2-取代酯类-γ-内酰胺化合物的合成及其抗老年痴呆作用的研究
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摘要
黄皮酰胺是从芸香科黄皮属植物黄皮叶的水提取液中分离得到的七种有效成分之一。药理学试验表明天然黄皮酰胺有明显的促智作用,能改善多种原因包括Aβ引起记忆障碍的作用、提高突触效能和新突触形成的作用、提高皮层,海马组织蛋白磷酸酯酶活性,同时研究还发现黄皮酰胺具有能明显降低四氯化碳引起的小鼠高谷丙转氨酶的作用,是很有前途的促智药物和保肝药物。但黄皮酰胺溶解性能较差,难溶于大部分有机溶剂,水溶性也比较差。本文以消旋黄皮酰胺为先导物,对黄皮酰胺的结构进行修饰,设计合成4个酯类目标化合物,均为2位取代酯类黄皮酰胺类化合物,以期能改善其药动学性能,提高其药效。
本课题实验内容包括先导物黄皮酰胺的合成和衍生物的合成两部分。先导物的合成参考文献方法,同时对黄皮酰胺酮的分离方法进行了优化。衍生物的合成综合文献方法,考虑到酰化剂的酰化能力、获取途径、副产物等方面的因素,对酰化方法进行了选择。先导物的酰化以对应的酸作为酰化剂,DCC/DMAP为催化剂,同时对酰化反应的反应物料摩尔比,反应温度、反应时间、反应后处理等进行了研究和摸索。先导物合成部分各步所得中间体对其理化性质进行了验证;衍生物合成部分所得2个中间产物及2个目标产物均经IR,1H-NMR,MS,和元素分析确证结构。
Clausenamide is isolated from aqueous extract of leaves of Clausena lansium. Base on the Pharmacological study, clausenamide could improve dysmnesia caused by multiagent including Aβ, enhance the efficacy of synapse, promote the formation of the new synapse, raise the activity of the cortex and the protein phosphatase of the Hippocampus and decrease the activity of mice serum ALT caused by CCl4. It can be used as nootropics or liver protectant. However, in water and most organic solvent, the dissolvability of clausenamide was low. Using clausenamide as the lead compound, four target compounds were designed in this article, for obtaining higher pharmacokinetics performance compounds.
The synthesis of the lead compound and the derivates of the clausenamide was included in this thesis. Method of clausenamidone’s separation was improved in the synthesis of the lead compound. In terms of ability, price acquisition and coproduct, corresponding organic acids were selected as acylating agents, DCC and DMAP were selected as catalysts. The better reaction routes were definited through studying the effect factor to the acylation reaction, for instance, the molar ratio of the reactant, reaction temperature, reaction time and postprocessing of the reaction, two intermediates and two target compounds were synthesized in the synthesis of the derivates. All of the target compounds were characterized by means of IR, 1H-NMR, MS and elemental analysis.
本课题实验内容包括先导物黄皮酰胺的合成和衍生物的合成两部分。先导物的合成参考文献方法,同时对黄皮酰胺酮的分离方法进行了优化。衍生物的合成综合文献方法,考虑到酰化剂的酰化能力、获取途径、副产物等方面的因素,对酰化方法进行了选择。先导物的酰化以对应的酸作为酰化剂,DCC/DMAP为催化剂,同时对酰化反应的反应物料摩尔比,反应温度、反应时间、反应后处理等进行了研究和摸索。先导物合成部分各步所得中间体对其理化性质进行了验证;衍生物合成部分所得2个中间产物及2个目标产物均经IR,1H-NMR,MS,和元素分析确证结构。
Clausenamide is isolated from aqueous extract of leaves of Clausena lansium. Base on the Pharmacological study, clausenamide could improve dysmnesia caused by multiagent including Aβ, enhance the efficacy of synapse, promote the formation of the new synapse, raise the activity of the cortex and the protein phosphatase of the Hippocampus and decrease the activity of mice serum ALT caused by CCl4. It can be used as nootropics or liver protectant. However, in water and most organic solvent, the dissolvability of clausenamide was low. Using clausenamide as the lead compound, four target compounds were designed in this article, for obtaining higher pharmacokinetics performance compounds.
