以具抗病毒潛力化合物BCH-189的骨架為藍本，利用我們已經建立之合成3'-異原子取代基的雙去氧核醣核苷及其核苷酸類似物的嶄新途徑，在循理性合成設計的策略下，一系列的核苷及其核苷酸類似物已順利完成製備，同時所得之部分類似物可進一步經由化學鍵結成為環狀核苷酸類似物，以期能獲得更佳之抗病毒活性。此外經由部分策略上的修飾，上述合成方法亦可用來合成2'-異原子取代基的雙去氧核醣核苷及其核苷酸類似物。一部份含3'-異原子取代基的核苷類似物亦進一步轉換成相對之單磷酸鹽基化合物以探討其抗病毒活性。藉由類似的合成途徑，以抗病毒藥物HPMPA及PMEA之骨架為基礎，一系列成環且具磷酸根之核苷化合物也以成功製得。

截至目前為止，上述所合成之新穎化合物已陸續接受多種抗病毒活性測試。雖然目前尚未發現對某些特定的病毒具高度活性，我們仍將繼續進行其他種類病毒的測試，尤其是對HBV及HIV兩種特定病毒。我們對此兩項病毒的測試抱高度的期望，因為這些化合物原本即為針對此二病毒所設計。除此之外，這些化合物也具有抗血管增生的活性，在這當中又以化合物109效果較佳，其針對血管調控因子的移行及管柱成型都呈現出良好競爭力。

除了製備上述具有潛在療效的化合物外，在以結構為基礎的循理性合成設計下我們也完成了一系列具抗精神病活性的類似物。以雙芳香環哌啶類似物化合物133的骨架為出發點，藉由收斂性的合成策略，具有1,3-雙氧戊環基或1,3-氧硫戊環基的多種類似物已經製備完成，體外活性測試的初步結果顯示這些化合物具有高度的活性。據此我們將進一步研發，期許獲得一新穎之抗精神病藥物。

Starting from the potent antiviral agent BCH-189 and taking a rational structure-based design approach, a series of nucleotide and nucleoside analogues were designed and a novel synthetic protocol amenable towards Structure-Activity Relationship study purposes was established. Using this synthetic process, a series of 3'-heteroatom substituted dideoxynucleosides as well as their corresponding nucleotides were generated. Additionally and with minor modifications, the abovementioned process was amended to allow for the synthesis of 2'-heteroatom substituted dideoxynucleosides and nucleotides, both series of which were also arrived at chemically. Representative members of the 3'-heteroatom containing nucleosides mentioned above were further elaborated to the corresponding mono-phosphonate to investigate a recent hypothesis in antiviral prodrug design. In a similar structure-based approach starting with well known antiviral agents HPMPA and PMEA, cyclic and phosphonate-containing nucleosides were conceptualized, a synthetic route towards their generation delineated, and members thereof arrived at synthetically.

Most of the derivatives arrived at in the abovementioned synthetic work were subjected to antiviral potential evaluation against viruses responsible for a wide range of viral indications of significance. Although significant antiviral activity from these cell based assays has yet to emerge, those against HBV and HIV, the two specific targets of this sub-project, are eagerly anticipated. Otherwise each of these derivatives exhibited a unique antiangiogenic profile. In the presence of all, compound 109 showed the better in vitro potency against VEGF migration or tube formation.

Apart from the aforementioned work towards the generation of novel and potentially therapeutically useful antiviral agents, a project relying on a rational structure-based design of novel antipsychotic agents was achieved. Starting from diarylmethylene-piperidine derivative 133, a known molecule possessing antipsychotic properties, a series of 1,3-dioxolane and 1,3-oxathiolane containing derivatives were designed and synthesized via a highly convergent synthetic protocol. In vitro assays of these compounds yielded several promising lead structures amenable towards the development of novel antipsychotic therapeutics.

