N-（4，5-二氢-1-甲基-[1，2，4]三氮唑并[4，3-a]喹啉-7-基）-2-（高哌嗪-1-基）乙酰胺衍生物的合成及正性肌力活性研究
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摘要
目前人类由心血管疾病引起的死亡率在逐年下降,但由充血性心力衰竭引起的死亡率却还在上升。据纽约心脏病学会统计,严重的心力衰竭病人年死亡率高达50%。目前,心力衰竭的治疗方法已倍受专家和学者的关注。
我课题组对三唑并二氢喹啉衍生物的合成及正性肌力活性研究已有多年,1999年朴虎日等根据电子等排原理设计合成了取代哌嗪乙酰氨基喹啉酮衍生物20个,并从中筛选出了活性较好的化合物PHR9612。PHR0007是2003年我课题组合成的活性显著的喹啉酮衍生物,其活性在各浓度条件下均强于或等于米力农(milrinone)。在PHR0007的基础上,我们又合成了化合物PHR0701-PHR0716,该系列化合物也显示出较好的生理活性。所以作者设想了以PHR0007为先导化合物对其进行结构修饰,即将哌嗪环变为高哌嗪环,同时改变支链苯环上的取代基,企图能找到正性肌力作用更强的化合物,这对于寻找新药和探索此类型化合物的构效关系具有一定的意义。
本论文设计合成了一系列N-(4,5-二氢-1-甲基-[1,2,4]三氮唑并[4,3-a]喹啉-7-基)-2-(高哌嗪-1-基)乙酰胺衍生物,同时通过测定这些化合物对家兔离体左心房搏出量的影响,初步评价了此系列化合物的正性肌力活性。结果显示,7个化合物在测试浓度下正性肌力作用优于对照药物米力农(3×10-5 M),尤其是化合物2-(4-甲基-苯基-1,4-高哌嗪-1-基)-N-(4,5-二氢-1-甲基-[1,2,4]三唑并[4,3-a]喹啉-7-基)乙酰胺(6m)以增强左心房搏出量8.38±0.16%的强度(米力农：2.45±0.06%)成为此系列衍生物中正性肌力活性最强的化合物。我们同时对那些具有正性肌力活性的化合物进行了变时性实验。论文中所合成的化合物都通过IR,1H-NMR, MS进行了确证。
At present, the death rate which caused by cardiovascular disease are gradually decreasing, however, the death rate which induced by congestive heart failure are still rising. According to the statistics of New York Cardiology Institute, the death rate of the patients who catch severe cardiac failure is about 50%. Now, more and more experts and scholars are paying close attention to the methods which can cure the cardiac failure.
Our researching team have been searching for compounds with favorable positive inotropic activities and fewer side effects in a series of 3,4-dihydro-2(1H)-quinolinone derivatives for many years. According to the rule of isostere, Piao et al synthesized 20 derivates of 2-(piperazin-1-yl)-N-(quinolin-6-yl)acetamide in 1999, from wich PHR9612 was screened out. As reported, PHR0007 is a 2(1H)-quinoline derivative which exhibited favorable activity compared with milrinone. Therefore, the author designed to optimize the structure of PHR0007 by replacing the piperazine ring with a 1,4-diazepan ring and changing the substituents on the benzene ring simultaneously to find compounds with stronger activity and to investigate the structure-activity relationship.
Thus, a series of N-(4,5-dihydro-l-methyl-[1.2,4]triazolo[4,3-a]quinolin-7-yl)-2- (diazepan-1-yl)acetamides was synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which2-(4-(4-methylbenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4, 3-a]quinolin-7-yl)acetamide (6m) was the most potent with 8.38±0.16%(Milrinone 2.45±0.06%) increased stroke volume at 3×10-5 M. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work. The compounds synthesized were characterized by IR,1H-NMR, MS.