The synthesis of the lead compound and the derivates of the clausenamide was included in this thesis. Method of clausenamidone’s separation was improved in the synthesis of the lead compound. In terms of ability, price acquisition and coproduct, corresponding organic acids were selected as acylating agents, DCC and DMAP were selected as catalysts. The better reaction routes were definited through studying the effect factor to the acylation reaction, for instance, the molar ratio of the reactant, reaction temperature, reaction time and postprocessing of the reaction, two intermediates and two target compounds were synthesized in the synthesis of the derivates. All of the target compounds were characterized by means of IR, 1H-NMR, MS and elemental analysis.
引文
[1] 马艳红. 我国痴呆发病形势严峻. 中国医药报,第 16 版,2003,10. 28
[2] 张德全. 老年性痴呆的药物治疗进展. 中国医学导报,2006.10,3～29
[3] 张均田.老年痴呆的发病机制及治疗策略 药学学报 2000,35(8):635-640
[4] 陈新平,陈彪 阿尔茨海默病病因学及发病机制研究进展 中国现在神经疾病杂志,2005,5(3):152
[5] 刘丽萍.阿尔茨海默症病理学研究进展.中国临床康复,2003,7(5):785～786
[6] 王红梅,谭迎春,耿德勤.阿尔茨海默病的分子生物学研究进展.徐州医学院学报,2003,23(4):366～369
[7] 王琳媛,刘献增.铜离子在阿尔茨海默病中的作用.国际神经病学神经外科杂志,2007,34(1):90～93
[8] 何小明,张振馨.胆固醇 24S-羟化酶与阿尔茨海默病.中国老年医学杂志,2006,25(8):634～636
[9] 陈生弟,杨红旗.胆固醇:阿尔茨海默病治疗的新方向?.内科理论与实践,2007,2(2):87～89
[10] 翁文,罗焕敏,高勤.β-淀粉样蛋白及相关老年性痴呆治疗药物研究进展. 中国老年学杂志,2007,27:906～908
[11] 陈美婉,路露,罗焕敏.阿尔茨海默病β淀粉样蛋白的研究进展.中国老年学杂志,2007,27:1112～1115
[12] 邵梅,陈生弟,刘振国.水溶性β-淀粉样蛋白 25-35 片段诱致大鼠嗜铬细胞瘤细胞的凋亡[J].中国神经免疫学和神经病学杂志,2002,9(1):24～28
[13] Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer’s disease-linked presenilin-1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo [J]. Neuron, 1996,17(5): 1005～1013
[14] Kim TW, Pettingell WH, Jung YK, et al. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease [J]. Science, 1997,277(5324):373～376.
[15] Palacino JJ, Berechid BE, Alexander P, et al. Regulation of amyloidprecursor protein processing by presenilin 1(PS1) and PS2 in PS1 knockout cells[J]. J Biol Chem, 2000,275(1):215～222.
[16] Bursztajn S, DeSouza R, McPhie DL, et al. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis[J]. J Neurosci, 1998, 18(23): 9790～9799.
[17] Tanzi RE. Agenetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders[J]. J ClinInvest,1999,104(9):1175～1179.
[18] Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease[J]. Nat Genet, 1998,19(4):357～360.
[19] Baskin D S, Browning J L, Pirozzolo F J,et al. Brain choline acetyl-transferase and mental function in Alzheimer’s disease [J].ArchNeual, 1999,56(9):1121～1123.
[20] 陶瑞松.老年痴呆症(AD)发病的 Aβ假说及相关药物研究进展.安徽教育学院学报,2007,25(3):99～101
[21] 王月华,杜冠华.治疗阿尔采末病的药物靶点:β-分泌酶.中国药理学通报,2003,19(6):609～613
[22] Olson R E, Copeland R A. Progress towards testing the amyloid hypo-thesis: inhibitors of APP processing[J]. Curr Opin Drug Discov Devel, 2001,4(4):390～401.