目 錄
中文摘要-------------------------------------------------I
英文摘要-------------------------------------------------II
謝誌----------------------------------------------------III
縮寫對照表-----------------------------------------------IV
目錄----------------------------------------------------VII
第一章 1,3-雙氧環己烷基、1,3-雙硫環己烷基和1,3-氧硫環己烷基核苷及核苷酸類似物之設計與合成---------------------------01
第一節 緒論---------------------------------------------01
1.1.1 核苷和核苷酸與HIV的關係----------------------------01
1.1.2 新型核苷類似物的研發及抗病毒活性-------------------03
1.1.3 非天然醣類骨架核苷類似物的研發及抗病毒活性---------07
1.1.4 研究動機及目標-------------------------------------10
第二節 研究構想-----------------------------------------14
第三節 結果與討論---------------------------------------17
1.3.1 氧硫環己烷基化合物45之合成-------------------------17
1.3.2 雙硫環己烷基核苷酸之合成---------------------------29
1.3.3 雙硫環己烷基核苷之合成-----------------------------52
1.3.4 雙氧環己烷基核苷酸及氧硫環己烷基核苷酸類似物之合成-64
第四節 結論---------------------------------------------76
第五節 實驗部分-----------------------------------------79
1.5.1 一般實驗方法---------------------------------------79
1.5.2 實驗步驟及光譜資料---------------------------------81
第六節 參考文獻----------------------------------------141
第二章 新穎非典型抗精神病試劑之研發: 具有1,3-雙氧環己烷基或1,3-氧 硫環己烷基雙芳香環哌啶類似物之合成及應用------152
第一節　緒論--------------------------------------------152
2.1.1 精神分裂症與神經傳導物質多巴胺之關係--------------152
2.1.2 典型抗精神病藥物之演進----------------------------154
2.1.3 非典型抗精神病藥物之演進--------------------------159
2.1.4 雙芳香環哌啶類似物及研究動機----------------------162
第二節 研究構想----------------------------------------165
第三節 結果與討論--------------------------------------168
2.3.1 雙氧環己烷基雙芳香環哌啶類似物之合成--------------168
2.3.2 氧硫環己烷基雙芳香環哌啶類似物之合成--------------171
2.3.3 氧硫環己烷基應用於新型病毒蛋白酶抑制劑之設計與合成-174
第四節　結論--------------------------------------------182
第五節　實驗部分----------------------------------------185
2.5.1 一般實驗方法--------------------------------------185
2.5.2 實驗步驟及光譜資料--------------------------------185
第六節 參考文獻----------------------------------------199
附錄一 MM3程式計算所得之資料----------------------------205
附錄二 化合物之1H, 13C, 19F, 31P, DEPT, NOE及2D HETCOR圖譜-----------------------------------------------------------207

1. (a) Gottlieb, M. S.; Schroff, R.; Schanker, H. M.; Weisman, J. D.; Fan, P. T.; Wolf, R. A.; Saxon, A. New Engl. J. Med. 1981, 305, 1425. (b) Nucleotide Analogues as Antiviral Agents; Martin, J. C., Ed.; American Chemical Society: Washington, DC, 1989. (c) Vorbruggen, H.; Ruh-Pohlenz, C. In Handbook of Nucleoside Synthesis; Overman, L. E., Ed.; John Wiley & Sons: New York, 2001. (d) Farrell, A. T.; Leighton, J.; Williams, G.; Pazdur, R. In Handbook of Anticancer Drug Development; Budman, D. R., Calvert, A. H., Rowinsky, E. K., Eds.; Lippincott Williams & Wilkins: New York, 2004; Chapter 1.
2. De Clercq, E.; Balzarini, J. Antiviral Res. 1985, Suppl. 1, 89□94.
3. De Clercq, E. J. Med. Chem. 1986, 29, 1561□1569.
4. Mitsuya, H.; Broder, S. Nature 1987, 325, 773□778.
5. Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533□1544.
6. Hirsch, M. S.; Kaplan, J. C. Ann. Intern. Med. 1985, 103, 750.
7. De Clercq, E. In Anti-AIDS Drug Development: Challenges Strategies and Prospects; Mohan, P., Baba, M., Eds.; Academic: Switzerland, 1995; Chapter 1.
8. Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St. Clair, M. H.; Nusinoff Lehrman, S.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7096.
9. Barre-Sinoussi, F.; Chermann, J. C.; Rey, R.; Nugeyre, M. T.; Chamaret, S.; Grust, J.; Dauguet, C.; Axler-Blin, C.; Venzinet-Brum, F.; Rouzioux, C.; Rozen-Baum, W.; Montagnier, L. Science 1983, 220, 868□871.
10. Gallo, R. C.; Salahuddin, H. Z.; Popovic, M.; Shearer, G. M.; Kaplan, M.; Haynes, B. F.; Palker, T. J.; Redfield, R. R.; Oleske, J.; Safai, B.; White, G.; Foster, P.; Markham, P. D. Science 1984, 224, 500.
11. Levy, J. A.; Hoffman, A. D.; Kramer, S. M.; Landis, J. A.; Shimabukuro, J. M.; Oshiro, L. S. Science, 1984, 225, 840□842.
12. Wong-Staal, F.; Gallo, R. C. Nature 1985, 317, 395□403.
13. (a) Gilboa, E.; Mitra, S. W.; Goff, S. P.; Baltimore, D. Cell 1980, 18, 93□100. (b) Prasad, V. R.; Goff, S. P. Ann. N.Y. Acad. Sci. USA 1990, 616, 11□21.
14. (a) Ahluwalia, G.; Cooney, D. A.; Mitsuya, H.; Fridland, A.; Flora, K. P.; Hao, Z.; Dalal, M.; Broder, S.; Johns, D. G. Biochem. Pharmacol. 1987, 36, 3797□3800. (b) Johnson, M. A.; Ahluwalia, G.; Cooney, D. A.; Connelly, M. C.; Fridland, A.; Broder, S.; Johns, D. G. J. Biol. Chem. 1988, 263, 15354□15357.
15. (a) St. Clair, M. H.; Richards, C. A.; Spector, T.; Weihold, K. J.; Miller, W. H.; Langlois, A. J.; Furman, P. A. Antimicrob. Agents Chemother. 1987, 31, 1972□1977. (b) Eriksson, B. F. H.; Chu, C. K.; Schinazi, R. F. Antimicrob. Agents Chemother. 1989, 33, 1729□1734. (c) De Clercq, E. Pharmaco Chemistry Library: Design of Anti-AIDS Drugs; Elsevier Science: Netherlands, 1990; Vol. 14, p 5.
