「諾羅病毒」 (Norovirus)為一種單股RNA病毒，是目前已知引起急性腸胃炎疫情，最主要的非細菌病原。在全球皆有疫情的發生，譬如美國大約有50%腸胃炎事件與「諾羅病毒」有關。雖然世界各地時常因「諾羅病毒」感染而爆發大規模的疫情，但現階段並沒有有效的藥物可以治療「諾羅病毒」，所以發展有效的抗「諾羅病毒」藥物是全球性的課題。
義大利米蘭大學的Bolognesi教授團隊發現8,8'-[carbonylbis(imino-3,1-phenylen¬ecarbonylimino)]bis-1,3,5-
naphthalene-trisulphonic¬ acid hexasodium salt及Suramin對於「諾羅病毒」有治療的潛力，但有脂溶性過低而不易進入細胞的問題。因此我們與其團隊合作並針對NF023作改善希望合成出有效抑制抗「諾羅病毒」的新型化合物。本人成功的利用「三光氣」(triphosgene) 在調控酸鹼值的情況下，成功的合成出三個新型「四磺基芳香環鈉鹽」化合物，並以氫譜、碳譜、高解析質譜儀佐證其結構 。藉由水溶性及脂溶性測試，探討結構對其脂溶性的影響。

Norovirus is a category of small non-enveloped and single-stranded RNA viruses from Caliciviridae family, that virus is a major cause of epidemics of acute nonbacterial gastroenteritis in the world. Approximately 50% of all gastroenteritis outbreaks have been reported to be caused by norovirus in the United States. Although outbreaks of norovirus infection often occur in the world, but there is no specific medicine to treat people with norovirus illness. There is thus an unmet need for potent antiviral compounds.

Prof. Bolognesi at the university of Milano found two high-potency norovirus inhibitors: Suramin and 8,8'-[carbonylbis(imino-3,1-phenylenecarbonylimino)]bis-
1,3,5-naphthalene-trisulphonic¬ acid hexasodium salt (NF023), thus we cooperate with his team and focus on NF023, that we hope to improve the activity by synthesizing structural analogs of NF023 as anti-norovirus agents.

We successfully synthesized three new conjugate compounds containing urea linker by using triphosgene under the condition of adjusted pH value, and confirmed the struture by 1H-NMR, 13C-NMR and high resolution mass spectrometry. From water solubility experiment and partition coefficient data, we can conclude we increase drug lipophilicity successfully compared with NF023 and Suramin.

目 錄
中文摘要 ……………………………………………………...…… i
英文摘要 …………………………….……...……………...……… ii
謝誌 ……………………………….…………...………………...… iii
目錄 ………………………….…………………...…………...…… iv
圖目錄 ………………...…..………………...……………….…… viii
表目錄 ……………………..……………………...………….…… ix
一、 緒論 ……………………….………………………...….…. 1
二、 結果 ……………….………………………………....……. 9
2-1 合成4,4'-(Carbonylbisimino)-bis-1,5-naphthalenedisulfonic¬
Acid Tatrasodium Salt (2)………………………......… 9
2-2 合成4,4'-[Carbonylbis(imino-3,1-phenylene- bis-1,5-
naphthalenedisulfonic¬ Acid Tatrasodium Salt (6)….… 10
2-3 合成4,4'-[carboCnylbis(imino-3,4-methyl,1- phenylenecarbonyl- imino)]-bis-1,5-naphthalenedisulfonic¬
Acid Tatrasodium Salt (10)…………………...….…... 11
2-4 鑑定Symmetry Urea化合物1、6及10 .…............... 12
2-5 製備已知具羥基Couramin 14 ...………….........….... 14
2-6 製備已知具鹵素基團Couramin 18a–c ……...……… 15
2-7 藥物水溶性測試和脂溶性測試 ……………………. 16
三、 討論 …………………………………..…………….......… 19
3-1 探討以「三光氣」取代「光氣」之反應性差異 ...….… 19
3-2 「磺基芳香環鈉鹽」化合物的脂溶性和
水溶性 ....................................................................... 20
3-3 將Coumarin連結在Suramin之可能性探討 (A) …… 22
3-4 將Coumarin連結在Suramin之可能性探討 (B) …… 26
四、 結論 ……………………………..……………...............… 28
五、 實驗部分 ……………………………………….….……..... 29
六、 參考文獻 ……………………………………....…….....… 36
七、 光譜 ………………………………………...….…………. 42
4,4'-(Carbonylbisimino)¬bis-1,5-naphthalene- disulfonic¬ Acid Tatrasodium Salt (2) 1H NMR spectrum .….........…… 42
4,4'-(Carbonylbisimino)¬bis-1,5-naphthalene- disulfonic¬ Acid Tatrasodium Salt (2) 13C NMR spectrum ..….......…… 43
4,4'-(Carbonylbisimino)¬bis-1,5-naphthalene- disulfonic¬ Acid Tatrasodium Salt (2) UV spectrum ..….................…… 43
4,4'-(Carbonylbisimino)¬bis-1,5-naphthalene- disulfonic¬ Acid Tatrasodium Salt (2) HPLC spectrum ..…............…… 44
4,4'-[carbonylbis(imino-3,1-phenylenecarbonyl-
imino)]bis-1,5-naphthalene-disulfonic¬ acid tatrasodium
salt (6) 1H NMR spectrum ..……..………..….………. 44