[23] Mcquade R, Young A H. Future therapeutic targets in mood disorders: the glucocorticoid receptor[J]. Br J Psychiatry, 2000, 177(2): 390～395.
[24] Markesbery W R. The role of oxidative stress in Alzheimer’s disease[J]. ArchNeurol, 1999,56:1449～1452.
[25] 张强.阿尔茨海默病与免疫炎性反应.医学综述,2007,13(16):1250～1252
[26] Weller R O, Massey A, Kuo Y M, et al. Cerebral amyloid angiopathy: accumulation of a beta in interstitial fluid drainage pathways in Alzheimer’s disease[J]. Ann N Y Acad Sci, 2000,903:117.
[27] 李嘉和,王颖实,尤海明.阿尔茨海默病新药开发现状.中国新药杂志,2003,12(10):794～803
[28] 耿红梅,王云志,张嫡群.治疗阿尔茨海默症的天然药物.中国药房,2006,17(13):1019～1021
[29] 任晓辉,周冠群,李中华.治疗阿尔茨海默病的天然药物活性成分研究现状.新疆医学,2006,36:268～271
[30] 杨频,李妙鱼.老年性痴呆的病因及其治疗药物的研究进展.山西大学学报(自然科学版),2004,27(4):427～431
[31] 姚莹.老年性痴呆治疗药物的研究进展.实用医药杂志,2005,22(2):159～161
[32] 贺桂泉.阿尔茨海默症的现代临床药物治疗及展望.职业与健康,2007,23(17):1551～1553
[33] 朱海升,刘鄂湖,鞠娟等.康老年性痴呆的天然药物研究进展.中国药房,2007,18(3):223～225
[34] 郁佶,任丽华,仇缀百等.老年痴呆药物治疗的临床应用现状和前景分析.中国临床要学杂志,2006,15(6):402～404
[35] 何学军,任丽莉,陈国广等.浅述治疗老年痴呆药物的研究进展.江苏药学与临床研究.2003,11(5):21～23
[36] 郑虎主编.药物化学(第四版).人民卫生出版社,2000
[37] 管锦群,姬萍.他汀类药物与老年痴呆的防治.中华老年心脑血管病杂志,2006,8(7):500～502
[38] 金虹.治疗老年痴呆中药对乙酰胆碱酯酶的体外抑制作用研究.时珍国医国药,2006,17(12):2410～2411
[39] 顾萍,王坚.代谢综合征与阿尔茨海默病.内科理论与实践,2007,2(5):344～347
[40] 蒋勤.中药抗氧化剂治疗老年痴呆症.中国药师,2006,9(10):966～967
[41] AM Hake and MR Farlow. New concepts in the drug therapy of Alzheimer’s disease[J]. Expert Opin Pharmacother ,2001 ,2 (12) :1975～1983
[42] 张均田.老年痴呆的发病机理及治疗策略[J].药学学报,2000,35(8):635～640
[43] Yang M H, Cao Y H, Li W X, et al. Isolation and structural eluciation of clausenamide from the leaves of Clausena lansium(Lour.) Skeels. Acta Pharm Sin,1987,22:33～34
[44] Rao E C, Cheng J C, Yang G Z, et al. Synthesis of clausemide. Acta Pharm Sin, 1994,29:502～505
[45] 张均田,段文贞,刘少林等.(-)黄皮酰胺的抗老年痴呆作用.医药导报,2001,20(7):403～404
[46] 姚庆强,王慕邹.右旋黄皮酰胺在大鼠肝微粒体中的代谢转化.药学学报,1999,34(4):303～307
[47] 钱文,王雷娜,宋敏等.左旋黄皮酰胺在大鼠体内的排泄.药学学报,2006,41(8):789～792
[48] 孔晓龙,蒋伟哲,林自中.黄皮酰胺对β-淀粉样多肽 25～35 片段诱导的大鼠学习记忆功能障碍的影响.广西医科大学学报,2003,20(5):673～674