16. (a) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319. (b) Knaus, E. E.; Naimi, E.; Zhou, A.; Khalili, P.; Wiebe, L. I.; Balzarini, J.; De Clercq, E. J. Med. Chem. 2003, 46, 995□1004. (c) Chu, C. K.; Choo, H.; Chong, Y. C.; Choi, Y.; Mathew, J.; Schinazi, R. F. J. Med. Chem. 2003, 46, 389□398. (d) Qing, F.-L.; Zhang, X.; Xia, H.; Dong, X.-C.; Jin, J.; Meng, W.-D. J. Org. Chem. 2003, 68, 9026□9033. (e) Huet, F.; Dubreuil, D.; Pipelier, M.; Marsac, Y.; Nourry, A.; Legoupy, S. Tetrahedron Lett. 2004, 45, 6461□6463. (f) Simons, C.; Balzarini, J.; De Clercq, E.; Hursthouse, M.; Hughes, D.; Maslen, H. L. J. Med. Chem. 2004, 47, 5482□5491. (g) You, T.; Song, M.; Lin, K.; Cai, D. Synth. Commun. 2004, 34, 159□170. (h) Qing, F.-L.; Qiu, X.-L. J. Org. Chem. 2005, 70, 3826□3837. (i) Alvarez-Larena, A.; March, P. D.; Figueredo, M.; Parella, T.; Font, J.; Rustullet, A.; Alibes, R. Org. Lett. 2006, 8, 491□494. (j) Camplo, M.; Hider, R. C.; De Clercq, E.; Neyts, J.; Balzarini, J.; Barral, K. J. Med. Chem. 2006, 49, 43□50.
17. (a) Herdewijin, P.; De Clercq, E.; Hoogmartens, J.; Busson, R.; Janssen, G.; Balzarini, J.; Averschot, A. V.; Jie, L. J. Med. Chem. 1990, 33, 2481□2487. (b) Reitz, A. B.; Goodman, M. G.; Pope, B. L.; Argentieri, D. C.; Bell, S. C.; et al. J. Med. Chem. 1994, 37, 3561□3578. (c) Wagner, C. R.; McIntee, E. J.; Radmer, M. R.; Griesgraber, G. W.; Iyer, V. V. J. Med. Chem. 2000, 43, 2266□2274. (d) Hakimelahi, G. H.; Mei, N.-W.; Moosavi-Movahedi, A. A.; Davari, H.; Hakimelahi, S.; King, K.-Y.; Hwu, J. R.; Wen, Y.-S. J. Med. Chem. 2001, 44, 1749□1757. (e) Brossette, T.; Klein, E.; Creminon, C.; Grassi, J.; Mioskowski, C.; Lebeau, L. Tetrahedron 2001, 57, 8129□8144. (f) Borch, R. F.; Meyers, C. L. F. Org. Lett. 2001, 3, 3765□3768. (g) Shaw, B. R.; Li, P. Org. Lett. 2002, 4, 2009□2012. (h) Piettre, S. R.; Gouhier, G.; Gautier, A.; Lopin, C. J. Am. Chem. Soc. 2002, 124, 14668□14675. (i) Secrist III, J. A.; Montgomery, J. A.; Shaddix, S. C.; Someya, H.; Paker, W. B.; Rose, J. D. J. Med. Chem. 2002, 45, 4505□4512. (j) Balzarini, J.; Muller, C.; Gorbig, U.; Meier, C. J. Med. Chem. 2005, 48, 8079□8086.
18. Chow, Y.-K.; Hirsch, M. S.; Merrill, D. P.; Bechtel, L. J.; Eron, J. J.; Kaplan, J. C.; D'Aquila, R. T. Nature 1993, 361, 650□654.
19. (a) Cao, Y.; Qin, L.; Zhang, G. L.; Safrit, J.; Ho, D. D. N. Engl. J. Med. 1995, 332, 201□208. (b) Perelson, A. S.; Neumann, A. U.; Markowitz, M.; Leonard, J.; Ho, D. D. Science 1996, 271, 1582□1586. (c) Perelson, A. S.; Essunger, P.; Cao, Y.; Vesanen, M.; Hurley, A.; Saksela, K.; Markowitz, M.; Ho, D. D. Nature 1997; 387:188□191. (d) Zhang, L.; Ramratnam, B.; Tenner-Racz, H. Y.; Vesanen, M.; Lewin, S.; Talal, A.; Racz, P.; Perelson, A. S.; Korber, B. T.; Markowitz, M.; Ho, D. D. N. Engl. J. Med. 1999, 340, 1605□1613.
20. Meng, T-C.; Fischl, M. A.; Boota, A. M.; Spector, S. A.; Bennett, D.; Bassiakos, Y.; Lai, S.; Wright, B.; Richman, D. D. Ann. Int. Med. 1992, 116, 13□20.
21. Rando, R. F.; Nguyen-Ba, N. Drug Discov. Today 2000, 5, 465□476.
22. (a) Balzarini, J.; Baba, M.; Pauwels, R.; Herdewijin, P.; De Clercq, E.; Broder, S.; Vanderhaeghe, H. J. Med. Chem. 1987, 30, 1270□1278. (b) Balzarini, J.; Baba, M.; Pauwels, R.; Herdewijin, P.; De Clercq, E. Biochem. Pharmacol. 1988, 37, 2847□2856. (c) Van Aerschot, A.; Herdewijin, D.; Balzarini, J.; Pauwels, R.; De Clercq, E. J. Med. Chem. 1989, 32, 1743□1749.
