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研究生:李致寬
研究生(外文):Chi-Kuan Li
論文名稱:CIJ-3-2F之新合成法及其活性機轉研究
論文名稱(外文):Investigation on the New Synthetic Strategy and Action Mechanism of CIJ-3-2F
指導教授:林宗平林宗平引用關係
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:藥物化學研究所碩士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:120
中文關鍵詞:烷基化環化綠色化學抗心律不整血管舒張
外文關鍵詞:akylationcyclizationgreen chemistryantiarrhythmicvasodilative effect
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N-benzyl-furoquinolone具有顯著的抗心律不整活性,為持續提供化合物,以利藥理機轉方面能有更進一步的新發現,著者期望透過新合成方式能使CIJ3-2F及其衍生物得到較高產率,以及降低對環境、人體的傷害。
N-benzyl-furoquinolone舊有合成方法,乃利用有毒化合物DMF為溶媒進行烷基化作用,再利用有毒化物Diphenyl ether為熱媒進行合環作用,DMF及Diphenyl ether在後續處理較為困難且對環境及人體有害;鑒於近來提倡綠色化學,著者欲利用對環境影響較低的ethanol為溶媒進行烷基化反應,再利用Polyphosporic acid為合環催化劑,進行合環作用。
N-benzyl-furoquinolone經研究對抗心律不整有顯著的活性,N-benzyl-furoquinolone利用對於血管具有舒張作用,以達到抗心律不整之作用,N-benzyl-furoquinolone作用於平滑肌細胞時,可藉由促進NO的釋放,活化guanylate cylcase,而產生血管舒張作用;N-benzyl-furoquinolone亦可抑制Ca2+的內流或IP3誘導細胞內Ca2+釋放,與刺激電位依賴型K+ Channel 開啟,以產生血管舒張。
In order to continuously supply CIJ-3-2F for further investigation on pharmacological mechanism, the author expects for a new synthetic strategy to elevate the yield and lower the damage to environment and human health.
The original synthetic method of CIJ-3-2F utilized toxic DMF as solvent to perform alkylation, and toxic diphenyl ether as heat transfer medium to achieve cyclization. The post-treatment process of DMF and Diphenyl ether is more difficult and harmful to human health. According to the recently-advocated green chemistry, the author tries to use ethanol, which produces less effect to environment, as solvent to perform alkylation and polyphosphoric acid to undergo Polyphosphoric acid catalyzed cyclization
CIJ-3-2F was proved to possess obvious antiarrhythmic activity. The antiarrhythmic effect of CIJ-3-2F was achieved via vasodilation. While acting on smooth muscle cells, CIJ-3-2F caused vasodilation by inducing the release of NO and activating guanylate cyclase. Besides, The CIJ-3-2F inhibited the influx of Ca2+ as well as IP3-induced intracellular Ca2+ release,stimulated the opening of voltage-dependent K+ channel, and thus produced the vasodilative effect.
目錄
中文摘要……………………………………………………..I
英文摘要…………………………………………………….II
第一章 緒言……………………………………………….1
第一節Furoquinolones類衍生物之研究概況…………...1
第二節 心律不整疾病與治療之概述……………………..4
第三節 抗心律不整藥物之概述………………………..6
第四節 綠色化學的初現、興起和定義………………..9
第五節 研究動機與目的 …………..…………………12
第二章 研究經過………………………...………………15
第一節 化學合成部分…………………………………..15
第三章 結論………………………………………………29
第一節 化學合成部分…………………………………..29
第二節 抗心律不整之研究結果……………………….33
第四章 實驗部份……………………………………...…39
第一節 試藥、溶媒與材料……………………………..39
第二節 儀器……………………………………………..42
第三節 實驗方法………………………………………..43
第四節 藥理實驗方法與材料……………………….…...65
參考文獻……………………………………………………….68
附圖(圖譜部分)………………………………………….76
(1) Chang*, G.J., Lin, T.P., Ko, Y.S. and Lin, M.S. (2008). Mechanisms of vasorelaxation induced by CIJ-3-2F, a novel benzyl-furoquinoline derivative with antiarrhythmic action, in isolated rat aorta

(2)Mitscher L. A.,T. Suzuki and Clark G., Total synthesis of 2,4-dioxy- quinoline alkaloids, Heterocycles, 1976, 5, 565-604 .

