臺灣博碩士論文加值系統

麩胺酸 (glutamate) 在哺乳類的中樞神經系統中，主要是擔任一種興奮性神經傳導物質，哺乳類動物腦中之中樞神經系統內的meta-
botropic glutamate receptors (mGluRs) ，是作為控制神經細胞之神經衝動和突觸神經進行傳輸的重要角色。N-(1,3-Diphenyl-1H-
pyrazol-5-yl)benzamide類衍生物是第一個被開發作為老鼠和人類metabotropic glutamate receptor 5 (mGluR5) 的正向異位調控因素之活化物質。本實驗在研究利用phenylhydrazine、benzoylacetonitrile和各種醯化試劑 (acylation) 以一種簡單便捷方法合成出N-(1,3-diphenyl-1H-pyrazol-5-yl)amide類衍生物。結合環化及胺基醯化兩種反應步驟，在one-pot條件下進行反應，可得到高產率N-(1,3-diphenyl-1H-pyrazol-5-yl)amide類衍生物。

Glutamate is the major excitatory transmitter in the mammalian central nervous system. Metabotropic glutamate receptors (mGluRs) play an important role in controlling neuronal excitability and synaptic transmission in the central nervous system (CNS) of the mammalian brain. N-(1.3-Diphenylare1-H-pyrazol-5-yl)benzamide derivatives were recently developed as the first centrally active positive allosteric modulator of rat and human metabotropic glutamate receptor mGluR5 subtype. N-(1,3-
diphenyl-1H-pyrazol-5-yl)amide derivatives were convenient and efficient synthesized by using phenylhydrazine, benzoylacetonitrile, and a series of acylation agents. Two steps of condensation-cyclization and acylation were performed in one-pot to give the corresponding N-(1,3-diphenyl-1H-pyrazol-5-yl)amide analogues in good to excellent yields (70–90%).

中文摘要.................................................Ⅰ
英文摘要.................................................Ⅱ
第一章 緒論.............................................1
1-1. 精神分裂症 (schizophrenia)...........................3
1-2. 麩胺酸受體 (glutamate receptor)......................9
1-3. 吡唑衍生物之介紹與發展..............................14
1-4. 合成步驟探討........................................16
1-5. 研究動機............................................19
第二章 結果與討論......................................20
2-1. 5-Amino-1,3-diphenyl pyrazole的合成.............20
2-2. 胺基醯化反應....................................21
2-3. One-pot合成反應.................................23
2-4. 具不同的苯醯胺之研究結果探討....................24
2-5. 延伸文獻雜環取代基的修飾........................28
第三章 結論............................................32
第四章 實驗部份........................................33
4-1. 試藥、溶媒與材料....................................33
4-2. 儀器................................................35
4-3. 實驗方法............................................36
參考文獻.................................................47
附錄 (圖譜部分)..........................................53

[1] Lindsley, C. W.; Wisnoski, D. D.; Duggan, M. E.;
Leister, W. H.; Hartman, G. D.; Huff, J. R.; Williams,
D. L.; O’Brien, J. A.; Lemaire, W.; Sur, C, J. Med.
Chem. 2004, 47, 5825.
[2] Kimey, G. G.; O’Brien, J. A.; Lemaire, W.; Burno, M.;
Bickel, D. J.; Clements, M. K.; Chen, T.-B.; Wisnoski,
D. D.; Lindsley, C. W.; Tiller, P. R.; Smith, S.;
Jacobson, M. A.; Sur, C.; Duggan, M. E.; Pettibone, D.
J.; Conn, P. J.; Williams, D. J. J. Pharmacol. Exp.
Ther. 2005, 313, 199.
[3] Lindsley, C. W.; Wisnoski, D. D. Pyrazole modulators of
metabotropic glutamate receptors. PCT Pat. Appl. WO
2005/030128, 2005.
[4] Paulis, T. de; Hemstapat, K.; Chen, Y.; Zhang, Y.;
Saleh, S.; Alagille, D.; Baldwin, R. M.; Tamagnan, G.