[49] 刘少林,赵明瑞,张均田.黄皮酰胺对清醒自由活动大鼠齿状回突触传递的影响.药学学报,1999,34(5):325～328
[50] 朱传江,张均田.(-),(+)-7-羟基-黄皮酰胺对大鼠海马齿状回突触传递功能的影响.药学学报,2004,39(1):34～36
[51] 刘少林,张均田.(-),(+)黄皮酰胺对大鼠海马突触传递功能的不同影响.药学学报,1998,33(4):254～258
[52] 段文贞,张均田. (-),(+)黄皮酰胺对鼠脑内 NMDA-受体的影响.药学学报,1997,32(4):259～263
[53] 刘勇军,祝其锋.(-)黄皮酰胺对硝普钠诱导的海马神经元凋亡的影响.中国老年学杂志,2006,26:936～938
[54] 吴宇群,刘耕陶.光学活性黄皮酰胺类化合物对黄曲霉毒素 B1损伤大鼠肝细胞非程序性 DNA 合成的保护作用.中国药理学与毒理学杂志,2006,20(5):393～398
[55] 饶尔昌,程家宠,黄量等.黄皮酰胺的合成.药学学报,1994,29(7):502～505
[56] Hartwig W and Born L. Diastereoselective and enantioselective total synthesis of the hepatoprotective agent clausenamide. J Org Chem 1987;52:4352
[57] Wolfgang Hartwig. Process for the preparation gamma-butyrolactams. U.S. Patent, Mar.15, 1988, Patent No.:4,731,455
[58] Ban Y, et al. The preparation of 2-(substituted phenyl)-ethanols. Chem Pharm Bull 1958;6:574
[59] 林汉森,卢丽霞.N-甲基-β-羟基苯乙胺制备方法的改进.化学试剂,2003,25(6):376
[60] 佘志刚,陈育平,张歧荣等.DMAP 催化合成苯甲酸苯酯的研究.化学试剂,2001,23(2):110;76
[61] Rao EC, Hong H, Cheng JC, et al. Chin Chem Lett, 5(4):267～268
[62] 曲凡歧,龙思会,戴志群等. 氢化均三嗪二酮双丙酸酯化物的合成.武汉大学学报(自然科学版),2000,46(4):425～428
[2] 张德全. 老年性痴呆的药物治疗进展. 中国医学导报,2006.10,3～29
[3] 张均田.老年痴呆的发病机制及治疗策略 药学学报 2000,35(8):635-640
[4] 陈新平,陈彪 阿尔茨海默病病因学及发病机制研究进展 中国现在神经疾病杂志,2005,5(3):152
[5] 刘丽萍.阿尔茨海默症病理学研究进展.中国临床康复,2003,7(5):785～786
[6] 王红梅,谭迎春,耿德勤.阿尔茨海默病的分子生物学研究进展.徐州医学院学报,2003,23(4):366～369
[7] 王琳媛,刘献增.铜离子在阿尔茨海默病中的作用.国际神经病学神经外科杂志,2007,34(1):90～93
[8] 何小明,张振馨.胆固醇 24S-羟化酶与阿尔茨海默病.中国老年医学杂志,2006,25(8):634～636
[9] 陈生弟,杨红旗.胆固醇:阿尔茨海默病治疗的新方向?.内科理论与实践,2007,2(2):87～89
[10] 翁文,罗焕敏,高勤.β-淀粉样蛋白及相关老年性痴呆治疗药物研究进展. 中国老年学杂志,2007,27:906～908
[11] 陈美婉,路露,罗焕敏.阿尔茨海默病β淀粉样蛋白的研究进展.中国老年学杂志,2007,27:1112～1115
[12] 邵梅,陈生弟,刘振国.水溶性β-淀粉样蛋白 25-35 片段诱致大鼠嗜铬细胞瘤细胞的凋亡[J].中国神经免疫学和神经病学杂志,2002,9(1):24～28
[13] Borchelt DR, Thinakaran G, Eckman CB, et al. Familial Alzheimer’s disease-linked presenilin-1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo [J]. Neuron, 1996,17(5): 1005～1013
[14] Kim TW, Pettingell WH, Jung YK, et al. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease [J]. Science, 1997,277(5324):373～376.
