N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类抗心绞痛化合物的设计与合成研究
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资料包括： 论文(27页12580字)
说明：
中文摘要i
Abstractii
第一章 前言1
1.1 心绞痛的病理生理学1
1.2 抗心绞痛药的作用方式1
1.3 心绞痛的临床分型2
1.4 抗心绞痛药物分类2
第二章 目标化合物的设计与合成10
2.1 研究设计背景10
2.2 目标化合物的设计11
第三章 合成路线的选择14
3.1 合成路线的设计14
3.2 2-氯甲基-咪唑[1,2-a]吡啶的制备14
3.3 2-[(哌嗪-1-基)甲基]-咪唑[1,2-a]吡啶的制备15
3.4 2-氯-N-芳基乙酰胺的制备16
3.5 N-芳基-4-(2-咪唑[1,2-a]吡啶)甲基-1-哌嗪乙酰胺的制备16
第四章 实验部分18
第五章 结论24
参考文献25
攻读学位期间发表的论文29
致谢30
谱图31
参考文献：
张首国, 王林, 彭涛. 抗心绞痛药物构效关系的研究进展. 涛综述国外医学药学分册, 2005, 32(4): 217-222
Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcom- mittee. Circulation, 2007, 115(5): e69-e71
Leal J, Luengo-Fernández R, Gray A, et al. Economic burden of cardiovascular diseases in the enlarged European Union. Eur Heart J, 2006, 27(13): 1610-1619
黄敬耀. 药理学. 北京: 人民卫生出版社, 2004, 219-220
刘国卿. 药理学. 北京: 中国医药科技出版社, 2006, 235-236
仉文升,李安良. 药物化学. 北京: 高等教育出版社, 2007, 269-270
陈旭东. 心绞痛药物治疗进展. 社区医学杂志, 2006, 4 (12): 46-47
李端. 药理学. 北京: 人民卫生出版社, 2002, 186
戴倩, 王俊. 不稳定型心绞痛治疗进展. 疑难病杂志, 2007, 6(8): 505-508
朱斌, 赵金宪, 叶铁虎. ATP敏感性钾通道的阻断剂与开放剂研究进展. 中国临床药理学杂志, 2005, 21(1): 70-73
Gomma AH, Purcell HJ, Fox KM. Potassium channel openers in myocardial ischaemia: therapeutic potential of nicorandil. Drug, 2001, 61(12): 1705-1710
梁可, 张浩, 曹蕾, 谭载友. 第一个窦房结If 电流选择特异性抑制剂—盐酸伊伐布雷定的研究进展. 中国处方药, 2007, 66: 18-19
张丁丁. 欧盟批准降心率药伊伐布雷定上市. Foreign Medical Information, 2006, 27: 35
Stanley WC, Lopaschuk GD, Hall JL, et al. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions.Cardiovasc Res, 1997, 33(2): 243-257
[15] Phipott A, Chandy S, Morris R, et al. Development of a regimen for rapid initiation of perhexiline therapy in acute coronary syndromes. Intern Med J, 2004, 34(6): 361-363
[16] Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res, 2000, 86: 580-588
[17] Kay L, Finelli C, Aussedat J, et al. Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: Effects on the energy state and mito-chondrial function. Circ Res, 2000, 86: 580-588
[18] Morin D, Elimadi A, Sapena R, et al. Evidence for the existence of [3H] -trimetazidine binding sites involved in the regulation of themitochondrial permeability transition pore. Br J Pharmacol, 1998, 123(7): 1385-1394
[19] Sentex E, Sergiel JP, Lucien A, et al. Trimetazidine increases phospholipid turnover in ventri- cularmyocyte. Mol Cell Biochem, 1997, 175(122): 153-162
[20] Porin M, Harpeyc, Alla J, et al. Lack of effects of trime tazidine on systemic hemody- namics in patients with coronary artery diseade: a placebo-ontrolled study. Clin Trials Metaanal, 1994, 29: 49-56
[21] Parang P, Singh B, Arora R. Metabolic modulators for chronic cardiac ischemia. J Cardiovasc Pharmacol Ther, 2005, 10: 217-223
[22] Pauly DF, Pepine CJ. Ischemic heart disease: metabolic app roaches to manage- ment. Clin Cardiol, 2004, 27: 439-441
[23] Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular
conditions. Circulation, 2006, 113: 2462-2472
[24] Antzelevitch C, Belardinelli L, Wu L, et al. Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther, 2004, 9: S65-S83
[25] Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart, 2006, 92(supp 1 IV): iv6-iv14
[26] Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet, 2006, 45: 469-491
[27] Zerumsky K, Mcbride BF. Ranolazine in the management of chronic stable angina. Am J Health Syst Pharm, 2006, 163: 2331-2338
[28] Lee L, Horowitz J, FrenneauxM. Metabolicmanipulation in ischaemic heart disease, a novel approach to treatment. Eur Heart J, 2004, 25: 634-641
[29] McCormack JG, Barr RL, Wolff AA, et al. Ranolazine stimulates glucose oxidetion in nor- moxic, ischemic, and reperfused ischemic rat hearts. Circulation, 1996, 93: 135-142
[30] Chaitman BR, Skettino SL, Parker JO, et al. Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004, 43: 1375-1382
[31] Song Y, Shryock JC, Wu L, et al. Antagonism by ranolazine of the proarrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J Cardiovasc Pharmacol, 2004, 44: 192-199
[32] Dow RJ, Ferrandon P. Ranolazine and related piperazines used in the treatment of tissues experiencing a physical or chemical insult. EP: 0407780A2, 1991.01.16
[33] Chiarini A, Rampa A, Valenti P, et al. 1,4-Dihydropyridines Bearing a Pharmacophoric Fragment of Lidoflazine. Bioorg Med Chem, 1996, 4(10): 1629-1635
[34] Hamdouchi C, Zhong B, Mendoza J, et al. Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases. Bioorg Med Chem Lett, 2005, 15: 1943-1947
[35] Sanfilippo PJ, Urbanski M, Press JB, et al. Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity. J Med Chem, 1988, 31(11): 2221-2227
[36] Trapani G, Franco M, Ricciardi L, et al. Synthesis and binding affinity of 2-phenylimida- zo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type. J Med Chem, 1997, 40(19): 3109-3118
[37] Ruth E. Imidazo[1,2-a]pyridines for the treatment of CNC and cardiac diseases. WO: 9625414, 1996.08.22
[38] Katritzky AR, Xu YJ, Tu H. Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio (oxy) ethyl]-1-isoindolinones. J Org Chem, 2001, 66(16): 5590-5594
[39] Rival Y, Grassy G, Michel G, et al. Synthesis and antibacterial activity of some imidazo [1,2-a]pyrimidine derivatives. Chem Pharm Bull, 1992, 40(5): 1170-1176
[40] Rival Y, Grassy G, Taudou A, et al. Antifungal activity in vitro of some imidazo[1,2-a]pyrimidine derivatives. Eur J Med Chem, 1991, 26(1): 13-18
[41] Hamdouchi C, de Blas J, del Prado M, et al. 2-Amino-3-substituted-6-[(E)-1-phenyl-2- (N-methylcarbamoyl)vinyl]imid azo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: stereospecific synthesis and antiviral activity. J Med Chem, 1999, 42(1): 50-59
[42] Kaminsky JJ, Doweyko AM. Antiulcer agents. 6. Analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2-a]pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies. J Med Chem, 1997, 40(4): 427-436