23. (a) Whittington, R.; Brogden, R. N. Drugs 1992, 44, 656□683. (b) Young, R. J.; Shaw-Ponter, S.; Thomson, J. B. Bioorg. Med. Chem. Lett. 1995, 5, 2599.
24. (a) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L. S.; Beach, J. W.; Choi, W. B.; Yeola, S.; Liotta, D. C. Antimicrob. Agents Chemother. 1992, 36, 672□676. (b) Coates, J. A. V.; Cammack, N.; Jenkinson, H. J.; Jowett, A. J.; Jowett, M. I.; Pearson, B. A.; Penn, C. R.; Rouse, P. L.; Viner, K. C.; Cameron, J. M. Antimicrob. Agents Chemother. 1992, 36, 733□739. (c) Doong, S.-L.; Tsai, C.-H.; Schinazi, R. F.; Liotta, D. C.; Chen, Y.-C. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8495□8499. (d) Beach, J. W.; Jeong, L. S.; Alves, A. J.; Pohl, D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K. J. Org. Chem. 1992, 57, 2217□2219. (e) Dwyer, O. Synlett 1995, 1163□1164. (f) Jin, H.; Siddiqui, M. A.; Evans, C. A.; Tse, H. L. A.; Mansour, T. S. J. Org. Chem. 1995, 60, 2621□2623.
25. (a) Yarchoan, R.; Mitsuya, H.; Thomas, R. V.; Pluda, J. M.; Hartman, N. R.; Perno, C. F.; Narczyk, K. S.; Allain, J. P.; Johns, D. G.; Broder, S. Science 1989, 245, 412□415. (b) Faulds, D.; Brogden, R. N. Drugs 1992, 44, 94□116.
26. (a) Lin, T.-S.; Schinazi, R. F.; Prusoff, W. H. Biochem. Pharmacol. 1987, 36, 2713. (b) Zhu, Z.; Ho, H.-T.; Hitchcock, M. J.; Sommadossi, J.-P. Biochem. Pharmacol. 1990, 39, R15□R19.
27. (a) Abacavir (Ziagen) is the carbocyclic nucleoside formerly known as 1592U89. (b) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N.; Reardon, J. E.; Dornsfife, R. E.; Averett, D. R. Krenitsky, T. A. Antimicrob. Agents Chem. 1997, 41, 1082□1093. (c) Faulds, D.; Brogden, R. N. Drugs 1998, 55, 729. (d) "Therapeutic Nucleosides". Daluge, S. M. U.S. Patent 5,034,394, 1991. (e) Daluge, S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A. Nucleosides Nucleotides Nucleic Acids 2000, 19, 297□327.
28. (a) Kim, H. O.; Shanmuganathan, K.; Alves, A. J.; Jeong, L. S.; Beach, J. W.; Schinazi, R. F.; Chang, C.-N.; Chu, C. K. Tetrahedron Lett. 1992, 33, 6899 and references cited therein. (b) Young, R. J.; Shaw-Ponter, S.; Thomson, J. B.; Miller, J. A.; Cumming, J. G.; Pugh, A. W.; Rider, P. Bioorg. Med. Chem. Lett. 1995, 22, 2599□2604.
29. Chu, C. K.; Ma, L.; Olgen, S.; Pierra, C.; Du, J.; Gumina, G.; Gullen, E.; Cheng, Y.-C.; Schinazi, R. F. J. Med. Chem. 2000, 43, 3906□3912 and references cited therein.
30. Thomas, G. Medicinal Chemistry: An Introduction; John Wiley & Sons: New York, 2000; pp 47□48.
31. (a) Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M. Tetrahedron Lett. 1989, 30, 6259□6262. (b) Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Weigele, M.; Sim, I.; Anderson, B. D.; Mitsuya, H.; Broder, S. J. Med. Chem. 1992, 35, 2347□2354.
32. (a) Secrist III, J. A.; Riggs, R. M.; Tiwari, K. N.; Montgomery, J. A. J. Med. Chem. 1992, 35, 533□538.
33. (a) Secrist III, J. A.; Riggs, R. M.; Tiwari, K. N.; Montgomery, J. A. J. Med. Chem. 1991, 34, 2361□2366. (b) Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Chem. Soc. Chem. Commun. 1991, 741□743. (c) Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Med. Chem. 1991, 34, 2782□2786. (d) Uenishi, J.; Motoyama, M.; Takahashi, K. Tetrahedron Asym. 1994, 5, 101□106.
34. (a) Branalt, J.; Kvarnstrom, I.; Niklasson, G.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59, 1783□1788. (b) Branalt, J.; Kvarnstrom, I.; Niklasson, G.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59, 4430□4432. (c) Mann, J.; Tench, A. J.; Weymouth-Wilson, A.; Shaw-Ponter, S.; Young, R. J. J. Chem. Soc. Perkin Trans. 1 1995, 677□681.
35. (a) Rassu, G.; Zanardi, F.; Battistini, L.; Gaetani, E.; Casiraghi, G. J. Med. Chem. 1997, 40, 168□180. (b) Choi, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.; Schinazi, R. F.; Chu, C. K. Org. Lett. 2002, 4, 305□307.
