合成脲鍵連結之「去甲替林」與「核苷」 共軛化合物用作抗腸病毒藥劑

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高銘洋(Ming-Yang Gao) 查詢紙本館藏

畢業系所

化學學系

論文名稱

合成脲鍵連結之「去甲替林」與「核苷」共軛化合物用作抗腸病毒藥劑
(Synthesis of Nortriptyline–Nucleoside Conjugates with a Urea Joint as Anti-enteroviral Agents)

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★ 設計及合成含藥物之新穎鉑錯合物

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摘要(中)

病毒所造成的疾病和死亡，是人類一直以來面對的重大問題之一，因此如何克服病毒影響人類發展的問題成為了重要課題。每年有數百萬感染者因缺乏合適的藥物導致死亡，其中又以變異性高的「核糖核酸病毒」(RNA virus)最為嚴重。
本實驗室參與歐盟「第七架構計畫」(Seventh Framework Programme)下核准之Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses (SILVER)大型跨國計畫，目的在針對「黃病毒科」、「微小核糖核酸病毒科」、「副黏液病毒科」、「冠狀病毒科」、「布尼亞病毒科」、「沙狀病毒科」、「杯狀病毒科」的藥物開發。
市面所售「去甲替林」被發現具有抑制「拉薩病毒」之活性，且本身為抗憂鬱藥物，所以本篇將利用去甲替林當作抗病毒藥物的主體之一。在過去本實驗室以「核苷」鍵結「香豆素」，發現其對於「C型肝炎病毒」具有良好的抑制活性，所以我們利用類似的設計架構，將「去甲替林」以「脲鍵」結合各種「核苷」與開發為藥物的核苷衍生物做為研究目標。其合成方法先將「去甲替林」與「N,N’-羰基二咪唑」進行取代反應，接著加入「碘化甲烷」對「咪唑」進行甲基化得到「咪唑碘鹽」。將「咪唑碘鹽」做為親電體與「核苷衍生物」進行偶合反應，再進行去保護反應得到目標物。
本人利用核磁共振光譜儀、高解析質譜儀和紅外線光譜（FT–IR）鑑定結構，證實本人成功地合成出目標化合物，並分析具有抑制病毒活性之化合物其活性與結構關係，以及對具有抗病毒活性化合物進行水溶性、脂溶性測試。

摘要(英)

Viruses are responsible for many human diseases and deaths around the world. The fast mutation of RNA viruses is responsible for the lack of effective drugs to treat millions of infections. Such drugs would prevent many deaths annually.
Our laboratory are participating in the Seventh Framework Programme of the European Union. Out project is called, “Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses’’ , and focuses on the discovery of drugs for treating Flavi-, Picorna-, Paramyxo-, Corona-, Bunya-, Arena- and Caliciviridae.
Scientists in the field of drug design, have recently discovered that nortriptyline exhibits anti-lassa virus activity, and can therefore be used as a tricyclic antidepressant. A series of nucleoside–coumarin conjugates with potent activity toward hepatitis C virus were synthesized at our laboratory. The developed molecules herein were designed with a similar architecture. A variety of nortriptyline-conjugated nucleoside derivatives with a urea joint was developed as anti-RNA virus agents. Nortriptyline–nucleoside was produced from carbamoyl imidazolium salts with nucleoside. Carbamoyl imidazolium salts are prepared by a reaction of N,N’-carbonyldiimidazole with nortriptyline, followed by alkylation with iodomethane.
Nuclear magnetic resonance spectra were obtained to verify the shift of the characteristic peak; mass spectrometry (FAB Mass) was utilized to determine the m/z ratio of compounds, and infrared spectroscopy (FT-IR) was used to verify the carbonyl group. The structure-activity relationship, the solubility of water and the solubility of lipid was discussed. Compound 18 has an anti-enterovirus 71 activity of EC50 = 3.07, a solubility of water in 125 g/mL and Log p = 2.31.
In the future we will use the above results to develop drugs that are more resistant to enterovirus 71.