[43] Rupert KC, Henry JR, Dodd JH, et al. Potent inhibitors of the MAP kinase p38. Bioorg Med Chem Lett, 1998, 8(23): 3335-3340
[44] Eva AC, Tibor G, Kalman H, et al. Process for preparation of piperazine derivatives. EP: 483932, 1992.05.06
[45] Cecile EG, Harald H, Alain G, et al. 2-[(4-Phenylpiperazin-1-yl)methyl]imidazo(di)azines as Selective D4-Ligands. Induction of Penile Erection by 2-[4-(2-Methoxyphenyl)piperazin-1-ylmethyl]imidazo [1,2-a]pyridine (PIP3EA), a Potent and Selective D4 Partial Agonist. J Med Chem, 2006, 49(13): 3938-3947
[46] 陆文超, 李瑛琦, 郭春, et al. 雷诺嗪的合成. 中国医药工业杂志, 2004, 35(11): 641-642
[47] Park JH, Choi JK, Roh EJ, et al. Lead discovery and optimization of T-type calcium channel blockers. Bioorg Med Chem, 2007, 15(3): 1409-1419
[48] Kuge AF, Clark RD, Strosberg AM, et al. Cardioselective aryloxy- and arythiohydroxyproPylenepiper-
azinyl acetanilides which affect calcium entry. US: 4567264, 1980.01.28
作者点评：
本论文对N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物进行了设计及合成研究。现在将本论文进行的研究工作总结如下：
1．以雷诺嗪为先导化合物，在保留了2-(4-甲基哌嗪-1-基)-N-苯基乙酰胺药效团的基础上，在4-甲基上引入咪唑并[1,2-a]吡啶基团，通过在N位引入具有不同取代基的苯胺基团，设计了一系列N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物；
2．设计了目标化合物的合成路线，并对多步反应条件进行优化与改进。以邻氨基吡啶为原料，经环合、取代等五步反应制得目标化合物，并合成了20个未见文献报道的化合物；
3．目标化合物的结构经MS、1H-NMR确证。
资料包括： 论文(27页12580字)
说明：
摘 要：本论文简述了抗心绞痛药物的作用机制，着重介绍了该类药物的研究进展。在此基础上，重点研究了N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物的设计及合成方法。
本论文以雷诺嗪为先导化合物，在保留了2-(4-甲基哌嗪-1-基)-N-苯基乙酰胺药效团的基础上，在4-甲基上引入咪唑[1,2-a]吡啶基团，通过在N-苯基上引入不同的取代基，设计了一系列N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物。设计了以邻氨基吡啶为原料的合成路线，经环合、取代等五步反应制得20个未见文献报道的化合物，其化学结构经MS、1H-NMR确证。
目标化合物的药理活性测试正在进行中。
关键词：抗心绞痛药物，咪唑[1,2-a]吡啶，设计，合成，雷诺嗪
第一章 前 言
心绞痛是危害人类健康的常见病。据报道，美国约有720万人患有心绞痛，并且以每年35万人的速度递增，因本病而死亡的人数高达50余万，占人口死亡总数的1/3~1/2，占心脏病死亡总数的50%~75%。随着人民生活水平的提高、生活方式的改变及生活节奏的加快，我国心血管疾病（尤其是冠心病）的发生率逐年增高，约2%~4%人群有心绞痛临床症状或由此产生并发症[2,3]。因此，积极开发抗心绞痛药物势在必行。
1.1 心绞痛的病理生理学
心绞痛（angina pectoris）是冠状动脉粥样硬化性心脏病的常见症状，由心肌急剧的、暂时性缺血和缺氧所引起。心肌对氧的需求急剧增高及冠状动脉供血不足是导致心绞痛的重要病理生理机制。心绞痛发作是由于心肌供氧及需氧失去平衡所致，一是因为心脏做功增加，使心肌对氧需求增加；二是因为冠状动脉粥样硬化，使冠状动脉管腔变小、弹性降低，或冠状动脉供血、供氧不足。
中文摘要i
Abstractii
第一章 前言1
1.1 心绞痛的病理生理学1
1.2 抗心绞痛药的作用方式1
1.3 心绞痛的临床分型2
1.4 抗心绞痛药物分类2
第二章 目标化合物的设计与合成10
2.1 研究设计背景10
2.2 目标化合物的设计11
第三章 合成路线的选择14
3.1 合成路线的设计14
3.2 2-氯甲基-咪唑[1,2-a]吡啶的制备14
3.3 2-[(哌嗪-1-基)甲基]-咪唑[1,2-a]吡啶的制备15
3.4 2-氯-N-芳基乙酰胺的制备16
3.5 N-芳基-4-(2-咪唑[1,2-a]吡啶)甲基-1-哌嗪乙酰胺的制备16
第四章 实验部分18
第五章 结论24
参考文献25
攻读学位期间发表的论文29
致谢30
谱图31
参考文献：
张首国, 王林, 彭涛. 抗心绞痛药物构效关系的研究进展. 涛综述国外医学药学分册, 2005, 32(4): 217-222
Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcom- mittee. Circulation, 2007, 115(5): e69-e71
Leal J, Luengo-Fernández R, Gray A, et al. Economic burden of cardiovascular diseases in the enlarged European Union. Eur Heart J, 2006, 27(13): 1610-1619
黄敬耀. 药理学. 北京: 人民卫生出版社, 2004, 219-220
刘国卿. 药理学. 北京: 中国医药科技出版社, 2006, 235-236