(3) Zhao W., Wolfender J. L., Hostettmann K., Xu R. and Qin G., Antifungal alkaloids and limonoid derivatives from Dictamnus dasycarpus, Phytochemistry, 1998,47 (1), 7-11 .

(4) Yu S. M. , Ko F. N., Su M. J., Wu T. S., Wang M. L., Ltuang T. F. and Teng C.M., Vaasorelaxing effect in rat thoracic aorta caused by Yaxinellon and dictamnine isolated from the Chinese herb Dictamnus daycarpus Turcz: comparison with cromakalim and Ca+2 channel blockers. Naunyn-Sch- miedeberg''s Arch. Pharmacol., 1992, 345, 349-355 .

(5) Chen K. S., Chang Y. L., Teng C. M., Chenand C. F., Wu Y. C., Furo- quinolines with antiplatelet aggregationactivity from leaves of Melicope confusa. Planta Medica, 2000,66, 80-81.

(6) Cheng J. T., Chang T. K., and Cheng I. S., Skimmianine and related furoquinolines function as antagonists of 5-hydroxytryptamine receptors in animals. J. Auto. Pharmacol., 1994, 14, 365- 374.

(7) Lahey F. N. and McCamish M., Acrophylline and Acrophyllidine. Two new alkaloids from Acronychia haplophylla. Tetrahedron Letters, 1968, 12, 1525-1527 .
(8) Sakar M., Kundu S. and Chakraborty D.P., Glycarpine, a new alkaloid from Glycosmis cyanocarpa. Phytochemistry, 1978, 17, 2145 -2146.

(9) Mohr N., Budzikiewicz H., EI-Tawil B. A. H. and EI-Beih F. K. A., Further furoquinolone alkaloids from Ruta chalepensis. Phytochemistry, 1982 ,21 (7), 1838-1839 .

(10) Govindachari T. R., Prabhakal S., Ramachandran V. N., and Pal B. R., Synthetic of Medicosmine. Indian J. Chem. ,1971, 9, 1031-1041

(11) Narasimhan N. S., Paradkar M. V. and Alurkar R. H., Synthetic application of lithiation reactions-IV novel synthesis of linear furoquinoline alkaloids and a synthesis of edulitine. Tetrahedron, 1971, 27, 1351-1356 .

(12) Narasimhan N. S. and Mall R. S., Synthetic application of lithiation reactions -VI new synthesis of linear fhroquinoline alkaloids. Tetrahedron, 1974 , 30, 4153 - 4157

(13) Narasimhan N. S. and Alurkar R. H., Synthesis of dihydro-γ-fagarine and edulitine, Chem. Lnd., 1968, 515

(14). Narasimhan N. S. and Paradkar M. V., A new synthesis of the furo[2,3-b] quinolines:a synthesis of dictamnine. Chem. Ind., 1967,831-832 .
(15). Huffman J. W., Garg S. P. and Cecil J. H., The furanoquinoline alkaloids III. An attempted synthesis of dl-lunacrine and correction of the structure of demethoxylunacrine. J. Org. Chem., 1966, 31, 1276-1279 .
(16) Huffman J. W. and Cecil J. H., Reaction of some acylquinolones with diazomethane,. J. Org. Chem., 1969 , 34, 2183-2187 .
(17). Hoffman B. F., and Cranefield P. F., The Physiological Basis of
Cardiac Arrhythmias. Am. J. Med.,1964,37,670-684
(18) http://www.doh.gov.tw/cht2006/index_populace.aspx(衛生署網站)
衛生署:首頁>衛生署新聞>97 年>97 年06 月份新聞---標題:
國人主要死因統計。
(19)張天鈞;台大內科學講義,橘井文化事業股份有限公司,台北市,
2001,第三版,192頁。