關鍵字(中)

★ 去甲替林
★ 核苷

關鍵字(英)

★ Nortriptyline
★ Nucleoside

論文目次

目錄
中文摘要 …………………………………………………….....…………..….. i
英文摘要 …………………………………………………….....……….....…. iii
目錄 …………………………………………………………….…...…............ v
圖目錄 ………………………………………………………......…...…........ xxi
表目錄 ............................................................................................................ xxii縮寫對照表 ……………..…………………...……………….......…..…..... xxiii
一、緒論 …………………………………………………...…..…………... 1
二、結果 ………………………………………………...…………...…….. 7
2-1　合成N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
5-ylidene)prop-1-carbamoyl]imidazole新化合物 (13)…....……. 7
2-2　合成N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
5-ylidene)prop-1-carbamoyl]-3-methylimidazol-3-ium Iodide 新
化合物 (14)………………………………………………...… 10
2-3　合成Nortriptyline–矽保護基之Adenosine與Nortriptyline–矽保
護基Vidarabine新化合物 (20–22)……...................................... 12
2-4　合成Nortriptyline–矽保護基之Cytarabine新化合物 (24)…… 17
2-5　合成Nortriptyline–矽保護基之Ribavirin新化合物 (26)…...… 18
2-6　合成Nortriptyline–矽保護基之Guanosine與Nortriptyline–矽保
護基之Acyclovir新化合物 (32–34)………….……………….. 19
2-7　合成合成Nortriptyline–Nucleoside新化合物 (35–42)…...…... 20
三、討論………………………………………………...…………...…….. 22
3-1　尿鍵化合物21最佳化合成條件 ……………..……………..… 22
3-2　探討尿鍵化合物33之合成位置 …………………………..….. 24
3-3　探討目標產物抑制「腸病毒71型」的活性表現 ……………… 27
3-4　測定nortriptyline–acyclovir共軛化合物34、42之水溶性 ........ 29
3-5　測定nortriptyline–acyclovir共軛化合物34、42之脂溶性 …… 31
3-6　脲鍵的合成方法 ……………………………………….……… 33
四、結論 ………………...…………..…………………………….…….... 35
五、實驗部分（Experimental Section） ................................................... 36
N6-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]deoxyadenosine (35) ...……............................... 37
N6-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]adenosine (36) …………………....…..………... 38
N2-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]deoxyguanosine (38) …………………….….…. 39
N2-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]guanosine (39) ……………………..…………... 40
N6-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37) ………...... 41
N3-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41) ………………………………………..………… 42
N4-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40) ……....…. 43
N2-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42) ….... 44
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]imidazole (13) ………………..….…..…...……. 45
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
prop-1-carbamoyl]-3’’-methylimidazol-3’’-ium Iodide (14) …...…. 46
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20) ……………………………….……….……... 47
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]adenosine
(21) ………………………………..…..…………………………… 48
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-
D-arabinofuranosyladenine (22) …………………….…....………... 49
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24) ……………………….……….……. 50
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26) …….…….… 51
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyguanosine (32) ……...…….……...………………..…..…….. 53
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]guanosine
(33) ……………………………...…………………...………..…… 54
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
hydroxyethoxy)methyl]guanine (42) …………...….……....……… 55
六、參考文獻 …………………………………………...……………... 57
七、光譜 ...................................................................................................... 63
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyadenosine (35)
1H NMR spectrum …………….…………...………………….… 65
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyadenosine (35)
13C NMR spectrum ……………………...……….……….……... 65
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyadenosine (35)
IR spectrum …………………...…….…………………………... 66
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyadenosine (35)
HPLC chromatogram ……………………………………….…… 66
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyadenosine (35)
UV spectrum ………………….…………………………….…… 67
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]adenosine (36)
1H NMR spectrum ………………………………...……......…… 67
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]adenosine (36)
13C NMR spectrum ………………………...…….…….….…….. 68
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
　　prop-1-carbamoyl]adenosine (36)
IR spectrum ………….…………………...…………….……….. 68
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
　　prop-1-carbamoyl]adenosine (36)
HPLC chromatogram ……………………………………….……69
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
　　prop-1-carbamoyl]adenosine (36)
UV spectrum ………….…………...……..…………….……….. 69
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyguanosine (38)
1H NMR spectrum …………………….……...………….……… 70
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyguanosine (38)
13C NMR spectrum………………………….……….…….…….. 70
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyguanosine (38)
IR spectrum………………………….……….………………….. 71
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyguanosine (38)
HPLC chromatogram ……………………………………….…….71
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]deoxyguanosine (38)
UV spectrum…………………..….……….…………………….. 72
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-　
　　prop-1-carbamoyl]guanosine (39)
1H NMR spectrum……………………….……….……………… 72
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]guanosine (39)
13C NMR spectrum ………...…………….………….…….…….. 73
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]guanosine (39)
IR spectrum …………………………...….….………………….. 73
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]guanosine (39)
HPLC chromatogram ……………………………………….…... 74
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]guanosine (39)
IR spectrum …………………………...….….………………….. 74
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37)
1H NMR spectrum………………………….….………………… 75
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37)
13C NMR spectrum…………………………….….……….…….. 75
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37)
IR spectrum…………………………….…….………………….. 76
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37)
HPLC chromatogram ……………………………………….…... 76
N6-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-β-D-arabinofuranosyladenine (37)
IR spectrum…………………………….…….………………….. 77
N3-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41)
1H NMR spectrum……………………………………….………. 77
N3-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41)
13C NMR spectrum……………………………....………………. 78
N3-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41)
IR spectrum……………………………………..….……………. 78
N3-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41)
HPLC chromatogram ……………………………………….…... 79
N3-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (41)
IR spectrum……………………………………..….……………. 79
N4-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40)
1H NMR spectrum………………………….…….……………… 80
N4-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40)
13C NMR spectrum…………………………….…….…….…….. 80