4,4'-[carbonylbis(imino-3,1-phenylenecarbonyl-
imino)]bis-1,5-naphthalene-disulfonic¬ acid tatrasodium
salt (6) 13C NMR spectrum ..…….……..……….……. 45
4,4'-[carbonylbis(imino-3,1-phenylenecarbonyl-
imino)]bis-1,5-naphthalene-disulfonic¬ acid tatrasodium
salt (6) IR spectrum ..…………….…….……….……. 45
4,4'-[carbonylbis(imino-3,1-phenylenecarbonyl-
imino)]bis-1,5-naphthalene-disulfonic¬ acid tatrasodium
salt (6) UV spectrum ..…………....…….……….……. 46
4,4'-[carbonylbis(imino-3,1-phenylenecarbonyl-
imino)]bis-1,5-naphthalene-disulfonic¬ acid tatrasodium
salt (6) HPLC spectrum ..…….………....……….……. 46
4-(3-Nitrobenzamido)naphthalene-1,5-disulfonic Acid
Disodium salt (8) 1H NMR spectrum ..………......…… 47
4-(3-Nitrobenzamido)naphthalene-1,5-disulfonic Acid
Disodium salt (8) 13C NMR spectrum ..……….....…… 47
4-(3-Nitrobenzamido)naphthalene-1,5-disulfonic Acid
Disodium salt (8) IR spectrum ..……………........…… 48
4-(3-Nitrobenzamido)naphthalene-1,5-disulfonic Acid
Disodium salt (8) UV spectrum ..……………......…… 48
4-(3-Nitrobenzamido)naphthalene-1,5-disulfonic Acid
Disodium salt (8) HPLC spectrum ..……………..…… 49
1H NMR 4-(3-Aminobenzamido)naphthalene-1,5-disulfonic Acid Disodium Salt (9) 1H NMR spectrum ..….……… 49
1H NMR 4-(3-Aminobenzamido)naphthalene-1,5-disulfonic Acid Disodium Salt (9) 13C NMR spectrum ...…...…… 50
1H NMR 4-(3-Aminobenzamido)naphthalene-1,5-disulfonic Acid Disodium Salt (9) IR spectrum ...……....…...…… 59
1H NMR 4-(3-Aminobenzamido)naphthalene-1,5-disulfonic Acid Disodium Salt (9) UVspectrum ...……..........…… 51
1H NMR 4-(3-Aminobenzamido)naphthalene-1,5-disulfonic Acid Disodium Salt (9) HPLC spectrum ...……....…… 51
4,4'-[Carbonylbis(imino-3,4-methyl,1-phenylene-
carbonylimino)]bis-1,5-naphthalenedisulfonic¬ Acid Tatrasodium Salt (10) 1H NMR spectrum ..………….… 52
4,4'-[Carbonylbis(imino-3,4-methyl,1-phenylene-
carbonylimino)]bis-1,5-naphthalenedisulfonic¬ Acid Tatrasodium Salt (10) 13C NMR spectrum …….…..… 52
4,4'-[Carbonylbis(imino-3,4-methyl,1-phenylene-
carbonylimino)]bis-1,5-naphthalenedisulfonic¬ Acid Tatrasodium Salt (10) IR spectrum …………….........… 53
4,4'-[Carbonylbis(imino-3,4-methyl,1-phenylene-
carbonylimino)]bis-1,5-naphthalenedisulfonic¬ Acid Tatrasodium Salt (10) UV spectrum ……………...…… 53
4,4'-[Carbonylbis(imino-3,4-methyl,1-phenylene-
carbonylimino)]bis-1,5-naphthalenedisulfonic¬ Acid Tatrasodium Salt (10) HPLC spectrum …………...…… 54

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