(20) Meinertz T., Hoffinann T., Kasper W., Significance of ventricular arrhy- thmias in idiopathic dilated cardiomyopathy. Am. J. Cardiol., 1984 , 53, 902 -907
(21) Chakko C. S., Gheorghiade M., Ventricular arrhythmia in severe heart failure incidence significance and effectiveness of antiarrhythmic therapy. Am. J. Cardiol., 1985, 52, 14 .
(22). Lathrop D. A., Varro A., Schwartz A., Rate-dependent electrophysiological effects of OPC-8212, Comparison to Sotalol. Eur. J. Phamacol., 1989, 164, 487-496 .
(23) Lathrop D. A., Nanasi P. P., Schwartz A., Varro A., Ionic basis for OPC-8212 induced increase in action potential duration in isolated rabbit guinea-pig and humaventricula myocytes. Eur. .J. Pharmacol., 1993, 240, 127-137 .
(24) Su M. J., Chang Y. M., Chi J. F., Lee S. S., Thaliporphine, a positive inotropic agent with a negative chrorotropic action. Eur. J. Pharmacol., 1994, 254, 141-150 .
(25) Beregi J. P., Escande P., Coudray N., Mery P., Mestre M., Chamta D., Lecarpentier Y., Positive inotropic eltbcts of RP- 62719, a new pure class 3 antiarrhythmic agent, on guinea-pig myocardium. Eur .J. Pharmacol., Exp. Ther., 1992, 263, 1369 .
(26) Bain A. I., Barrett T. D., Beatch G. N., Fedida D., Hayes E. S., Plouvier B., Pugsly M. K., Walker M. J. A.,Walker M. L., Wall R. A., Yong S. L., Zolotoy A., Better arrhythmics? Development of antiarr- hythmic drugs selective for ischemia-dependent arrhythmias. Drug Dev. Res. 1997, 42, 198-210 .
(27) Camm A. J., Yap Y.G., What should we expect from the next genera- tion of antiarrhythmic drugs? J. Cardiovasc Eletrophysiol., 1999, 10, 307-317

(28) Coplen S. E., Antman E. M., Berlin J. A., Hewitt P., Chalmers T. C., Efficacy and safety of quinidine therapy for maintaince of sinus rhythm after cardioversion. Circulation , 1990, 82,1106-1116 .
(29) Curtis M. J., Hearse D. J., Ischemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: implications for mechanisms of initiation and maintenance of ventricular fibrillation. J. Mol. Cardiol., 1989, 21, 21-40 .
(30) Danish Investigator of Arrhythmia and Mortality on Dofetilide. Dof- etilide in patients with left ventricular dysfunction and either heart failure or acute myocardial infraction: rational design, and patient characteristics of the DIAMOND studies. Clin. Cardiol., 1997, 20, 704-710
(31) Doval H. C., Nul D. R., Grancelli H. O., Perrone S. V., Bortman G.R., Curiel R., Randomized trial of low-dose amiodarone in severe cong- estive heart failure. Lancet ,1994, 344, 493-498
(32). Garg R., Packer M., Pitt B., Yusuf S., Heart failure in the 1990s: evolution of a major public health problem in cardiovascular medi- cine. J. Am. Coll. Cardio., 1993, 22(Suppl A): 3A-5A .
(33). Echt D. S., Liebson P. R., Mitchel L. B., Peters R. W., Obiasmanno D.,Baker A. H., and The CAST Investigators., Mortality and morb- idlity in patients receiving encainide, fleicainide, or placebo.The cardiac arrhythmia suppression trial. N. Engl. J. Med., 1991, 324, 781-788 .
(34) Gibson J. K., Kersten J. A., In vivo assessment of class III antiarrh- tyhmic agents and their antiarrhythmic activity. Drug Dev. Res.,1990, 19, 173-185.
(35) Hamill O. P., Marty J. A., Neher E., Sakmann B., Sigworth F. J., Improved patch-clamp techniques for high resolution current recording from cells and cell-free menbrane patches. Pflűgers Arch.,1981, 391, 85 -100

(36) Hilleman D., Miller M. A., Paker R., Doering P., Pieper J. A., Opti- mal management of amiodarone therapy: efficacy and side effects. Pharmacotherapy, 1998, 18, 138S-145S .

(37) Hondeghem L. M., Development of class II antiarrhythmic agents . J. Cardiovasc Pharmacol.,1992, 20(Suppl. 2), S17-22 .

(38) Hondeghem L. M, Synders D. J., Class II antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use-dependence. Circulation, 1990, 81, 680-690 .