[15] Palacino JJ, Berechid BE, Alexander P, et al. Regulation of amyloidprecursor protein processing by presenilin 1(PS1) and PS2 in PS1 knockout cells[J]. J Biol Chem, 2000,275(1):215～222.
[16] Bursztajn S, DeSouza R, McPhie DL, et al. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis[J]. J Neurosci, 1998, 18(23): 9790～9799.
[17] Tanzi RE. Agenetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders[J]. J ClinInvest,1999,104(9):1175～1179.
[18] Blacker D, Wilcox MA, Laird NM, et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease[J]. Nat Genet, 1998,19(4):357～360.
[19] Baskin D S, Browning J L, Pirozzolo F J,et al. Brain choline acetyl-transferase and mental function in Alzheimer’s disease [J].ArchNeual, 1999,56(9):1121～1123.
[20] 陶瑞松.老年痴呆症(AD)发病的 Aβ假说及相关药物研究进展.安徽教育学院学报,2007,25(3):99～101
[21] 王月华,杜冠华.治疗阿尔采末病的药物靶点:β-分泌酶.中国药理学通报,2003,19(6):609～613
[22] Olson R E, Copeland R A. Progress towards testing the amyloid hypo-thesis: inhibitors of APP processing[J]. Curr Opin Drug Discov Devel, 2001,4(4):390～401.
[23] Mcquade R, Young A H. Future therapeutic targets in mood disorders: the glucocorticoid receptor[J]. Br J Psychiatry, 2000, 177(2): 390～395.
[24] Markesbery W R. The role of oxidative stress in Alzheimer’s disease[J]. ArchNeurol, 1999,56:1449～1452.
[25] 张强.阿尔茨海默病与免疫炎性反应.医学综述,2007,13(16):1250～1252
[26] Weller R O, Massey A, Kuo Y M, et al. Cerebral amyloid angiopathy: accumulation of a beta in interstitial fluid drainage pathways in Alzheimer’s disease[J]. Ann N Y Acad Sci, 2000,903:117.
[27] 李嘉和,王颖实,尤海明.阿尔茨海默病新药开发现状.中国新药杂志,2003,12(10):794～803
[28] 耿红梅,王云志,张嫡群.治疗阿尔茨海默症的天然药物.中国药房,2006,17(13):1019～1021
[29] 任晓辉,周冠群,李中华.治疗阿尔茨海默病的天然药物活性成分研究现状.新疆医学,2006,36:268～271
[30] 杨频,李妙鱼.老年性痴呆的病因及其治疗药物的研究进展.山西大学学报(自然科学版),2004,27(4):427～431
[31] 姚莹.老年性痴呆治疗药物的研究进展.实用医药杂志,2005,22(2):159～161
[32] 贺桂泉.阿尔茨海默症的现代临床药物治疗及展望.职业与健康,2007,23(17):1551～1553
[33] 朱海升,刘鄂湖,鞠娟等.康老年性痴呆的天然药物研究进展.中国药房,2007,18(3):223～225
[34] 郁佶,任丽华,仇缀百等.老年痴呆药物治疗的临床应用现状和前景分析.中国临床要学杂志,2006,15(6):402～404
[35] 何学军,任丽莉,陈国广等.浅述治疗老年痴呆药物的研究进展.江苏药学与临床研究.2003,11(5):21～23
[36] 郑虎主编.药物化学(第四版).人民卫生出版社,2000
