臺灣博碩士論文加值系統

中文摘要
離子通道普存在於哺乳動物的組織細胞膜上，並在控制不同的生理機能過程中，扮演著重要的角色。鈉離子通道阻斷劑已用於局部麻醉藥物(procaine和xylocaine)以及防治心率不整的藥物(procainamide和lidocaine)；之後鈣離子通道阻斷劑經過許多研究，發展出像(nifedipine和verapamil)的藥物可用於治療多種的心臟血管疾病。
鉀離子通道活化劑可經由過度極化血管平滑肌的細胞膜，促進肌肉細胞的鬆弛而造成血管舒張的功能特別是應用在氣喘、高血壓、大小便失禁等。1985年cromakalim 經由研究被發現，為一有效的抗高血壓用劑，同時它也是第一個進入臨床實驗的benzopyran類鉀離子通道打開劑，之後便廣受相關研究學者注意；許多以cromakalim為lead compound 所衍生出的類似化合物，已被陸續合成出來。
基於上述理念我們合成了一系列cromakalim衍生物3-substited-2,2-dimethyl-6-benzopyran共15個化合物(10a~10j, 14~17,19)。
並對這15個化合物對老鼠動脈血管進行體外生物活性試驗，探討這一系列3取代benzopyran化合物其結構與血管舒張活性的關係。

ABSTRACT
Ion channels, including sodium, calcium, and potassium channels, are present in all mammalian cells and play a major role in the control of a variety of physiological functions. Sodium channel blockers have been used for many years as local anesthetics (procaine and xylocaine) and antiarrhythmics (procainamide and lidocaine). Subsequently calcium channel blockers underwent a vigorous development and resulted in a number of drugs such as nifedipine and verapamil that are used in cardiovascular diseases. Currently there is an increasing interest in the therapeutic potential of substances that modulate potassium channels.
Since 1985, cromakalim was found as a potent antihypertensive agent and was the first benzopyran potassium channel opener to enter clinical trials. A lot of structurally distinct potassium channel openers have been reported. By hyperpolarizing the cell membrans of vascular smooth muscle potassium channel openers lead to vasorelaxation which may be used in the treatment of different kinds of diseases especially in hypertension, asthma, and incontinence.
During our studies aimed at the discovery of novel potassium channel openers related to cromakalim, a new series of 3-substituted-2,2-dimethyl-6-nitro-2H-1-benzopyrans have been prepared and their vasorelaxant activity has also evaluated.

目 錄
中文摘要……………………………………………………………………I
英文摘要………………………………………………………..........II
一、前言………………………………………………….…………..……1
二、實驗儀器和材料………………………………………...…..…….13
三、使用藥品一覽表……………………………………………………..14
四、合成方法
(一)Scheme I……………………...……………...…………17
(二)Scheme II……………………………………………...……..18
(三)Scheme III………………………………………………………19
五、合成步驟
(一)Scheme I……………………………………………...……...20
(二)Scheme II…………………………………………...………..21
(三)Scheme III………………………………………………………22
六、實驗內容
(一)合成部………………………………………………...……….23
(二)血管舒張活性部份……………………………………….…….39
七、結果與討論
(一)合成部份……………………….………………..…………….40
(二)儀器鑑定部份……………………………………………….44
(三)血管舒張活性部份……………………………………………46
八、結論……………………………………………………………………47
九、參考文獻………………………………………………………………48
十、附圖……………………………………………………………………52