我课题组对三唑并二氢喹啉衍生物的合成及正性肌力活性研究已有多年,1999年朴虎日等根据电子等排原理设计合成了取代哌嗪乙酰氨基喹啉酮衍生物20个,并从中筛选出了活性较好的化合物PHR9612。PHR0007是2003年我课题组合成的活性显著的喹啉酮衍生物,其活性在各浓度条件下均强于或等于米力农(milrinone)。在PHR0007的基础上,我们又合成了化合物PHR0701-PHR0716,该系列化合物也显示出较好的生理活性。所以作者设想了以PHR0007为先导化合物对其进行结构修饰,即将哌嗪环变为高哌嗪环,同时改变支链苯环上的取代基,企图能找到正性肌力作用更强的化合物,这对于寻找新药和探索此类型化合物的构效关系具有一定的意义。
本论文设计合成了一系列N-(4,5-二氢-1-甲基-[1,2,4]三氮唑并[4,3-a]喹啉-7-基)-2-(高哌嗪-1-基)乙酰胺衍生物,同时通过测定这些化合物对家兔离体左心房搏出量的影响,初步评价了此系列化合物的正性肌力活性。结果显示,7个化合物在测试浓度下正性肌力作用优于对照药物米力农(3×10-5 M),尤其是化合物2-(4-甲基-苯基-1,4-高哌嗪-1-基)-N-(4,5-二氢-1-甲基-[1,2,4]三唑并[4,3-a]喹啉-7-基)乙酰胺(6m)以增强左心房搏出量8.38±0.16%的强度(米力农：2.45±0.06%)成为此系列衍生物中正性肌力活性最强的化合物。我们同时对那些具有正性肌力活性的化合物进行了变时性实验。论文中所合成的化合物都通过IR,1H-NMR, MS进行了确证。
At present, the death rate which caused by cardiovascular disease are gradually decreasing, however, the death rate which induced by congestive heart failure are still rising. According to the statistics of New York Cardiology Institute, the death rate of the patients who catch severe cardiac failure is about 50%. Now, more and more experts and scholars are paying close attention to the methods which can cure the cardiac failure.
Our researching team have been searching for compounds with favorable positive inotropic activities and fewer side effects in a series of 3,4-dihydro-2(1H)-quinolinone derivatives for many years. According to the rule of isostere, Piao et al synthesized 20 derivates of 2-(piperazin-1-yl)-N-(quinolin-6-yl)acetamide in 1999, from wich PHR9612 was screened out. As reported, PHR0007 is a 2(1H)-quinoline derivative which exhibited favorable activity compared with milrinone. Therefore, the author designed to optimize the structure of PHR0007 by replacing the piperazine ring with a 1,4-diazepan ring and changing the substituents on the benzene ring simultaneously to find compounds with stronger activity and to investigate the structure-activity relationship.
Thus, a series of N-(4,5-dihydro-l-methyl-[1.2,4]triazolo[4,3-a]quinolin-7-yl)-2- (diazepan-1-yl)acetamides was synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which2-(4-(4-methylbenzyl)-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4, 3-a]quinolin-7-yl)acetamide (6m) was the most potent with 8.38±0.16%(Milrinone 2.45±0.06%) increased stroke volume at 3×10-5 M. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work. The compounds synthesized were characterized by IR,1H-NMR, MS.
引文
[1]Masahiro Ueno, Seinosuke Kawashima, Kiyomitsu Ikeoka, et al. The Delayed Recovery of Impaired Endothelium-Dependent Vasodilatory Response After H-emodynamic Improvement in Dogs With Congestive Heart Failure. Jpn Circ J, 1997,61:936-942.
[2]Kentaro SETOYAMA, Hiromi OTA, Naoki MIURA, et al. Effects of Milrinone on Hemodynamics and Regional Blood Flow in the Hypoxic Dog. J. Vet. Med. Sci..2002,64:499-504.
[3]Ayan R., Patel Marvin A. K.. Recent Advances in the Treatment of Heart Failure. Circulation Journal,2002,66:117-121.
[4]MacIntyre K, Capewell S, Stewart S, et al. Evidence of Improving Prognosis in Heart Failure:Trends in Case Fatality in 66 547 Patients Hospitalized Between 1986 and 1995. Circulation,2000,102:1126-1131.
[5]The SOLVD Investigators. Effect of enalapril on survival in patients with redu-ced left ventricular ejection fractions and congestive heart failure.N EnglJ Med, 1991,325:293-302.