[37] 管锦群,姬萍.他汀类药物与老年痴呆的防治.中华老年心脑血管病杂志,2006,8(7):500～502
[38] 金虹.治疗老年痴呆中药对乙酰胆碱酯酶的体外抑制作用研究.时珍国医国药,2006,17(12):2410～2411
[39] 顾萍,王坚.代谢综合征与阿尔茨海默病.内科理论与实践,2007,2(5):344～347
[40] 蒋勤.中药抗氧化剂治疗老年痴呆症.中国药师,2006,9(10):966～967
[41] AM Hake and MR Farlow. New concepts in the drug therapy of Alzheimer’s disease[J]. Expert Opin Pharmacother ,2001 ,2 (12) :1975～1983
[42] 张均田.老年痴呆的发病机理及治疗策略[J].药学学报,2000,35(8):635～640
[43] Yang M H, Cao Y H, Li W X, et al. Isolation and structural eluciation of clausenamide from the leaves of Clausena lansium(Lour.) Skeels. Acta Pharm Sin,1987,22:33～34
[44] Rao E C, Cheng J C, Yang G Z, et al. Synthesis of clausemide. Acta Pharm Sin, 1994,29:502～505
[45] 张均田,段文贞,刘少林等.(-)黄皮酰胺的抗老年痴呆作用.医药导报,2001,20(7):403～404
[46] 姚庆强,王慕邹.右旋黄皮酰胺在大鼠肝微粒体中的代谢转化.药学学报,1999,34(4):303～307
[47] 钱文,王雷娜,宋敏等.左旋黄皮酰胺在大鼠体内的排泄.药学学报,2006,41(8):789～792
[48] 孔晓龙,蒋伟哲,林自中.黄皮酰胺对β-淀粉样多肽 25～35 片段诱导的大鼠学习记忆功能障碍的影响.广西医科大学学报,2003,20(5):673～674
[49] 刘少林,赵明瑞,张均田.黄皮酰胺对清醒自由活动大鼠齿状回突触传递的影响.药学学报,1999,34(5):325～328
[50] 朱传江,张均田.(-),(+)-7-羟基-黄皮酰胺对大鼠海马齿状回突触传递功能的影响.药学学报,2004,39(1):34～36
[51] 刘少林,张均田.(-),(+)黄皮酰胺对大鼠海马突触传递功能的不同影响.药学学报,1998,33(4):254～258
[52] 段文贞,张均田. (-),(+)黄皮酰胺对鼠脑内 NMDA-受体的影响.药学学报,1997,32(4):259～263
[53] 刘勇军,祝其锋.(-)黄皮酰胺对硝普钠诱导的海马神经元凋亡的影响.中国老年学杂志,2006,26:936～938
[54] 吴宇群,刘耕陶.光学活性黄皮酰胺类化合物对黄曲霉毒素 B1损伤大鼠肝细胞非程序性 DNA 合成的保护作用.中国药理学与毒理学杂志,2006,20(5):393～398
[55] 饶尔昌,程家宠,黄量等.黄皮酰胺的合成.药学学报,1994,29(7):502～505
[56] Hartwig W and Born L. Diastereoselective and enantioselective total synthesis of the hepatoprotective agent clausenamide. J Org Chem 1987;52:4352
[57] Wolfgang Hartwig. Process for the preparation gamma-butyrolactams. U.S. Patent, Mar.15, 1988, Patent No.:4,731,455
[58] Ban Y, et al. The preparation of 2-(substituted phenyl)-ethanols. Chem Pharm Bull 1958;6:574
[59] 林汉森,卢丽霞.N-甲基-β-羟基苯乙胺制备方法的改进.化学试剂,2003,25(6):376
[60] 佘志刚,陈育平,张歧荣等.DMAP 催化合成苯甲酸苯酯的研究.化学试剂,2001,23(2):110;76
[61] Rao EC, Hong H, Cheng JC, et al. Chin Chem Lett, 5(4):267～268
[62] 曲凡歧,龙思会,戴志群等. 氢化均三嗪二酮双丙酸酯化物的合成.武汉大学学报(自然科学版),2000,46(4):425～428
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