36. (a) Reist, E. J.; Gueffroy, D. E.; Goodman, L. J. Am. Chem. Soc. 1964, 86, 5658□5663. (b) Reist, E. J.; Fisher, L. V.; Goodman, L. J. Org. Chem. 1968, 33, 189□192.
37. (a) Wang, W.; Jin, H.; Mansour, T. S. Tetrahedron Lett. 1994, 35, 4739. (b) Nokami, J.; Ryokume, K.; Inada, J. Tetrahedron Lett. 1995, 36, 6099-6100. (c) Nguyen-Ba, N.; Brown, W. L.; Lee, N.; Zacharie, B. Synthesis 1998, 759□762.
38. Palumbo, G.; Caputo, R.; Guaragna, A.; Pedatella, S. Eur. J. Org. Chem. 1999, 1455□1458.
39. Kraus, J. L.; Graciet, J. C.; Faury, P.; Camplo, M.; Charvet, A. S.; Mourier, N.; Trabaud, C.; Niddam, V.; Simon, V. Nucleosides Nucleotides 1995, 14, 1379□1392.
40. Chun, M. W.; Shin, D. H.; Moon, H. R.; Lee, J.; Park, H.; Jeong, L. S. Bioorg. Med. Chem. Lett. 1997, 7, 1475□1480.
41. Nguyen-Ba, N.; Brown, W. L.; Lee, N.; Zacharie, B.; Chan, L.; Brasili, L.; Lafleur, D. Chem. Commun. 1999, 1245□1246.
42. Palumbo, G.; Caputo, R.; Guaragna, A.; Pedatella, S. Eur. J. Org. Chem. 2003, 346□350.
43. Yoshimura, Y.; Sakata, S.; Yamada, K. J. Org. Chem. 1998, 63, 6891□6899.
44. Jeong, L. S.; Moon, H. R.; Kim, H. O.; Lee, S. K.; Choi, W. J.; Chun, M. W. Bioorg. Med. Chem. 2002, 10, 1499□1507.
45. (a) Qing, F.-L.; Zhang, X. J. Org. Chem. 2002, 67, 1016□1019. (b) Chu, C. K.; Choi, Y.; Choo, H.; Chong, Y.; Lee, S.; Olgen, S.; Schinazi, R. F. Org. Lett. 2002, 4, 305□307. (c) Jeong, L. S.; Moon, H. R.; Kim, H. O.; Lee, S. K.; Choi, W. J.; Chun, M. W. Org. Lett. 2002, 4, 529□531. (d) Qing, F.-L.; Meng, W.-D.; Zhang, X.; Wu, Y.-Y. Org. Lett. 2004, 6, 3941□3944.
46. (a) De Clercq, E.; Holy, A.; Rosenburg, I.; Balzarini, J.; Maudgal, P. C. Nature 1986, 323, 464□467. (b) Bronson, J. J.; Ghazzouli, I.; Hitchcock, M. J. M.; Webb, R. R.; Martin, J. C. J. Med. Chem. 1989, 32, 1457□1463. (c) Balzar, J.; De Clercq. J. Biol. Chem. 1991, 266, 8686□8689.
47. (a) Lonnberg, H.; Oivanen, M.; Ora, M.; Tomperi, J.; Maki, E.; Poijarvi, P. Helv. Chim. Acta 2002, 85, 1869□1876. (b) McGuigan, C.; Harris, S. A.; Daluge, S. M.; Gudmundsson, K. S.; Mclean, Ed W.; Burnnette, T. C.; Marr, H.; Hazen, R.; Condreay, L. D.; Johnson, L. J.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2005, 48, 3504□3515.
48. Quimpere, M.; Nguyen-Ba, P.; Lee, N.; Mitchell, H.; Chan, L. Bioorg. Med. Chem. Lett. 1998, 8, 3555□3560.
49. (a) Bedard, J.; May, S.; Lis, M.; Tryphonas, L.; Drach, J.; Huffman, J.; Sidwell, R.; Chan, L.; Bowlin, T.; Rando, R. Antimicrob. Agents. Chemother. 1999, 43, 557□567. (b) Bubenik, M.; Preville, P.; Dugas, J.; Attardo, G.; Chan, L. Tetrahedron Lett. 2003, 44, 8261□8263.
50. (a) Hakimelahi, G. H.; Ugolini, A. Tetrahedron Lett. 1982, 23, 913□914. (b) Hakimelahi, G. H.; Zarrinehzad, M.; Jarrahpour, A. A.; Sharghi, H. Helv. Chim. Acta 1987, 70, 219□231.
51. Holy, A. Tetrahedron Lett. 1967, 881□884.
52. Hwu, J. R.; Lai, L.-L.; Hakimelahi, G. H.; Davari, H. Helv. Chim. Acta 1994, 77, 1035□1045.
53. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Textbook of Practical Organic Chemistry; John Wiley & Sons: New York, 1989; p. 439.
54. Gu, X. P.; Ikeda, I.; Okhara, M. Bull. Chem. Soc. Jpn. 1987, 60, 397.
55. Adrian, Jr. J. C.; Barkin, J. L.; Fox, R. J.; Chick, J. E.; Hunter, A. D.; Nicklow, R. A. J. Org. Chem. 2000, 65, 6264□6267.