[6]The SOLVD Investigators. Effect of enalapril on mortality and the development of heartfailure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med,1992,327:685-691.
[7]The CONSENSUS Trial Study Group. Effects of enalapril on mortality in sev-ere congestiveheart failure:results of the Cooperative North Scandinavian En-alapril Survival Study(CONSENSUS). N Engl J Med,1987,316:1429-1435.
[8]The Digitalis Investigation Group. The effect of digoxin on mortality and morbi-dity in patients with heart failure. N Engl J Med,1997,336:525-533.
[9]Takafumi F, Shuji T, Toyoki M, et al.. Novel positive inotropic agents:synthe-sis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolin-one derivatives. J Med Chem,1992,35(20):3607-3612.
[10]Packer M, Carver JR, Rodeheffer RJ, et al.. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med,1991,325:1468-1475.
[11]Cohn JN, Goldstein SO, Greenberg BH, et al.. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N EnglJ Med,1998,339:1810-1816.
[12]Harada K, Supriatno, Yoshida H, et al.. Vesnarinone inhibits angiogenesis and tumorigenicity of human oral squamous cell carcinoma cells by suppressing the expression of vascular endothelial growth factor and interleukin-8. Int J Oncol. 2005;27:1489-1497.
[13]Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, et al.. Acute hemody-namic and clinical effects of levosimendan in patientswith severe heart failure. Circulation,2000; 102:2222-2227.
[14]Gauthier N, Anselm AH, Handdad H. New therapies in acute decompensated heart failure. Curr Opin Cardiol,2008,23:134-140.
[15]Xie ZF, Kyu-Yun Chai, Hu-Ri Piao, et al.. Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines. Bioorg Med Chem Lett,2005,15:4803-4805.
[16]Al-Soud YA, Al-Dweri MN, Al-Masoudi NA. Synthesis, antitumor and antiviral properties of some 1,2,4-triazole derivatives. Farmaco,2004,59: 775-783.
[17]Labanauskas L, Udrenaite E, Gaidelis P, et al.. Synthesis of 5-(2-,3-and 4-met-hoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity. Farmaco,2004,59:255-259.
[18]Abak K, Sezer O, Akar,Anac A. Synthesis and investigation of tuberculosis inh-ibition activities of some 1,2,3-triazole derivatives. Eur J Med Chem,2003,38: 215-218.
[19]Gulerman NN, Dogan HN, Rollas S, et al.. Synthesis and structure elucidation of some new thioether derivatives of 1,2,4-triazoline-3-thiones and their antimicro-bial activities. Farmaco,2001,56:953-956.
[20]Collin X, Sauleau A, Coulon J.1,2,4-Triazolo mercapto and aminonitriles as pot-nt antifungal agents. Bioorg Med Chem Lett,2003,13:2601-2605.
[21]Cwiklicki A, Rehse K. Antiaggregating and antithrombotic activities of new 1,2,
3-triazolecarboxamides. Arch Pharm, (Weinheim, Ger.) 2004,337:156-163.
[22]Cunha AC, Figueiredo JM, et al. Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives.Bioorg Med Chem,2003,11: 2051-2059.
[23]Kane JM, Baron BM, Dudley MW, et al.2,4-Dihydro-3H-1,2,4-triazol-3-ones as anticonvulsant agents. J Med Chem,1990,33:2772-2777.
[24]Zhang CB, Cui X, Hong L, Quan ZS, Piao HR. Synthesis and positive inotropic activity of N-(4,5-Dihydro-[1,2,4] triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives. Bioorg Med Chem Lett,2008,18:4606-4609.
[25]Ying Lan, Huri Piao, Xun Cui. Positive inotropic effect of PHR0007(2-(4-(4-(Ben zyloxy)-3-methoxybenzyl)piperazin-1-)-N-(1-methyl-4,5-dihydro[1,2,4]triazolo[ 4,3-a]quinolin-7-yl)acetamide) on atrial dynamics in beating rabbit atria. Drug Discov Ther,2009; 3(6):272-277.
[26]Zhang CB, Piao HR, Quan ZS. Synthesis of 4,5-dihydro-[1,2,4]Triazolo[4,3-a] quinolin derivatives. Chem Res & Appl,2002,5:618-619.