仉文升,李安良. 药物化学. 北京: 高等教育出版社, 2007, 269-270
陈旭东. 心绞痛药物治疗进展. 社区医学杂志, 2006, 4 (12): 46-47
李端. 药理学. 北京: 人民卫生出版社, 2002, 186
戴倩, 王俊. 不稳定型心绞痛治疗进展. 疑难病杂志, 2007, 6(8): 505-508
朱斌, 赵金宪, 叶铁虎. ATP敏感性钾通道的阻断剂与开放剂研究进展. 中国临床药理学杂志, 2005, 21(1): 70-73
Gomma AH, Purcell HJ, Fox KM. Potassium channel openers in myocardial ischaemia: therapeutic potential of nicorandil. Drug, 2001, 61(12): 1705-1710
梁可, 张浩, 曹蕾, 谭载友. 第一个窦房结If 电流选择特异性抑制剂—盐酸伊伐布雷定的研究进展. 中国处方药, 2007, 66: 18-19
张丁丁. 欧盟批准降心率药伊伐布雷定上市. Foreign Medical Information, 2006, 27: 35
Stanley WC, Lopaschuk GD, Hall JL, et al. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions.Cardiovasc Res, 1997, 33(2): 243-257
[15] Phipott A, Chandy S, Morris R, et al. Development of a regimen for rapid initiation of perhexiline therapy in acute coronary syndromes. Intern Med J, 2004, 34(6): 361-363
[16] Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res, 2000, 86: 580-588
[17] Kay L, Finelli C, Aussedat J, et al. Improvement of long-term preservation of the isolated arrested rat heart by trimetazidine: Effects on the energy state and mito-chondrial function. Circ Res, 2000, 86: 580-588
[18] Morin D, Elimadi A, Sapena R, et al. Evidence for the existence of [3H] -trimetazidine binding sites involved in the regulation of themitochondrial permeability transition pore. Br J Pharmacol, 1998, 123(7): 1385-1394
[19] Sentex E, Sergiel JP, Lucien A, et al. Trimetazidine increases phospholipid turnover in ventri- cularmyocyte. Mol Cell Biochem, 1997, 175(122): 153-162
[20] Porin M, Harpeyc, Alla J, et al. Lack of effects of trime tazidine on systemic hemody- namics in patients with coronary artery diseade: a placebo-ontrolled study. Clin Trials Metaanal, 1994, 29: 49-56
[21] Parang P, Singh B, Arora R. Metabolic modulators for chronic cardiac ischemia. J Cardiovasc Pharmacol Ther, 2005, 10: 217-223
[22] Pauly DF, Pepine CJ. Ischemic heart disease: metabolic app roaches to manage- ment. Clin Cardiol, 2004, 27: 439-441
[23] Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular
conditions. Circulation, 2006, 113: 2462-2472
[24] Antzelevitch C, Belardinelli L, Wu L, et al. Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther, 2004, 9: S65-S83
[25] Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart, 2006, 92(supp 1 IV): iv6-iv14
[26] Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet, 2006, 45: 469-491
[27] Zerumsky K, Mcbride BF. Ranolazine in the management of chronic stable angina. Am J Health Syst Pharm, 2006, 163: 2331-2338
[28] Lee L, Horowitz J, FrenneauxM. Metabolicmanipulation in ischaemic heart disease, a novel approach to treatment. Eur Heart J, 2004, 25: 634-641
[29] McCormack JG, Barr RL, Wolff AA, et al. Ranolazine stimulates glucose oxidetion in nor- moxic, ischemic, and reperfused ischemic rat hearts. Circulation, 1996, 93: 135-142