九、參考文獻
1.傅祖慶、林富美、林則彬；賴亮全翻譯，蓋統生理學─生理及疾病機轉（上冊），華杏出版股份有限公司，1995，初版，Arthur, C. Guyton, Ed.: Human physiology and mechanisms of disease. 5th edition, W.B. Saunders Co. USA. (1992).
2.Hamilton, T.C.: Weir, S.W. and Weston, A.H. Br. J. Pharmacol. 88, 103-111(1986).
3.Foster C.D.; Fujii, K.; Kington, J. and Brading, A.F. Br. J. Pharmacol. 97, 281-299. (1989)
4.Gillespie, J. S. and Sheng, H. Br. J. Pharmacol. 94, 1189-1197(1988).
5.Edwards, G.; Henshaw, M.; Miller, M. and Weston, A. H. Br. J. Pharmacol. 102, 679-686(1991).
6.Robertson, D. W. and Steinberg, M. I. J. Med. Chem. 33, 1529-1544 (1990).
7.Andersson, K.-E. Pharmacol. Toxicol. 70, 244-254 (1992).
8.Takemoto, T.; Eda, M.; Okada, T.; Sakashita, H.; Matzno, S.; Gohda, M.'; Ebisu, H.; Nakamura, N.; Fukaya, C.; Hihara, M.; Eiraku, M.; Yamanouchi, K.; and Yoko-yama, K. J. Med. Chem. 37, 18-25(1994) and references therein.
9.Patrick Henry and Denis Escande, Cardiovascular Research 28, 754-759 (1994).
10.Ashwood, V. A.; Buckingham, R.E.; Cassidy, F.; Evans, J. M.; Faruk, E.A.; Hamilton, T. C.; Nash, D. J.; Stemp, G. and Willcocks, K. J. Med. Chem. 29, 2194-2201 (1986).
11.Hamilton, T.C.; Weir, S.W. and Weston, A. H. Br. J. Pharmacol. 86, 443p (1985).
12.Evans, J. M. and Longman, S. D. Ann. Rep. Med. Chem. 24, 73-82 (1991).
13.Smith, D. G. J. Chem. Soc., Perkin Trans. 1, 3187-3191 (1990).
14.Burrell, G.; Cassidy, F.; Evans, J. M.; Lightowler, D. and Stamp, G. J. Med. Chem. 33, 3023-3207 (1990).
15.Buckle, D. R.; Arch, J. R. S.; Edge, C.; Foster, K. A.; Houge-Frydrych, C.S.V.; Pinto, I. L.; Smith, D. G.; Taylor, J. F.; Taylor, S. G.; Tedder, J. M. and Webster, R. A. B. J. Med. Chem. 34, 919-926 (1991).
16.Ashwood, V. A.; Cassidy, F.; Evans, J. M.; Gagliardi, S. and Stemp, G. J. Med. Chem. 34, 3261-3267 (1991).
17.Buckle, D. R.; Eggleston, D. S.; Houge-Frydrych, C.S.V.; Pinto, I.L.; Readshaw, S.A.; Smith, D.G. and Webster, R.A.B. J. Chem Soc., Perkin Trans. 1, 2763-2771 (1991).
18.Sanfilippo, P. J.; McNally, J.J.; Press, J. B.; Fitzpatrick, L.J.; Urbanski, M.J.; Katz, L.B.; Giardino, E.; Falotico, R.; Salata, J.; Moore, Jr. J.B. and Miller, W. J. Med. Chem. 35, 4425-4433 (1992).
19.Almansa, C.; Gomez, L. A.; Cavalcanti, F.L.; Rodriguez, R.; Carceller, E.; Bartroli, J.; Garcia-Rafanell, J. and Forn, J. J. Med. Chem. 36, 2121-2133 (1993).
20.(a)Matsumoto, Y.; Tsuzuk, R.; Matsuhisa, A.; Takaymam, K.; Yoden, T.; Uchida, W.; Asano, M.; Fujita, S.; Yanagisawa, I. and Fujikura, T. Chem. Pharm. Bull. 44, 103-114 (1996). (b)Yamamoto, S.; Hashiguchi, S.; Miki, S.; Igata, Y.; Watanabe, T. and Shiraishi, M. Chem. Pharm. Bull. 44, 734-745 (1996).
21.Cassidy, F.; Evans, J. M.; Hadley, M. S.; Haladij, A. H.; Leach, P. E. and Stemp, G. J. Med. Chem. 35, 1623-1627(1993).
22.(a) Kaga, H.; Ohta, M.; Ishizawa, T. and Nabata, H.; Bioorg. Med. Chem. Lett. 3, 625-631(1993). (b) Kaga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Nabata, H.; Imagawa, J.-I; Yoshida, S. and Sugo, I. Bioorg. Med. Chem. Lett. 3, 1111-1114(1993). (c) Kaga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Makino, T.; Taka, N.; Takahashi, T.; Sato, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3, 1115-1118(1993). (d) Sato, H.; Kaga, H.; Ishizawa, T.; Makino, T.; Kuromaru, K.; Taka, N.; Takahashi, T.; Sato, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3, 2627-2630(1993).
23.Cushman, M.; Nagarathnam, D.; Burg, D. L. and Geahlen, R. L. J. Med. Chem. 34, 798-806(1991).
24.Kaga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Nabata, H.; Imagawa, J.-I.; Yoshida, S. and Sugo, I. Bioorg. Med. Chem. Lett. 3, 1111-1114(1993).
25.Kaga, H.; Sato, H.; Ishizawa, T.; Taka, N. and Takahashi, T. Tetrahedron Lett. 36, 87-90(1995).
26.Bergmann, R. and Gericke, R. J. Med. Chem. 33, 492-504(1990).
27.Press, J. B.; Mcnally, J. J.; Sanfilippo, P. J.; Addo, M. F.; Loughney, D.; Giardino, E.; Katz, L. B.; Falotico, R.; Haertlein, B. J. Bioorg. Med. Chem. 1, 423-435(1993).
28.Takahashi, T.; Koga, H.; Sato, H.; Ishizawa, T.; Taka, N. and Imagawa, J.-I.. Bioorg. Med. Chem. 6, 323-337(1998).
29.Buckle, D. R.; Arch, J. R. S.; Fenwick, A. E.; Houge-Frydrych, C. S. V.; Pinto, I. L.; Smith, D. G.; Taylor, S. G. and Tedder, J. M. J. Med. Chem.33, 3028-3034(1990).
30.Bergmann, R. and Gericke, R. J. Med. Chem. 33, 492-504(1990).
31.Koga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Makino, T.; Taka, N.; Takahashi, T.; Sato, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3, 1115-1118(1993).
32.Koga, H.; Sato, H.; Imagawa, J.-I Ishizawa, T.; Yoshida, S.; Sugo, I.; Taka, N.; Takahashi, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3, 2005-2010(1993).
33.Sato, H.; Koga, H.; Ishizawa, T.; Makino, T.; Kuromaru, K.; Taka, N.; Takahashi, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3, 2627-2630(1993).
34.Koga, H.; Sato, H.; Ishizawa, T.; Taka, N.; and Takahashi, T. Tetra. Lett. 36, 87-90(1995).
35.Koga, H.; Sato, H.; Ishizawa, T.; Kuromaru, K.; Makino, T.; Taka, N.; Takahashi, T.; Sato, T. and Nabata, H. Bioorg. Med. Chem. Lett. 3,1115-1118(1993).