[27]Liao X. C. Synthesis of phenyl(piperazin-1-yl)methanone. Chin. J. Pharm.1993, 1:21-22.
[1]Torre AG, Kapadis S, Benedlia S, et al. Proinflammatory cytokine levels in parients with depressed left ventrieular ejection fraction:a report from study of left ventricular dysfunction(SOLVD)[J]. J Am Coll Cardiol,1996,27(5): 1201-1206.
[2]戴闺柱走出对心力衰竭“常规治疗”认识的误区[J].中华心血管杂志.2002,30(2)：68-69.
[3]郑三晖,庄霖鹏,曾哲.766例住院慢性心衰患者病因分析[J].河北医学2004,10(2)：130-132.
[4]曹洪富.110例地高辛中毒临床相关因素分析[J].齐齐哈尔医学院学报,2005,26(8),894-895.
[5]咎安丽,朱新年.地高辛中毒致心律失常19例分析[J].实用医技杂志,2008(3)：339-340.
[6]王守力,王文武.难治性心力衰蝎的研究进展[J].中国实用内科志,2006,26：1484-1485.
[7]Sato A, Saruta T. Aldosterone escape during angiotensin-convertingenzyme inhibitor therapy in essential hypertensive patients with leftventricular hypertrophy [J]. J Int Med Res,2001,29 (1):13-21.
[8]Tautamoto T, Wada A, Maeda K, et al. Transcardiac gradient of aldosterone before and after spironolactone in patients with congestive heartfailur[J]. J
Cardiovasc Pharmacol,2003,41(1):19-20.
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[23]Foody JM, Shah R, Galusha D, et al. Statins and mortality among elderly patients hospitalized with heart failure[J].Circulation,2006,113:1086-1092.
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[2]Kentaro SETOYAMA, Hiromi OTA, Naoki MIURA, et al. Effects of Milrinone on Hemodynamics and Regional Blood Flow in the Hypoxic Dog. J. Vet. Med. Sci..2002,64:499-504.
[3]Ayan R., Patel Marvin A. K.. Recent Advances in the Treatment of Heart Failure. Circulation Journal,2002,66:117-121.
[4]MacIntyre K, Capewell S, Stewart S, et al. Evidence of Improving Prognosis in Heart Failure:Trends in Case Fatality in 66 547 Patients Hospitalized Between 1986 and 1995. Circulation,2000,102:1126-1131.
[5]The SOLVD Investigators. Effect of enalapril on survival in patients with redu-ced left ventricular ejection fractions and congestive heart failure.N EnglJ Med, 1991,325:293-302.
[6]The SOLVD Investigators. Effect of enalapril on mortality and the development of heartfailure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med,1992,327:685-691.
[7]The CONSENSUS Trial Study Group. Effects of enalapril on mortality in sev-ere congestiveheart failure:results of the Cooperative North Scandinavian En-alapril Survival Study(CONSENSUS). N Engl J Med,1987,316:1429-1435.
[8]The Digitalis Investigation Group. The effect of digoxin on mortality and morbi-dity in patients with heart failure. N Engl J Med,1997,336:525-533.
[9]Takafumi F, Shuji T, Toyoki M, et al.. Novel positive inotropic agents:synthe-sis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolin-one derivatives. J Med Chem,1992,35(20):3607-3612.
[10]Packer M, Carver JR, Rodeheffer RJ, et al.. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med,1991,325:1468-1475.
[11]Cohn JN, Goldstein SO, Greenberg BH, et al.. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N EnglJ Med,1998,339:1810-1816.
[12]Harada K, Supriatno, Yoshida H, et al.. Vesnarinone inhibits angiogenesis and tumorigenicity of human oral squamous cell carcinoma cells by suppressing the expression of vascular endothelial growth factor and interleukin-8. Int J Oncol. 2005;27:1489-1497.
[13]Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, et al.. Acute hemody-namic and clinical effects of levosimendan in patientswith severe heart failure. Circulation,2000; 102:2222-2227.
[14]Gauthier N, Anselm AH, Handdad H. New therapies in acute decompensated heart failure. Curr Opin Cardiol,2008,23:134-140.