56. Janicki, S. Z.; Fairgrieve, J. M.; Petillo, P. A. J. Org. Chem. 1998, 63, 3694□3700.
57. (a) Colin, J. L.; Loubinoux, N. Synthesis 1983, 7, 568□571. (b) Seneci, P.; Leger, I.; Souchet, M.; Nadler, G. Tetrahedron 1997, 53, 17097□17114.
58. (a) Cekovic, Z.; Cvetkovic, M. Tetrahedron Lett. 1982, 23, 3791□3794. (b) Folkins, P. L.; Harpp, D. N. J. Org. Chem. 1992, 57, 2013□2017.
59. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Textbook of Practical Organic Chemistry; John Wiley & Sons: New York, 1989; p. 62.
60. Hilbert, G. E.; Johnson, T. B. J. Am. Chem. Soc. 1930, 52, 2001.
61. (a) Mikolajczyl, M.; Luczak, T.; Graczyk, P. P.; Wieczorek, M. W.; Blaszczyk, J. J. Organomet. Chem. 1997, 536, 355□360. (b) Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.; Alexander, R. Org. Lett. 2002, 4, 1227□1229.
62. (a) Frieden, M.; Giraud, M.; Reese, C. B.; Song, Q. J. Chem. Soc. Perkin Trans. 1 1998, 2827□2832. (b) Choi, Y.; George, C.; Strazewski, P.; Marquez, V. E. Org. Lett. 2002, 4, 589□592.
63. Robbe, Y.; Fernandez, J.-P.; Dubief, R.; Chapat, J.-P.; Sentenac-Roumanou, H. Eur. J. Med. Chem. Chim. Ther. 1982, 17, 235□244.
64. Protective Groups In Organic Synthesis; Greene, T. W., Muts, P. G. M., Eds.; John Wiley & Sons: New York, 1999; pp 141□144.
65. (a) Ludek, O. R.; Meier, C. Synlett 2005, 3145. (b) Ludek, O. R.; Meier, C. Synlett 2006, 324.
66. (a) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827. (b) Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512.
67. Marchand, P.; Gulea, M.; Masson, S.; Averbuch-Pouchot, M.-T. Synthesis 2001, 11, 1623□1626.
68. Gokel, G. W.; Gerdes, H. M.; Dishong, D. M. J. Org. Chem. 1980, 45, 3634□3639.
69. (a) Cashman, J. R.; Proudfoot, J.; Ho, Y.-K.; Chin, M. S.; Olsen, L. D. J. Am. Chem. Soc. 1989, 111, 4844□4852. (b) Organic Chemistry; Clayden, J., Greeves, N., Warren, S.; Wothers, P., Eds.; Oxford: New York, 2001; p 1254. (c) Organic Synthesis, 2nd ed.; Smith, M., Ed.; McGraw-Hill: New York, 2002; pp 280□281.
70. Hakimelahi, G. H.; Mei, N.-W.; Moosavi-Movahedi, A. A.; Davari, H.; Hakimelahi, S.; King, K.-Y.; Hwu, J. R.; Wen, Y.-S. J. Med. Chem. 2001, 44, 1749□1757.
71. (a) Choi, W.-B.; Wilson, L. J.; Yeola, S.; Liotta, D. C.; Schinazi, R. F. J. Am. Chem. Soc. 1991, 113, 9377□9379. (b) Nishizono, N.; Koike, N.; Yamagata, Y.; Fujii, S.; Matsuda, A. Tetrahedron Lett. 1996, 37, 7569□7572.
72. Efimtseva, E. V.; Mikhailov, S. N.; Meshkov, S.; Hankamaki, T.; Oivanen, M.; Lonnberg, H. J. Chem. Soc. Perkin Trans. 1 1995, 1409□1416.
73. (a) Seela, F.; Muth, H. P.; Roeling, A. Helv. Chim. Acta 1991, 74, 554□564. (b) Zhang, J.; Nemati, N.; Pommier, Y.; Nair, V. Bioorg. Med. Chem. Lett. 1998, 8, 1887□1890.
74. 癌細胞有血管新生 (angiogenesis) 的現象，其中血管內皮生長因子 (vascular endothelial growth factor, VEGF) 為主要調控因子，有效抑制VEGF即能抑制癌細胞的生長及轉移，詳細文獻可參考: Haroon, Z. A., Peters, K. G., Greenberg, C. S., Dewhirst, M. W.; In Antiangiogenic Agents in Cancer Therapy; Teicher, B. A., Ed.; Humana: New Jersey, 1999; Chapter 1.
75. Branes, D. M. Science 1987, 235, 430□433.
76. http://www.who.int/mental_health/management/schizophrenia/en/
77. Stahl, S. M. Essential Psychopharmacology of Antipsychotics and Mood Stabilizers; Cambridge University Press: New York, 2002.
78. Kebabian, J. W.; Calne, D. B. Nature 1979, 277, 93□96.
79. Meltzer, H. Y. Psychopharmacology 1989, 99, 18□27.
80. Bogeso, K. P.; Bang-Andersen, B. Dopamine and Serotonin Receptor and Transporter Ligands. In Textbook of Drug Design and Discovery, 3rd ed.; Krogsgaard-Larsen, P., Liljefors T., Madsen, U., Eds.; Taylor & Francis: New York, 2002; Chapter 11.