D.; Conn, P. J. J. Med. Chem. 2006, 49, 3332.
[5] 李明濱，實用精神醫學，第二版，台灣大學醫學院，2000。
[6] http://www1.vghtpe.gov.tw/msg/%E7%B2%BE%E7%A5%9E%E7
%A7%91%E4%BC%81%E5%9C%96%E8%87%AA%E6%AE%B
A%E4%BD%8F%E9%99%A2%E9%9D%92%E5%B0%91%E5%B
9%B4%E4%B9%8B%E5%89%96%E6%9E%90941108.htm(圖片來源)
[7] Gelder, M.; Mayou, R.; Geddes, J. Psychiatry,Oxford,
1999.
[8] 孔繁鐘，DSM-IV 精神疾病的診斷與統計，合計圖書出版社，
1997。
[9] http://health.enorth.com.cn/system/2005/04/28/0010144
86.shtml(圖片來源)
[10] 陳世芬，PDE4B、CDH8基因與精神分裂症的關係，慈濟大學人
類遺傳研究所碩士論文 2007。
[11] Tsuang, M. T.; Winokur, G.; Crowe, R. Br.
J.Psychiatry. 1980, 137, 497.
[12] Gottesman, I. I. Schizophrenia genesis: The origins
of madness.Freeman, 1991.
[13] Hoston, L. L. Br. J. Psychiatry. 1966, 112, 819.
[14] http://www.als-mda.org/publications/als/als9_9.html(圖
片來源)
[15] Chen, K. P.; Chen, C. H. Review of NMDA receptor.1997.
[16] Tolle, TR. Neuroreport. 1999, 16, 3861.
[17] Hollmann, M.; Heinemann, S. Annual Reviews of
Neuroscience. 1994, 17, 31.
[18] Meador-Woodruff, J. H.; Healy, D. J. Brain Research
Reviews. 2000, 31, 288.
[19] Al-Amin, H. A.; Schwarzkopf, S. B. Biol. Psychiatry.
1996, 40, 744.
[20] Olney, J. W.; Farber, N. B. Arch Gen Psychiatry.
1995, 52, 998.
[21] (a) Olney, J. W.; Farber, N. B. Arch Gen Psychiatry.
1995, 52, 998.
(b) Olney, J. W.; Newcomer, J. W.; Farber, N. B. J.
Psychiatr. Res. 1999, 33, 523.
[22] Mohn, A. R.; Gainetdinov, R. R.; Caron, M. G.;
Koller, B. H. Cell. 1999, 98, 427.
[23] Sakurai, K.; Toru, M.; Yamakawa-Kobayashi, K.;
Arinami, T. Neurosci. lett. 2000, 296, 168.
[24] Ohnuma, T.; Tessler, S.; Arai, H.; Faull, R-L.M.;
McKenna, P. J.; Emson, P. C. Mol. Brain Res. 2000,
85, 24.
[25] Mannaioni, G.; Marino, M. J.; Valenti, O.; Traynelis,
S. F.; Conn, P. J. J. Neurosci. 2001, 21, 5925.
[26] Conn, P. J.; Pin, J. P. Annu. Rev. Pharmacol.
Toxicol. 1997, 37, 205.
[27] Ritzen, A.; Mathiesen, J. M.; Thomsen, C. Basic Clin.
Pharmacol. Toxicol. 2005, 97, 202.
[28] Marino, M. J.; Conn, P. J. Curr. Drug Targets CNS
Neurol. Disord. 2002, 1, 1.
[29] Javitt, D. C. Mol. Psychiat. 2004, 9, 984.
[30] 廖曉梅，一.mGluR6基因於精神分裂症之分子遺傳研究 二.以
cDNA微陣列晶片分析精神分裂症患者血液單核球細胞之基
表現，慈濟大學人類遺傳研究所碩士論文 2001。
[31] Buck, J.; Derguini, F.; Levi, E.; Nakanishi, K.;
Hammerling, U. Science. 1991, 254, 1654.
[32] Mosbacher, J.; Schoepfer, R.; Monyer,H.; Burnashev,
N.; Seeburg, P. H.; Ruppersberg, J. P. Science. 1994,
266, 1059.