[15]Xie ZF, Kyu-Yun Chai, Hu-Ri Piao, et al.. Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines. Bioorg Med Chem Lett,2005,15:4803-4805.
[16]Al-Soud YA, Al-Dweri MN, Al-Masoudi NA. Synthesis, antitumor and antiviral properties of some 1,2,4-triazole derivatives. Farmaco,2004,59: 775-783.
[17]Labanauskas L, Udrenaite E, Gaidelis P, et al.. Synthesis of 5-(2-,3-and 4-met-hoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity. Farmaco,2004,59:255-259.
[18]Abak K, Sezer O, Akar,Anac A. Synthesis and investigation of tuberculosis inh-ibition activities of some 1,2,3-triazole derivatives. Eur J Med Chem,2003,38: 215-218.
[19]Gulerman NN, Dogan HN, Rollas S, et al.. Synthesis and structure elucidation of some new thioether derivatives of 1,2,4-triazoline-3-thiones and their antimicro-bial activities. Farmaco,2001,56:953-956.
[20]Collin X, Sauleau A, Coulon J.1,2,4-Triazolo mercapto and aminonitriles as pot-nt antifungal agents. Bioorg Med Chem Lett,2003,13:2601-2605.
[21]Cwiklicki A, Rehse K. Antiaggregating and antithrombotic activities of new 1,2,
3-triazolecarboxamides. Arch Pharm, (Weinheim, Ger.) 2004,337:156-163.
[22]Cunha AC, Figueiredo JM, et al. Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives.Bioorg Med Chem,2003,11: 2051-2059.
[23]Kane JM, Baron BM, Dudley MW, et al.2,4-Dihydro-3H-1,2,4-triazol-3-ones as anticonvulsant agents. J Med Chem,1990,33:2772-2777.
[24]Zhang CB, Cui X, Hong L, Quan ZS, Piao HR. Synthesis and positive inotropic activity of N-(4,5-Dihydro-[1,2,4] triazolo[4,3-a]quinolin-7-yl)-2-(piperazin-1-yl)acetamide derivatives. Bioorg Med Chem Lett,2008,18:4606-4609.
[25]Ying Lan, Huri Piao, Xun Cui. Positive inotropic effect of PHR0007(2-(4-(4-(Ben zyloxy)-3-methoxybenzyl)piperazin-1-)-N-(1-methyl-4,5-dihydro[1,2,4]triazolo[ 4,3-a]quinolin-7-yl)acetamide) on atrial dynamics in beating rabbit atria. Drug Discov Ther,2009; 3(6):272-277.
[26]Zhang CB, Piao HR, Quan ZS. Synthesis of 4,5-dihydro-[1,2,4]Triazolo[4,3-a] quinolin derivatives. Chem Res & Appl,2002,5:618-619.
[27]Liao X. C. Synthesis of phenyl(piperazin-1-yl)methanone. Chin. J. Pharm.1993, 1:21-22.
[1]Torre AG, Kapadis S, Benedlia S, et al. Proinflammatory cytokine levels in parients with depressed left ventrieular ejection fraction:a report from study of left ventricular dysfunction(SOLVD)[J]. J Am Coll Cardiol,1996,27(5): 1201-1206.
[2]戴闺柱走出对心力衰竭“常规治疗”认识的误区[J].中华心血管杂志.2002,30(2)：68-69.
[3]郑三晖,庄霖鹏,曾哲.766例住院慢性心衰患者病因分析[J].河北医学2004,10(2)：130-132.
[4]曹洪富.110例地高辛中毒临床相关因素分析[J].齐齐哈尔医学院学报,2005,26(8),894-895.
[5]咎安丽,朱新年.地高辛中毒致心律失常19例分析[J].实用医技杂志,2008(3)：339-340.
[6]王守力,王文武.难治性心力衰蝎的研究进展[J].中国实用内科志,2006,26：1484-1485.
[7]Sato A, Saruta T. Aldosterone escape during angiotensin-convertingenzyme inhibitor therapy in essential hypertensive patients with leftventricular hypertrophy [J]. J Int Med Res,2001,29 (1):13-21.
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Cardiovasc Pharmacol,2003,41(1):19-20.
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