和风湿热。

The primary objective is the design, synthesis and pharmacological evaluation of novel and medicinally important N-amino-1,2,3,6- tetrahydropyridine derivatives. We reported the synthesis of novel N- iminopyridium ylides using the method employed by Tamura and modified in our laboratory. Sodium borohydride reduction of the ylides afforded the stable N-amino-1, 2,3,6-tetrahydropyridines in good yields. We also recently reported preliminary pharmacological test results of a few tetrahydropyridines that exhibited analgesic and anti-inflammatory activities with no observed toxicity, even at very high dose levels. Our earlier work provides the basis for new and exciting studies so that a series of compounds related to the most active analogs could be prepared, and retested and the octanol-water partition coefficient determined. Once sufficient data are accumulated, the compounds prepared will be subjected to structure activity analysis to study the electronic, steric and lipophilic effects of substituents. The physical and pharmacologic data obtained in this study will then be used to design drugs with more beneficial biological activity. The primary focus of the pharmacological studies will be to develop and easily synthesize effective and safe non- steroidal anti-inflammatory agents for the treatment of rheumatic diseases, including rheumatoid arthritis, osteoarthritis, gout and rheumatic fever.