【作者】 韩翔宇；

【导师】 仲伯华；

【作者基本信息】 中国人民解放军军事医学科学院 ， 药物化学， 2005， 博士

【摘要】 M受体即毒蕈碱样乙酰胆碱受体,属G蛋白耦联受体,现已确认有5种亚型(M1-M5)。许多重大疾病如帕金森氏综合症、老年痴呆、慢性阻塞性肺病、尿失禁等与M受体的功能失调密切相关。目前临床使用的M受体拮抗剂由于缺乏受体亚型的选择性,引起广泛的毒副作用,极大地限制了疗效的发挥和临床使用。M受体手性拮抗剂分子对受体亚型的选择性和对组织器官的特异性不仅决定于其化学结构,更决定于其立体结构。因此,研究M受体拮抗剂分子的立体结构与药理活性的关系,对于提高M受体拮抗剂对受体亚型的选择性,降低毒副作用,具有重要的意义。 盐酸苯环壬酯(8021)和盐酸戊乙奎醚(8018)为我所开发的新型M受体拮抗剂。8021对位置性眩晕具有较好的治疗作用,其活性异构体为R构型。8018临床上用于有机磷中毒的治疗;研究表明8018具有M3/M1受体选择性,显示出治疗慢性阻塞性肺病的应用前景,其活性异构体为R构型异构体。然而到目前为止尚无立体选择性合成方法的报道。本文首次对8021、8018光学异构体的立体选择性合成方法进行了研究;并利用关键中间体手性α-叔羟基乙酸为结构单元设计合成了一系列新型M受体手性拮抗剂。本课题为国家自然科学基金资助项目。论文工作主要包括以下内容: 1、8021及8018立体选择性合成的研究运用不对称合成方法,以(R)及(S)-扁桃酸及环戊酮为起始原料,经缩合、还原等反应合成8021及8018共同的中间体手性α-叔羟基乙酸5(Scheme a);然后将手性α-叔羟基乙酸通过酯化及酯交换反应完成盐酸苯环壬酯(8021)光学异构体的合成(Scheme b);高效毛细管电泳测定其异构体的光学纯度大于99.9%。更多还原

【Abstract】 Muscarinic acetylcholine receptors are members of the huge superfamily of G-protein-coupled receptors (GPCRs). To date, five pharmacologically distinct receptor subtypes (M1-M5) have been defined. Many vital diseases such as Parkinsonian syndromes, Alzheimer’s disease(AD), chronic obstructive pulmonary disease(COPD) and irritable bowel syndrome(IBS) are associated with M receptors. However, the lack of receptor subtype selectivity or organ specificity of M receptor antagonists limited their clinical utility and the therapeutic applicability. It has been well established that the receptor subtype selectivity and organ specificity not only depends on the chemical properties but also the stereochemical properties. In order to improve the selcetivities and reduce side effects of muscarinic receptor antagonists, it is very important to study the stereostructure-activity relationship of these antagonists.Phencynonate hydrocloride (8021) and Penehyclidine hydrocloride (8018) are two new anti-cholinerigic M receptor antagonists developed by our research institute. 8021 exhibited good curative effect for motion sickness and its active optical isomer adopted R configuration. 8018 exhibited good curative effect for the pesticides poison of organic phosphorus. Furthermore, 8018 had far greater selectivity for M3 over Ml receptor subtype, which makes it has potentially use in the treatment of respiratory disorders such as COPD. The optical isomer of 8018 with R configuration is the active one. However, no any diastereoselective synthetic methods for 8021 and 8018 optical isomers were reported. This paper is focused on the study of diastereoselective synthetic methods of 8021 and 8018. Then a series of new class of M receptor antagonists were designed and synthesized by utilizing the chiral intermediate, a-Cyclopentyl-a- hydroxy phenyl acetic acid, as the key structural unit. Project supported by the National Natural Science Foundation of China. The results are showed as follow.1. Diastereoselective synthetic methods of 8021 and 8018 a-Cyclopentyl-a-hydroxy phenyl acetic acid 5, the key intermediate for the synthesis of 8021 and 8018, was firstly synthesized through a practical diastereoselective method by utilizing thereadily available and inexpensive starting materials, (S) or (R)-mandelic acid and cyclopentanone (Scheme a). Then the aimed optical pure products of 8021 were synthesized through esterification and ester-change reaction for the first time in this paper (Scheme b). The ee values of 8021 optical isomers were over 99.9%.Scheme b Synthetic route of 8021 and its optical pure derivatives After attempting some unsuccessful synthetic routes for the preparation of Penehyclidine hydrocloride (8018), a practical diastereoselective synthetic method for 8018 four enantiopure isomers was developed by utilizing the ring opening of epoxide intermediate If for the first time. The epoxide intermediate 19 was synthesized from the reduction of chiral tertiary a-hydroxy acid 5, the mono-sulfonation of diol and intramolecular Williamson ether synthetic method (Scheme c). The four optical isomers were obtained with moderate yields in 99-100% ee values.Scheme c Synthetic route of 8018 and its optical pure derivatives2. Diastereoselective synthesis of 8021 and 8018 derivatives The aimed optical pure products of 8021 derivatives were synthesized through ester-change reaction by utilizing the methyl ester of chiral tertiary α-hydroxy acid 5 and corresponding optical alcohol as starting materials (Scheme b). The optical purity of these aimed products were determined by High Performance Capillary Electrophoresis (HPCE) and with over 99.9% ee values, respectively. Moreover, in order to study the effects of aromatic heterocyclic on the bioactivity of 8021, two optical isomers of Thiencynonate Hydrochloride were synthesized through resolution method.The optical 8018 derivatives with piperidine structures were synthesized through ring opening reaction of epoxide 19 with corresponding 4-hydroxy piperidine derivatives (Scheme c). The isomers were obtained with moderate yields in 99-100% ee values. The preliminary biological results suggested that the piperidine derivatives with R configuration were active optical isomers, in which the competitive inhibitory rate of compounds 20a, 20e, 20f, 20j, 20k with QNB at 1 × 10-5mol/L could reach 91%, 88%, 78%, 77% and 83%, respectively. However, the affinity on M receptor of these piperidine derivatives reduced significantly compared to their parent compound 8018.3. Diastereoselective synthesis of M receptor antagonists with C-N bond Based on the synthetic methods of 8021 and 8018 optical isomers, a simplepractical diastereoselective method for the synthesis of a new class of M receptor antagonists with C-N linker bond was designed and developed for the first time.Thirty compounds with R and S configuration were synthesized through condensation, hydrogenation, reductive amination and the amide intermediate reduction by utilizing the chiral tertiary α-hydroxy acid 5 as starting materials (Scheme d).Because the reaction did not involve the changing of chiral center of chiral tertiary α-hydroxy acid, the ee values of these aimed products have the same ee values as the starting materials chiral tertiary α-hydroxy acid with 99.9% ee values. The results also suggested that solvents significantly affected the yields of reduction process of amides, and toluene was the suitable solvent for this reaction.Scheme d Synthetic route of chiral M receptor antagonists with C-N bond更多还原