(39) Jafari-Fesharaski M., Scheinman M. M.,Adverse effects of amiodar- one. Pacing Clin. Electrophysiol. ,1998, 21, 108-120 .
(40) Jewitt D. W., Haemodynamic effects of a newer antiarrhythmic agents. Am. Heart J. , 1989, 100,984-989 .
(41) Josephson M. E., Seides S. F., Clinical cardiac electrophysiology. Technique and interpretations. Philadephia: Lea and Febiger, 1979, 41-65 .
(42) Julian D. G., Camm A. J., Frangin G., Janse M. J., Munoz A., Schwartz P. J., Simon P., Randomized trial of effect of aminodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infraction: EMIAT-European Myocardial Infract Amio- darone Trial, Investigators, Lancet. , 1997, 349, 667-674 .
(43) Julian D. G., Jackson F. S., Szekely P., Prescott R. J., A controlled trial of sotalol for 1 year after myocardial infraction: EMIAT- European Myocardial Infraction, Circulation, 1993, 67, 667-674 .
(44) Massie B. M., Fisher S. G., Radford M., Deewania P. C., Singh B. N., Fletcher R. D., Singh S. N., Effect of amiodarone on clinic status and left ventricular function in patients with congestive heart failure. Circulation, 1996, 3, 2112-2134
(45) Mätyus P., Varro A., Papp J. G., Wamhoff H., Varga I., Virag L.,Anti- arrhythmic agents: current status and perspectives. Med. Res. Rev. , 1997, 17, 427-451 .
(46) Mätyus P., Rettegi T., Varro A., Papp J. G. Y.,New antiarrhythmic agents : a conceptually novel approach. Med. Res. Rev. , 2000, 20, 294-303
(47) O’Connor C. M., Gattis W. A., Swedberg K., Current and novel phar-
macological approaches in advanced heart failure. Am. Heart J., 1998, 135, S249- S263 .

(48) Olshausen K. V., Witt T., Pop T., Treese N., Bethge K., Meyer J., Sudden cardiac death while wearing a Holter monitor. Am.J. Cardiol, 1991, 67: 381-386 .
(49) Sanguinetti M. C., Modulation of potassium channels by antiarrhy- thmic and antihypertensive drugs. Hypertension, 1992, 19, 228-236 .
(50) Schlepper M., Cardiodepressive effects of antiarrhythmic drugs. Eur. Heart J., 1999, 10, E73-E80 .
(51) Sim I., McDonald K. M., Lavori P. W., Norbutas C. M., Hlatky M. A, Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation, 1997, 96, 2823-2829 .
(52) Singh B. N., Nademanee K., Control of cardiac arrhythmia by selec- tive lengthening of repolarization: Therapeutic considerations and clinic observations. Am. Heart J., 1985, 109, 421- 430 .
(53) Smith 3rd E. F., Griswold D. E., Egan J. W., Hillegass L. M., Dimartino M. J., Reduction of myocardial damage and polymor- phonuclear leucocyte accumulation of following coronary artery occlusion and reperfusion by the thromboxane receptor antagonist BM 13.505. J. Cardiovasc Pharmacol.,1989, 13, 715-722 .
(54) Hilleman D., Miller M. A., Paker R., Doering P., Pieper J. A., Opti- mal management of amiodarone therapy: efficacy and side effects. Pharmacotherapy, 1998, 18, 138S-145S .
(55) Jafari-Fesharaski M., Scheinman M. M.,Adverse effects of amioda- rone. Pacing Clin. Electrophysiol. ,1998, 21, 108-120
(56) Massie B. M., Fisher S. G., Radford M., Deewania P. C., Singh B. N., Fletcher R. D., Singh S. N., Effect of amiodarone on clinic status and left ventricular function in patients with congestive heart failure. Circulation, 1996, 3, 2112-2134.
(57) Sim I., McDonald K. M., Lavori P. W., Norbutas C. M., Hlatky M. A, Quantitative overview of randomized trials of amiodarone to prevent sudden cardiac death. Circulation, 1997, 96, 2823-2829 .
(58) 閔恩澤,吳蘶 /綠色化學與化工/ 五南出版社(2003)/第10-16頁
(59) Waldo A. L., Camm A. J., de Ruyter H., Friedman P. L., MacNiel D. J., Pauls J. F., Pitt B., Pratt C. M., Schwartz P. J., Veltri E. P., Effect of d-sotalol on mortality in patients with left ventricular dysfuction after recent and remote myocardial infraction. The SWORD Inves- tigators, Suvival With Oral d-Sotalol. Lancet, 1996, 348, 7-12 .
(60) Walker M. J., Curtis M. J., Hearse D. J. et al.,The Lambeth Conven- tions : guidelines for the study of arrhythmias in ischemia infraction, and reperfusion. Cardiovasc Res., 1998, 22, 447-455 .

