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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李水盛 | |
dc.contributor.author | Shang Hsuan Lee | en |
dc.contributor.author | 李尚軒 | zh_TW |
dc.date.accessioned | 2021-06-13T16:30:30Z | - |
dc.date.available | 2008-07-15 | |
dc.date.copyright | 2005-07-15 | |
dc.date.issued | 2005 | |
dc.date.submitted | 2005-07-12 | |
dc.identifier.citation | 1 Jaime N. Delgado and William A. Remers. Wilson and Gisvold’s textbook of organic medicinal and pharmaceutical chemistry. 10th edition, pp. 435-477.
2 Aloke K. Dutta, Cen Xu, and Maarten E. A. Reith. Structure-activity relationship studies of novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1- (3-phenylpropyl)piperidine analogs: synthesis and biological evaluation at the dopamine and serotonin transportor sites. J. Med. Chem. 1996, 39, 749-756. 3 Aloke K. Dutta, Lori L. Coffey, and Maarten E. A. Reith. Highly selective, novel analogs of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine for the dopamine transportor: effect of different aromatic substitutions on their affinity and selectivity. J. Med. Chem. 1997, 40, 35-43. 4 Aloke K. Dutta, Xiang-Shu Fei, Patrick M. Beardsley, Jennifer L. Newman, and Maarten E. A. Reith. Structure-activity relationship studies of 4-[2- (diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: evaluation of behavioral activity of O- and N-analogues and their binding to monoamine transportors. J. Med. Chem. 2001, 44, 937-948. 5 Richard A. Harvey and Pamela C. Champe. Lippincott’s illustrated reviews pharmacology. pp. 161-178. 6 Rohit Kolhatkar, Charles D. Cook, Sujit K. Ghorai, Jeffrey Deschamps, Patrick M. Beardsley, Maarten E. A. Reith, and Aloke K. Dutta, Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl) benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1] nonane derivatives and evaluation of their biological properties for the monoamine transportors. J. Med. Chem. 2004, 47, 5101-5113. 7 Giuseppe Campiani, Stefania Butini, Caterina Fattorusso, Bruno Catalanotti, Sandra Gemma, Vito Nacci, Elena Morelli, Alfredo Cagnotto, Ilario Mereghetti, Tiziana Mennini, Miriana Carli, Patrizia Minetti, M. Assunta Di Cesare, Domenico Mastroianni, Nazzareno Scafetta, Bruno Galletti, M. Antonietta Stasi, Massimo Castorina, Licia Pacifici, Mario Vertechy, Stefano Di Serio, Orlando Ghirardi, Ornella Tinti and Paolo Carminati. Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents. J. Med. Chem. 2004, 47, 143-157. 8 Atsuro Nakazato, Toshihito Kumagai, Kohmei Ohta, Shigeyuki Chaki, Shigeru Okuyama and Kazuyuki Tomisawa. Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4- methoxy-3-(2-phenylethoxy)phenylethylamine to discover ligands. J. Med. Chem. 1999, 42, 3965-3970. 9 Javier Fernandez, Jose M. Alonso, Jose I. Andres, Jose M. Cid, Adolfo Dıaz, Laura Iturrino, Pilar Gil, Anton Megens, Victor K. Sipido, and Andres A. Trabanco. Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents. J. Med. Chem. 2005, 48, 1709-1712. 10 Atsuro Nakazato, Kohmei Ohta, Yoshinori Sekiguchi, Shigeru Okuyama, Shigeyuki Chaki, Yutaka Kawashima, and Katsuo Hatayama. Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine igands as potential antipsychotic drugs. J. Med. Chem. 1999, 42, 1076-1087. 11 Giuseppe Campiani, Stefania Butini, Caterina Fattorusso, Francesco Trotta, Sandra Gemma, Bruno Catalanotti, Vito Nacci, Isabella Fiorini, Alfredo Cagnotto, Ilario Mereghetti, Tiziana Mennini, Patrizia Minetti, M. Assunta Di Cesare, M. Antonietta Stasi, Stefano Di Serio, Orlando Ghirardi, Ornella Tint and Paolo Carminati. Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological studies. J. Med. Chem. 2005, 48, 1705-1708. 12 董國棟. Pavine類生物鹼結構之化學修飾與心血管活性研究(III). 國立台灣大學醫學院 藥學研究所碩士論文, 1995. 13 邱聖友. I. 台灣厚殼桂莖部生物鹼之研究(三) II. Protoberberine類生物鹼結構之化學修飾. 國立台灣大學醫學院 藥學研究所碩士論文, 2001. 14 Shoei-Sheng Lee, Yi-Chu Liu, Shu-Hwei Chang and Chung-Hsiung Chen. N-demethylation studies of pavine alkaloids. Heterocycles, 1993, 36, 1971-1974. 15 Shoei-Sheng Lee and Kuo-Tung Tung. Preparation of N-alkylnorpavines via competitive N-dealkylation of quaternary pavines. Heterocycles, 1996, 43, 1403-1414. 16 Chi-Ming Chiou, Jaw-Jou kang and Shoei-Sheng Lee. Litebamine N-homologues: preparation and anti-acetylcholinesterase activity. J. Nat. Prod., 1998, 61, 46-50. 17 黃偉展 I. 阿朴芬生物鹼之化學:1. 結構修飾研究 2. 全合成研究 II. 高價碘對isoquinoline之氧化研究. 國立台灣大學醫學院 藥學研究所博士論文, 2002. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38327 | - |