81. Charpentier, T. U.S. Patent 2,519,886, 1950; U.S. Patent 2,530,451, 1950.
82. (a) Carlsson, A.; Lindquist, M. Acta Pharmacol. Toxicol. 1963, 20, 140□144. (b) Creese, I.; Burt, D. R.; Snyder, S. H. Science 1976, 192, 481□483.
83. Schering Co. U.S. Patent 2,860,138, 1956.
84. Smith Kline & French Lab. U.S. Patent 3,058,979, 1957; Chem. Abstr. 1963, 58, 6841g.
85. Kefalas A/S. G.B. Patent 932,494, 1958; Chem. Abstr. 1964, 61, 9477g.
86. Kaiser, C.; Pavloff, A. M.; Gavey, E.; Fowler, P. J.; Tedeschi, D. H.; Zirkle, C. L. J. Med. Chem. 1972, 15, 665-673.
87. Am. Cyanamid Co. F.R. Patent 1,508,536, 1968; Chem. Abstr. 1965, 70, 57923c.
88. Protiva et al. C.S. Patent 121,337, 1964; Chem. Abstr. 1968, 68, 105247t.
89. (a) Dr. A. Wander AG. N.L. Patent 293,201, 1962; Chem. Abstr. 1966, 64, 8221. (b) Hunziker et al. Helv. Chim. Acta 1967, 50, 1558.
90. Fundamentals of Medicinal Chemistry; Thomas, G., Ed.; John Wiley & Sons: New York, 2003; Chapter 4.4.
91. Review of Organic Functional Groups: Introduction to Medicinal Organic Chemistry, 4th ed.; Lemke, T. L., Ed.; Williams & Wilkins: Baltimore, MD, 2003; Chapter 18.
92. Swain, C. G.; Lupton, E. C. Jr. J. Am. Chem. Soc. 1968, 90, 4328.
93. Taft, R. W. Jr. In Steric Effects in Organic Chemistry; Newman, M. S. Ed.; John Wiley & Sons: New York, 1956; p 598.
94. Vogel, A. I.; Cresswell, W. T.; Jeffery, G. H.; Leicester, J. J. Chem. Soc. 1952, 514.
95. (a) Craig, P. N. J. Med. Chem. 1971, 14, 680. (b) Hansch, C.; Leo, A.; Hoekman, D. In Exploring QSAR: Hydrophobic, Electronic, and Steric Constants; Heller et al. Eds.; American Chemical Society: Washington, DC, 1995.
96. An Introduction to Medicinal Chemistry, 2nd ed.; Patrick, G. L., Ed.; Oxford University Press: New York, 2001; Chapter 5.
97. Janssen et al. J. Med. Pharm. Chem. 1959, 281, 284.
98. (a) Isaacson, E. I. In Textbook of Organic Medicinal and Pharmaceutical Chemistry, 10th ed.; Delgado, J. N., Remers, W. A. , Eds.; Williams & Wilkins: Baltimore, MD, 1998; Chapter 14, pp 449-456. (b) Hutson, P. H.; Bristow, L. J.; Rowley, M. J. Med. Chem. 2001, 44, 477.
99. (a) White, F. J.; Wang, R. Y. Science 1983, 221, 1054. (b) Rupniak et al. Psychopharmacology 1984, 84, 512. (c) Meltzer, H. Y. Drug Dev. Res. 1986, 9, 23. (d) Fitton, A.; Heel, R. C. Clozapine: A Review of its Pharmacological Properties, and Therapeutic Use in Schizophrenia. Drugs 1990, 40, 722□747.
100. (a) Lieberman, J. A.; John, C. A.; Kane, J. M.; Rai, K.; Pisciotta, A. V.; Saltz, B. L.; Howard, A. J. Clin. Psychiatry 1988, 49, 271. (b) Navas III, F.; Tang, F. L. M.; Schaller, L. T.; Norman, M. H. Bioorg. Med. Chem. 1998, 6, 811□823.
101. (a) Moore, N. A.; Bymaster, F. P.; Calligaro, D. O.; Tye, N. C.; Wong, D. T. Curr. Opin. Invest. Drugs. 1993, 2, 281□293. (b) Calligaro, D. O.; Fairhurst, J.; Hotten, T. M.; Moore, N. A.; Tupper, D. E. Bioorg. Med. Chem. Lett. 1997, 7, 25□30.
102. Warawa, E. J.; Migler, B. M.; Ohnmacht, C. J.; Needles, A. L.; Gatos, G. C.; McLaren, F. M.; Nelson, C. L.; Kirkland, K. M. J. Med. Chem. 2001, 44, 372-389.
103. (a) Dondio, G.; Ronzoni, S. W.O. Patent 9,636,620, 1996.