[33] Davies, S. N.; Lester, R. A.; Reymann, K. G.;
Collingridge, G. L. Nature. 1989, 338, 500.
[34] Nakanishi, N.; Axel, R.; Shneider, N. A.; Proc Natl
Acad Sci USA. 1992, 89, 8552.
[35] Nakanishi, S. Science. 1992, 258, 597.
[36] Tsuzuki, K.; Takeuchi, T.; Ozawa, S. Brain Res Mol
Brain Res. 2006, 16, 105.
[37] 張靜宜，CART Peptides增強大白鼠脊髓背角神經元上NMDA
調控之去極化反應：蛋白質激酶A和蛋白質激酶C之角色，慈
濟大學神經科學研究所碩士論文2006。
[38] http://www.mona.uwi.edu/fpas/courses/physiology/neuro
physiology/CNSMetabolism.htm(圖片來源)
[39] Yeh, H. H.; Kolb, J. E. Alcoholism: Clinical ＆
Experimental Research. 1997, 21, 647.
[40] Steele, J. E.; Robinson, T. N.; Cross, A. J.; Bowen,
D. M.; Green, A. R. J. Neurochem. 1991, 56, 1248.
[41] Turski, L.; Bressler, K.; Rettig, k. J.; Loschmann,
P. A. Wachtel, H. Nature, 1991, 349, 414.
[42] http://www.chrisparsons.de/Chris/nmda.htm(圖片來源)
[43] Cull-Candy, S.; Brickley, S.; Farrant, M. Current
Opinion in Neurobiology. 2001, 11, 327.
[44] Kleckner, N. W.; Dingledine, R. Science. 1988, 241,
835.
[45] Peters, S.; Koh, J.; Chol, D. W. Science. 1987, 236,
589.
[46] Mayer, M. L.; Westbrook, G. L.; Guthrie, P. B.Nature.
1984, 309, 261.
[47] Nowak, L.; Bregestovski, P.; Ascher, P.; Herbet, A.;
Prochiantz, A. Nature. 1984, 307, 462.
[48] Ransom, R. W.; Stec, N. L. Neurochemistry. 1988,
51, 830.
[49] Chizh, B. A.; Headley, P. M.; Tzschentke, T. M.
Trends Pharmacol. Sci. 2001, 22, 636.
[50] http://www.securitylab.ru/analytics/241606.php (圖片來
源)
[51] Moss, S. J.; Blackstone, C. D.; Huganir, R. L.
Neurochemical Research. 1993, 18, 105.
[52] McGlade-McCulloh, E.; Yamamoto, H.; Tan, S. E.;
Brickey, D. A.; Soderling, T. R. Nature. 1993, 362,
640.
[53] 許靜怡，急性乙醇投予對大白鼠交感節前神經元麩胺酸鹽受體
之影響，慈濟大學藥理暨毒理學研究所碩士論文 2001。
[54] Tasir, S. H.; Seifu, T.; Jovita, M. J. Med. Chem.
2002, 45, 4669.
[55] John, R.; Steffen, B.; Pier, C. J. Med. Chem. 2002,
45, 2994.
[56] Chiara, B. V.; Donatella, M.; Alfredo, T. J. Agric.
Food. Chem. 2004, 52, 1898.
[57] Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.;
Kitamikado, T.; Asai, H.; Kato, K. J. Med. Chem.
1977, 20, 80.
[58] Behr, L. C.; Fusco, R.; Jarboe, C. H. Interscience
Publishers: New York. 1967, 1.
[59] Wiley, R. H.; Wiley, P. John Wiley and Sons: New
York. 1964, 102.
[60] Rosiere, C. E.; Grossman, M. I. Science. 1951, 113,
651.
[61] Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman,
E. R.;Pearl, J.; Defelice, A. F.; Feigenson, M. E. J.
Med. Chem. 1985, 28, 256.
[62] Kurowaski, M.; Dunky, A.; Geddawi, M. Eur.J. Clin.
Pharmacol. 1987, 307, 31.