dc.description.abstract | 三環架構化合物在中樞神經用藥當中扮演一個重要的角色,如抗憂鬱症與抗精神病藥物。這些藥物擁有在結構上相似的特徵但卻針對不同的作用標的,因此在選擇性的問題上有待改善。這些藥物在藥物化學與作用機轉方面已是被充分清楚了解的領域。有鑑於此,本研究便針對於天然富含的新穎三環架構化合物,以適當的化學反應條件,合成出一些具有特殊架構的化合物以供日後藥理作用之研究。
本研究之類三環目標化合物是以富含於厚殻桂 (Cryptocarya chinensis) 之pavine類生物鹼 (-)-caryachine N-metho salt當起始物而加以製備。此四級銨鹽可經過三個步驟轉變成關鍵中間體之二級胺 (-)-O-benzylnorcaryachine,分別是氧-苄基化反應與去氮-烷基反應 (4oN → 3oN, 3oN → 2oN)。 像3-(4-alkylpiperazin-1-yl)propyl等藥效基團被導入本研究之目標化合物。利用piperazine與morpholine在適當的化學條件下可以合成出這些藥效基團。以氮-烷基化反應將 (-)-O-benzyl norcaryachine與合成出之藥效基團連結,接著去苄基而合成出兩類化合物,即 (-)-N-3-piperazin-1-ylpropylnorcaryachine (48-53) 和 (-)-N-3-morpholinopropylnorcaryachine (55)。在此研究當中亦發現 (-)-N,N’-ethylenylbisnorcaryachine (59) 與 (-)-N,N’-propylenylbisnorcaryachine (60) 兩個產率中等之二元體化合物,可藉由二級胺與1,w-dihaloalkane於鹼性條件下而得。 這些製備出的化合物之中樞神經作用,將以臨床用藥為對照組進一步探討。希望藉此建立結構活性關係而供往後之中樞神經藥物研究之參考。 | zh_TW |
dc.description.abstract | Compounds of tricyclic structure play a role in the development of antidepression and antipsychotic drugs. These drugs possess similar structural characteristics but have different targets. Therefore, the issue of selectivity of these drugs still remains to be improved. The pharmaceutical chemistry and the action mechanism of these drugs have been clarified to a great extent. Based on these, this study was aimed to add pharmacophores to a naturally abundant new tricyclic-like skeleton by appropriate chemical reactions to produce some unique compounds for further pharmacological study.
The tricyclic-like compound used as starting material in this study is a pavine alkaloid (-)-caryachine N-metho salt, which is abundant in Cryptocarya chinensis. This quaternary ammonium salt was converted into the key intermediate (-)-O-benzylnorcaryachine via three steps, i.e. O-benzylation, and two successive N-demethylation reactions (4oN → 3oN, 3oN → 2oN). Some pharmacophores such as 3-(4-alkylpiperazin-1-yl)propyl group were selected from clinically used drugs. They were synthesized starting from piperazine or morpholine by appropriate N-alkylation procedure. Coupling of (-)-O-benzyl norcaryachine with these halogenated pharmacophores via N-alkylation followed by deprotection yielded two types of products, i.e. (-)-N-3-piperazin-1-yl propylnorcaryachine (48-53) and (-)-N-3-morpholinopropylnorcaryachine (55). During this study, (-)-N,N’-alkenylbisnorcaryachine (59 and 60) were also prepared unexpectedly by reacting the secondary amine with 1,2-dihaloethane or 1,3-dihalopropane in moderate yields. The CNS activity of these prepared compounds will be elucidated using the clinically used drugs as positive control. Hopefully, some SAR will be drawn and the result will be served as a reference for further exploration of CNS drugs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T16:30:30Z (GMT). No. of bitstreams: 1 ntu-94-R91423023-1.pdf: 60292953 bytes, checksum: c30bd36f1e86bde47457cbc6ca1526cc (MD5) Previous issue date: 2005 | en |
dc.description.tableofcontents | 總目錄 頁數
總目錄 I 圖目錄 II 流程目錄 III 表目錄 IV 中文摘要 V 英文摘要 VI 壹、序論與研究目的 1 貳、結果與討論 27 參、結論 58 肆、實驗部分 59 伍、參考文獻 100 附錄 103 | |
dc.language.iso | zh-TW | |
dc.title | 衍自Pavinane架構之中樞神經藥物研發 | zh_TW |
dc.title | Development of central nervous system drugs derived from Pavinane skeleton | en |
dc.type | Thesis | |
dc.date.schoolyear | 93-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳繼明,陳春雄,忻凌偉 | |
dc.subject.keyword | 抗憂鬱,抗精神病,三環,厚殻,桂,氮-烷基化,二元體, | zh_TW |
dc.subject.keyword | Pavine,tricyclic antidepressants,phenothiazines,Pavinane,(-)-caryachine N-metho perchlorate, | en |
dc.relation.page | 170 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2005-07-12 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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