N4-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40)
IR spectrum…………………………………..………………….. 81
N4-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40)
HPLC chromatogram ……………………………………….…….81
N4-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-1-β-D-arabinofuranosylcytosine (40)
UV spectrum………………………………....………………….. 82
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42)
1H NMR spectrum………………………….…….……………… 82
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42)
13C NMR spectrum………………………….………….….…….. 83
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42)
IR spectrum……………………….……………….…………….. 83
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42)
HPLC chromatogram ……………………………………….…… 84
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-9-[(2-hydroxyethoxy)methyl]guanine (42)
UV spectrum……………………...……………….…………….. 84
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl] imidazole (13)
1H NMR spectrum …...………………………….………………. 85
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl] imidazole (13)
13C NMR spectrum ……………………..………….....…………. 85
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl] imidazole (13)
IR spectrum ……………………………..…………....…………. 86
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl] imidazole (13)
HPLC chromatogram ……………………………………….…... 86
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl] imidazole (13)
UV spectrum …………………………....…………....…………. 87
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-3’’-methylimidazol-3’’-ium Iodide (14)
1H NMR spectrum……………………………….………………. 87
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-3’’-methylimidazol-3’’-ium Iodide (14)
13C NMR spectrum …………………………...……....…………. 88
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-3’’-methylimidazol-3’’-ium Iodide (14)
IR spectrum …………….….…………………...………….……. 88
N-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
　　prop-1-carbamoyl]-3’’-methylimidazol-3’’-ium Iodide (14)
UV spectrum …………….…...………………...………….……. 89
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20)
1H NMR spectrum ……………………………....………………. 89
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20)
13C NMR spectrum ……………………………….......…………. 90
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20)
IR spectrum …………….….….………………..………….……. 90
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20)
HPLC chromatogram ……………………………………….…... 91
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
deoxyadenosine (20)
UV spectrum …………….….….…..…………..………….……. 91
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
adenosine (21)
1H NMR spectrum ……………………………...….……....……. 92
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
adenosine (21)
13C NMR spectrum …………………………......……….………. 92
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
adenosine (21)
IR spectrum …………...……….…….……...…………..………. 93
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
adenosine (21)
HPLC chromatogram ………………………………………...…. 93
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
adenosine (21)
UV spectrum …………...……….…….….....…………..………. 94
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-D-
arabinofuranosyladenine (22)
1H NMR spectrum ………………......................................…..…. 94
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-D-
arabinofuranosyladenine (22)
13C NMR spectrum ………...................................................……. 95
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-D-
arabinofuranosyladenine (22)
IR spectrum …………..….………………...……………………. 95
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-D-
arabinofuranosyladenine (22)
HPLC chromatogram ………………………..………….………. 96
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-β-D-
arabinofuranosyladenine (22)
UV spectrum …………..….…………..…...……………………. 96
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24)
1H NMR spectrum ………..…………………...……………...…. 97
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24)
13C NMR spectrum ……………………………...………...….…. 97
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24)
IR spectrum …………….…………………...……………..……. 98
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24)
HPLC chromatogram ……………………………………….…... 98
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-β-D-
arabinofuranosylcytosine (24)
UV spectrum …………………………….……...………...….…. 99
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26)
1H NMR spectrum …………………………….……….……..…. 99
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26)
13C NMR spectrum ………………………………..…….……... 100
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26)
IR spectrum ……………...………….……...……….…..……... 100
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26)
HPLC chromatogram ………………………………………...... 101
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (26)
UV spectrum ……………...………….…….....…….…..…..…. 101
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]deoxy-
guanosine (32)
1H NMR spectrum….…….………….............................………. 102
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]deoxy-
guanosine (32)
13C NMR spectrum………………………………..……………. 102
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]deoxy-
guanosine (32)
IR spectrum…………….………..…………..……..….….……. 103
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]deoxy-
guanosine (32)
HPLC chromatogram ……………………………………….…. 103
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]deoxy-
guanosine (32)
UV spectrum…………….………..………………..….….……. 104
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
guanosine (33)
1H NMR spectrum ……………………………...……...………. 104
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
guanosine (33)
13C NMR spectrum ………………………..……….......………. 105
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
guanosine (33)
IR spectrum ………………......................................…………... 105
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
guanosine (33)
HPLC chromatogram ……………………………………...…... 106
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-
　　5H-dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-
guanosine (33)
UV spectrum ………………....................................…………... 106
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
　　hydroxyethoxy)methyl]guanine (34)
　　1H NMR spectrum ………………………...………….....…...…. 107
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
　　hydroxyethoxy)methyl]guanine (34)
　　13C NMR spectrum …….……………….....………..….….……. 107
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
　　hydroxyethoxy)methyl]guanine (34)
IR spectrum ………………………………...….……..……….….108
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
　　hydroxyethoxy)methyl]guanine (34)
HPLC chromatogram ………………………………………...…. 108
2’-O-(tert-Butyldimethylsilyl)-N2-[N-methyl-3-(10,11-dihydro-5H-
　　dibenzo[a,d]cyclohepten-5-ylidene)prop-1-carbamoyl]-9-[(2-
　　hydroxyethoxy)methyl]guanine (34)
UV spectrum ………………………………...………………….. 109