[63] Leenen, F. H. H.; Smith, D. L.; Unger, W. P. Br. J.
Clin. Pharmacol. 1988, 26, 481.
[64] Mahajan, R. N.; Havaldar, F. H.; Fernandes, P. S. J.
Indian Chem. Soc. 1991, 68, 245.
[65] Lepage, F.; Hubiot, B. Eur. Pat. Appl. EP, 459, 887,
Chem. Abstr. 1992, 116, 128914.
[66] Chauhan, P. M. S.; Singh, S.; Chatterjee, R. K.
Indian J. Chem. B. 1993, 32, 858.
[67] Dutra, G. A.; Hamper, B. C.; Mischke, D. A.;
Moedritzer, K.; Rogers, M. D. PCT Int. Appl., WO
8206, 962; Chem. Abstr. 1992, 117, 69859.
[68] Suzuki, H.; Hanaue, M. Nishikubo, M. Jpn. Kokai
Tokkyo Koho JP, 03, 236, 368; Chem. Abstr. 1993. 116,
106285.
[69] Natsume, B.; Kyomura, N.; Kikutake, K.; Fukuch, T.
Eur. Pat. Appl. EP., 462, 573; Chem. Abstr. 1992,
116, 128.
[70] Londershausen, M. Pestic. Sci. 1996, 48, 269.
[71] Windholz, M. The Merk Index, 9th ed. Merck and Co.
Rahway: New Jersey, 1976, 8851.
[72] Fahmy, B. S. M.; Elnagdi, M. H. Chem. Abstr. 1981,
94, 48804.
[73] Lubs, H. A. The Chemistry of Synthetic Dyes and
Pigments’, American Chemical Society: Washington.
1970.
[74] Garcia, H.; Iborra, S.; Miranda, M. A.; Morera, I.
M.; Primo, J. Heterocycles. 1991, 32, 1745.
[75] Busev, A. I.; Akimov, V. K.; Gusev, S. I. Russ. Chem.
Rev. 1965, 34, 237.; Chem. Abstr. 1965, 62, 15395.
[76] (a) Uzoukwu, A. B. Polyhedron. 1993, 12, 2719. (b)
Maurya, R. C.; Verma, R. Indian J. Chem. 1997, 36,
596. (c) Pettinari, C.; Marchetti, F.; Pettinary, R.;
Drozdov, A.; Troyanov, S.; Voloshin, A. I.;
Shavaleen, N. M. J. Chem. Soc. Dalton Trans. 2002,
1409 (d) Garnii, A. D.; Uraev, A. I.; Minkin, V. I.
Arkivoc. 2004, 29.
[77] Singh, P.; Paul, K.; Holzer, W. Bioorg. Med. Chem.
2006, 5061.
[78] Chen, C.; Wilcoxen, K.; McCarthy, J. R. Tetrahedron
Lett. 1998, 39, 8229.
[79] Anderson, E. L.; Casey, J. E.; Greene, L. C.;
Lafferty, J. J.; Reiff, H. E. J. Med. Chem. 1964, 7,
259.
[80] Bruno, O.; Brullo, C.; Bondavalli, F.; Schenone, S.;
Ranise, A.; Arduino, N.; Bertolotto, M. B.;
Montecucco, F.; Ottonello, L.; Dallegri, F.;
Tognolini, M.; Ballabeni, V.; Bertoni, S.; Barocelli,
E. J. Med. Chem. 2007, 50, 3618.
[81] Pinkerton, A. B.; Huang, D.; Cube, R. V.; Hutchinson,
J. H.; Struthers, M.; Ayala, J. M.; Vicario, P. P.;
Patel, S. R.; Wisniewski, T.; DeMartino J. A.;
Vernier, J-M. Bioorg. Med. Chem. Lett. 2007, 807.
[82] Ertan, T.; Yildiz, I.; Ozkan, S.; Temiz-Arpaci, O.;
Kaynak, F.; Yalcin, I.; Aki-Sener E.; Abbasoglu, U.
Bioorg. Med. Chem. 2007, 2032.