(61) Kuo S. C., Lin T. P., Lin L. D., Hsu H. Y. and Wu C. H., Synthetic Investigation of Glycarpine.J. Nat Prod, 1984, 47, 47-51 .
(62) Kuo S. C., Lin T. P., Chang S. S., Wu C. H., Shieh B. J. and Chou T. C., Synthetic Investigation of Taifine, J .Nat. Prod., 1986, 49, 48-55.
(63) Lin T. P. and Shieh B. J., Study on the constituents of Furoquinoline alkaloids from Pai-Shen pi (Dictamnus dasycarpus Turz) in Ruta- ceae , Chemistry (Chinese), 1986, 44,96-100 .
(64) Lin T. P., Shieh B. J. and Kuo S. C., Study on the constituents of Furoquinolone alkaloids in Rutaceae, Synthetic Investigation of Isomaculosidine, J .Nat. Prod. ,1986, 44, 631 .
(65) Lin T. P., Shieh B. J. and Kuo S. C., Study on the constituents of Furoquinolone alkaloids in Rutaceae, Synthetic Investigation of Isodictamnine. Chemistry (Chinese),1987,45, 45-49 .
(66) Shieh B. J. and Lin T. P., Study on the constituents of Furoquinolone alkaloids in Rutaceae,Synthetic Investigation of Isotaifine Chemi- stry,(Chinese), 1990, 48,309-316 .
(67) Shieh B. J. and Lin T. P., Study on the constituents of Furoquinlone alkaloids in Rutaceae, Synthetic Investigation of acrophylline. Chemistry, (Chinese), 1990, 48, 259-264 .
(68) Kuo S. C.,Huang S. C.,Cheng H. E.,Lin T. P.,Wu C. H.,Ishii K. and Nakamura H. K., Synthesis and antiinflammatory and antiallergic activity of N-Alkyl-2,3,4,9-tetrahydrofuroquinolindione and Related compounds. J. Heterocyclic Chem. 1991, 28, 955-963 .
(69) Wang J. P., Tsao L. T., Raung S. L., Hsu M. F., and Kuo S. C.,Inhibition by HAJ11 of respiratory burst in neutrophils and the involvement of protein tyrosine phosphorylation and phospholipase D activation, 1997, 120, 79-83 .
(70) Chang C. P., Lin T. P., Wang J. P, and Kuo S. C., Synthesis and biological activity of N-substituted benzyl-6(or7)-ethyl-2,3,4,9-tetra- hydrofuro[2,3-b]quinolin-3,4-diones. Chin. Pharm.J.,2001,53(5),239 -256 .
(71) Lin T. P., Chang C. P., Tsung Z. T. and Wang J. P., Synthesis and biological activity of N-substituted benzyl-6(or7)-chloro-2,3,4,9-tet- rahydrofuro[2,3-b]quinolin-3,4-diones. Chin. Pharm. J., 2002, 54, 115-126.
(72) Su M. J., Chang G. J., Wu M. H. and Kuo S. C, Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA-7, a furoquinoline alkaloid derivative, in rat heart. British J. of Pharmacology, 1997, 122,1285-1298 .
(73) Chang G. J., Wu M. H., Chen W. P., Kuo S. C.,.Su M. J. , The elec- trophysiological characteristics of the antiarrhythmic potential of acrophyllidine, an alkaloid isolated from Acrophylla hallophylla. Drug Dev. Res. , 2000, 50, 170-185 .
(74) Chang G. J., Su M.. J., Kuo S. C., Lin T. P., and Lee Y. S., Multiple cellular Electrophysiological Effects of a Novel Antiarrhythmic Furoquinoline Derivative HA-7〔N-Benzyl-7-methoxy-2,3,4,9-
tetrahydrofuro[2,3-b]quinoline-3,4-dione〕in Guinea Pig Cardiac
Preparations. J. Pharmacol. Exp. Ther.,2006,316 (1):380-91
(75) Cheng Y. C., Synthesis and Biological Activity of N-substituted
benzyl-6(7 or 8)-bromo-2,3,4,9-tetrahydrofuro[2,3-b]quinolin-3,4-
dione , 2001, 中國醫藥大學藥化所碩士論文 蘇怡芳
(76) Synthesis and Biological Activity of Ethyl 2-[N-substituted benzyl-4¢(or 3¢)-bromo]anilino-4-oxo-4,5-dihydro- furan-3-carboxylate 中國醫藥大學藥學化物所碩士論文 陳瑩潔
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