圖目錄
Figure 1. 抗「腸病毒71型」抑制劑之分子式……………............................ 2
Figure 2. 胡紀如教授實驗室合成對於RNA病毒具有抑制活性之先導藥物
…………………………………………………………………..… 4
Figure 3. 三圓環衍生物抑制劑…..….................................................. 5
Figure 4. 「腺苷」、「鳥苷」及「胞嘧啶」衍生物之抗病毒藥物.................. 6
Figure 5. 「脲鍵」連結「核苷」與「去甲替林」之目標物………..……… 6
Figure 6. 由核磁共振氫譜（1H NMR）判斷「咪唑」化合物13結構......… 8
Figure 7. 由核磁共振氫譜（13C NMR）判斷「咪唑」化合物13結構....… 9
Figure 8. 由核磁共振氫譜（1H NMR）判斷「咪唑碘鹽」14結構………..….11
Figure 9. 由核磁共振氫譜（1H NMR）判斷產物21結構…….............….… 15
Figure 10. 由核磁共振碳譜（13C NMR）判斷產物21結構............................ 16
Figure 11. Cation-π interaction..…......................................................…… 23
Figure 12. 合成N2-acyl derivatives之可能反應位置……….……..........… 24
Figure 13. 起始物30之IR圖譜………...…………..………………........… 25
Figure 14. 脲鍵化合物之IR圖譜………...……………………..….........… 26
Figure 15. 「去甲替林」與「鳥嘌呤」共軛化合物........................................ 28
Figure 16. Nortriptyline–acyclovir derivative............................................... 28
Figure 17. 「去甲替林」與「核苷」共軛化合物............................................ 29
Figure 18. nortriptyline–acyclovir 34、42於DMSO中之溶解度與吸收度檢
量線圖………………………………………..…………..……… 30
Figure 19. nortriptyline–acyclovir 42於正辛醇中之溶解度與吸收度檢量線
圖…………………..........………………………………..……… 31
Figure 20. nortriptyline–acyclovir 34於正辛醇中之溶解度與吸收度檢量線
圖………………………..………………………………..……… 32
Figure 21. Log P與Oral Bioavailability關係圖........................................... 32
表目錄
Table 1. 化合物18在不同條件下反應產率.................................................... 22
Table 2. 抑制腸病毒活性表…………………………………………………. 27
Table 3. Compound Purity by HPLC…………………………………….....… 64

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指導教授

胡紀如(Jih-Ru Hwu)

審核日期

2013-7-25

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