104. (a) Walsh, D. A.; Franzyshen, S. K.; Yanni, J. M. J. Med. Chem. 1989, 32, 105□118. (b) Ismaiel, A. M.; Arruda, K.; Teitler, M.; Glennon, R. A. J. Med. Chem. 1995, 38, 1196□1202. (c) Zhang, M.-Q.; Wada, Y.; Sato, F.; Timmerman, H. J. Med. Chem. 1995, 38, 2472□2477. (d) Wei, Z.-Y.; Brown, W.; Takasaki, B.; Plobeck, N.; Delorme, D.; Zhou, F.; Yang, H.; Jones, P.; Gawell, L.; Gagnon, H.; Schmidt, R.; et al. J. Med. Chem. 2000, 43, 3895□3906. (e) Prisinzano, T.; Greiner, E.; Johnson II, E. M.; Dersch, C. M.; Marcus, J.; Partilla, J. S.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C. J. Med. Chem. 2002, 45, 4371□4374. (f) Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, M. C.; Garcia, N.; Cortizo, L.; Labeaga, L.; Innerarity, A. J. Med. Chem. 2003, 46, 5512□5532. (g) Lee, J.; Kang, S.-U.; Lim, J.-O.; Choi, H.-K.; Jin, M.-k.; Toth, A.; Pearce, L. V.; Tran, R.; Wang, Y.; Szabo, T.; Blumberg, P. M.; Bioorg. Med. Chem. 2004, 12, 371□386.
105. (a) Bogeso, K. P.; Andersen, K.; Liljefors, T.; Gundertofte, K.; Perregaard, J. J. Med. Chem. 1994, 37, 950□962. (b) Liljefors, T.; Bogeso, K. P. J. Med. Chem. 1988, 31, 306□312.
106. Talaga, P.; Matagne, A.; Klitgaard, H. Bioorg. Med. Chem. Lett. 2001, 11, 1313□1316.
107. (a) Teodori, E.; Gualtieri, F.; Angeli, P.; Brasili, L.; Giannella, M. J. Med. Chem. 1987, 30, 1934□1938. (b) Beach, J. W.; Jeong, L. S.; Alves, A. J.; Pohl, D.; Kim, H. O.; Chang, C.-N.; Doong, S.-L.; J. Org. Chem. 1992, 57, 2217□2219. (c) Gallo-Rodrigue, C.; Ji, X.; Melman, N.; Seigman, B. D.; Sanders, L. H.; Orlina, M. E.; Van Galen, P. J. M.; Stiles, G. L.; Jacobson, K. A. J. Med. Chem. 1994, 37, 636□646. (d) Branalt, J.; Kvarnstroem, I.; Classon, B.; Samuelsson, B. J. Org. Chem. 1996, 61, 3611□3615. (e) Malmusi, L.; Mucci, A.; Schenetti, L.; Gulini, U.; Marucci, G.; Brasili, L. Bioorg. Med. Chem. 1996, 4, 2071-2080. (f) Pan, B.-C.; Cheng, Y.-C.; Chu, S.-H. J. Heterocycl. Chem. 1997, 34, 909□916.(g) Wang, P.; Gullen, B.; Newton, M. G.; Cheng, Y.-C.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 1999, 42, 3390□3399. (h) Chu, C. K.; Ma, L.; Olgen, S.; Pierra, C.; Du, J.; Gumina, G.; Gullen, E.; Cheng, Y.-C.; Schinazi, R. F. J. Med. Chem. 2000, 43, 3906□3912. (i) Manfredini, S.; Lampronti, I.; Vertuani, S.; Solaroli, N.; Recanatini, M.; Bryan, D.; McKinney, M. Bioorg. Med. Chem. 2000, 8, 1559□1566. (j) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. Eur. J. Org. Chem. 2003, 2, 346□350.
108. For reviews on biologically active organofluorine compounds see: (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Organofluorine Chemistry: Principles and Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Publishing: New York, 1994. (c) Davis, F. A., Qi, H., Sundarababu, G. In Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets; Soloshonok, V. A., Ed.; Wiley & Sons: New York, 1999; Chapter 1. (d) Fluorine Chemistry for Organic Chemists: Problems and Solutions; Hudlicky, M., Ed.; Oxford University Press: New York, 2000.
109. Bondi, A. J. Phys. Chem. 1964, 68, 441.
110. Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron 1996, 52, 12613.
111. (a) Wilkinson, J. A. Chem. Rev. 1992, 92, 505. (b) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.
112. Watanabe, Y.; Usui, H.; Kobayashi, S.; Yoshiwara, H.; Shibano, T.; Tanaka, T.; Morishima, Y.; Yasuoka, M.; Kanao, M. J. Med. Chem. 1992, 35, 189□194.
113. Fassler, A.; Bold, G.; Capraro, H.-G.; Cozens, R.; Mestan, J.; Poncioni, B.; Rosel, J. J. Med. Chem. 1996, 39, 3203□3216.
114. (a) Dahlgren, A.; Kvarnstrom, I.; Vrang, L.; Hamelink, E.; Hallberg, A.; Rosenquist, A.; Samuelsson, B. Bioorg. Med. Chem. 2003, 11, 3423□3437. (b) Ekegren, J. K.; Unge, T.; Safa, M. Z.; Wallberg, H.; Samuelsson, B.; Hallberg, A. J. Med. Chem. 2005, 48, 8098□8102.
115. Computer-Assisted Lead Finding and Optimization: Current Tools for Medicinal Chemistry; Waterbeemd, H. V. D., Testa, B., Folkers, G., Eds.; John Wiley & Sons: New York, 1997; Chapter 14.
116. Kramer, B.; Rarey, M.; Lengauer, T. Proteins 1999, 37, 228□241.
117. Willett, G. J. P.; Glen, R.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
118. Dao, D. H.; Okamura, M.; Akasaka, T.; Kawai, Y.; Hida, K.; Ohno, A. Tetrahedron Asymmetry 1998, 9, 2725□2738.