[30] Chaitman BR, Skettino SL, Parker JO, et al. Antiischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004, 43: 1375-1382
[31] Song Y, Shryock JC, Wu L, et al. Antagonism by ranolazine of the proarrhythmic effects of increasing late INa in guinea pig ventricular myocytes. J Cardiovasc Pharmacol, 2004, 44: 192-199
[32] Dow RJ, Ferrandon P. Ranolazine and related piperazines used in the treatment of tissues experiencing a physical or chemical insult. EP: 0407780A2, 1991.01.16
[33] Chiarini A, Rampa A, Valenti P, et al. 1,4-Dihydropyridines Bearing a Pharmacophoric Fragment of Lidoflazine. Bioorg Med Chem, 1996, 4(10): 1629-1635
[34] Hamdouchi C, Zhong B, Mendoza J, et al. Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin dependent kinases. Bioorg Med Chem Lett, 2005, 15: 1943-1947
[35] Sanfilippo PJ, Urbanski M, Press JB, et al. Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity. J Med Chem, 1988, 31(11): 2221-2227
[36] Trapani G, Franco M, Ricciardi L, et al. Synthesis and binding affinity of 2-phenylimida- zo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type. J Med Chem, 1997, 40(19): 3109-3118
[37] Ruth E. Imidazo[1,2-a]pyridines for the treatment of CNC and cardiac diseases. WO: 9625414, 1996.08.22
[38] Katritzky AR, Xu YJ, Tu H. Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio (oxy) ethyl]-1-isoindolinones. J Org Chem, 2001, 66(16): 5590-5594
[39] Rival Y, Grassy G, Michel G, et al. Synthesis and antibacterial activity of some imidazo [1,2-a]pyrimidine derivatives. Chem Pharm Bull, 1992, 40(5): 1170-1176
[40] Rival Y, Grassy G, Taudou A, et al. Antifungal activity in vitro of some imidazo[1,2-a]pyrimidine derivatives. Eur J Med Chem, 1991, 26(1): 13-18
[41] Hamdouchi C, de Blas J, del Prado M, et al. 2-Amino-3-substituted-6-[(E)-1-phenyl-2- (N-methylcarbamoyl)vinyl]imid azo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: stereospecific synthesis and antiviral activity. J Med Chem, 1999, 42(1): 50-59
[42] Kaminsky JJ, Doweyko AM. Antiulcer agents. 6. Analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2-a]pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies. J Med Chem, 1997, 40(4): 427-436
[43] Rupert KC, Henry JR, Dodd JH, et al. Potent inhibitors of the MAP kinase p38. Bioorg Med Chem Lett, 1998, 8(23): 3335-3340
[44] Eva AC, Tibor G, Kalman H, et al. Process for preparation of piperazine derivatives. EP: 483932, 1992.05.06
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[46] 陆文超, 李瑛琦, 郭春, et al. 雷诺嗪的合成. 中国医药工业杂志, 2004, 35(11): 641-642
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作者点评：
本论文对N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物进行了设计及合成研究。现在将本论文进行的研究工作总结如下：
1．以雷诺嗪为先导化合物，在保留了2-(4-甲基哌嗪-1-基)-N-苯基乙酰胺药效团的基础上，在4-甲基上引入咪唑并[1,2-a]吡啶基团，通过在N位引入具有不同取代基的苯胺基团，设计了一系列N-芳基-2-[4-[(咪唑并[1,2-a]吡啶-2-基)甲基]哌嗪-1-基]乙酰胺类化合物；
2．设计了目标化合物的合成路线，并对多步反应条件进行优化与改进。以邻氨基吡啶为原料，经环合、取代等五步反应制得目标化合物，并合成了20个未见文献报道的化合物；
3．目标化合物的结构经MS、1H-NMR确证。