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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77477完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 忻凌偉 | zh_TW |
| dc.contributor.author | 李鎮宏 | zh_TW |
| dc.contributor.author | Cheng-Hung Lee | en |
| dc.date.accessioned | 2021-07-10T22:03:55Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-09 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77477 | - |
| dc.description.abstract | 血清素受器的調節在許多中樞神經及腸胃道疾病治療中扮演重要的角色，然而針對血清素受器的藥物在發展上時常面臨選擇性與代謝分佈的挑戰，故新穎、高選擇性的化合物值得開發作為受體各亞型作用與藥理機轉的研究。本研究配體以7-羥基四氫異喹啉 (1,2,3,4-tetrahydroquinolin-7-ol) 作為優化骨架，這類型化合物合成關鍵步驟包含親電芳香取代成環反應、有機金屬催化耦合反應等，在建構時有所限制使得過往的研究著重在多電子系統的芳香系統上。缺電子芳香結構包含拉電子基團取代、異原子取代芳香環等，其在電荷分佈、平面性的異質除了表現在合成路徑的改變，亦可能展現活性或代謝上的差異。為促使成環化反應，親電芳香反應的由以腈鎓離子 (nitrilium ion) 為中間體的Bichler-Napieralski反應更換為透過亞胺離子生成的Pictet-Spengler反應。且在磺醯基團修飾起始物活化反應下，最終缺電子性7-羥基四氫異喹啉系列物 (C-6氫取代、氟取代) 被合成取得，其反應路徑可作為進一步衍伸的參考。本系列經血清素受器測試初步評估保有相當的親和力與脂溶性，可作為未來進一步優化選擇性血清素受器配體的新穎骨架。 | zh_TW |
| dc.description.abstract | Serotonin receptors regulation had been known to play an important role in many CNS and GI diseases yet selectivity and distribution are both problems often cross pass within the developmental stage, thus novel skeleton are still in need for research of the studies of 5-HT subtypes and pharmacology. In this study, 1,2,3,4-tetrahydroquinolin-7-ol was used for modification. Key steps of the construction of these type of compounds were electrophilic substitution cyclization and organic-metallic catalyzed coupling, limiting past development to be on electron-rich systems. Electron deficient systems include electron-withdrawing-group substituted and hetero-replaced aromatic system, the difference in electron distribution and planarity may affect not only the synthetic route but also in binding affinity or metabolic profile. To avoid competition of complex side reactions, key cyclization reaction changed from Bischer-Napieralski reaction, which undergo active nitrilium ion as intermediate, to Pictet-Spengler passing though iminium. Furthermore, activation and selection was gained by tosylating the amine group. At last, electron-deficient 1,2,3,4-tetrahydroisoqunolin-7-ols including C-6 hydrogen-substituded and fluoro-substituded were obtained. The modified synthesis pathway can be used for further studies and retain comparable affinity and lipophilicity shown as potential serotonin receptor ligands. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T22:03:55Z (GMT). No. of bitstreams: 1 ntu-107-R05423019-1.pdf: 5405629 bytes, checksum: 2a5e5357fc601eeeca255a0407bebd09 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 目錄
致謝 II 摘要 III Abstract IV 英文縮寫列表 V 目錄 總目錄 VI 圖目錄 VII 表目錄 VIII 路徑目錄 VIII 緒論 1.1 血清素受器之研究 1 1.2 化合物結構設計 3 1.3 研究動機與目的 5 結果與討論 2.1 N-取代四氫異喹啉之合成 7 2.1.1 逆合成分析 7 2.1.2 N-取代側鏈製備 8 2.1.3 N-取代目標化合物14, 15之合成研究 9 2.2 C-6取代四氫異喹啉之合成 11 2.2.1 逆合成分析 11 2.2.2 選擇性去甲基化研究分析 12 2.2.3 羥基性官能基轉換探討 16 2.2.4 C-6取代目標化合物52, 56之合成研究 18 結論 23 實驗部分 4.1 實驗藥品及溶劑來源 24 4.2 一般儀器與方法 27 4.3 合成步驟與分析 28 參考文獻 72 附錄 目錄 76 附圖 78 圖目錄 圖一、色胺酸與5-HT之結構 1 圖二、阿立哌唑與SB-269970之結構 2 圖三、阿朴啡系列生物鹼之結構 3 圖四、7-Hydroxy-8-phenyltetrahydroisoquinoline系列基本架構 4 圖五、8-Phenyltetrahydroisoquinoline作為選擇性5-HT2受器配體 4 圖六、受器模擬選擇性5-HT7拮抗劑藥效基團預測 5 表目錄 表一、Omerprazole氧上去甲基化反應 13 表二、鄰位氧保護選擇性氧上去甲基化方法探討 14 表三、選擇性去甲基化條件優化 15 表四、羥基性官能基轉換探討 17 路徑目錄 路徑一、缺電子性四氫異喹啉過去合成路徑 6 路徑二、缺電子性四氫異喹啉C-1環化反應 6 路徑三、N-取代四氫異喹啉之逆合成分析 7 路徑四、共同中間體4之合成 8 路徑五、N-取代側鏈9之合成 8 路徑六、N-取代側鏈12之合成 9 路徑七、N-取代目標化合物14, 15之合成 10 路徑八、C-6取代四氫異喹啉之逆合成分析 11 路徑九、C-6取代官能基轉換步驟 12 路徑十、氧上甲基化反應 15 路徑十一、羥基性官能基轉換步驟 16 路徑十二、甲醯胺中間體之合成 18 路徑十三、Bischler-Napieralski環化 19 路徑十四、Pictet-Spengler環化 20 路徑十五、去磺羧基化反應 20 路徑十六、目標化合物52之合成 21 路徑十七、目標化合物56之合成 22 路徑十八、C-6取代拉電子基團修飾合成步驟 22 | - |
| dc.language.iso | zh_TW | - |
| dc.title | 新穎性四氫異喹啉化合物之合成研究 | zh_TW |
| dc.title | Synthetic Study of Novel Tetrahydroisoquinolines | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 李水盛;陳基旺;梁碧惠 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 四氫異??,缺電子性,血清素受器, | zh_TW |
| dc.subject.keyword | Tetrahydroisoquinoline,Electron-deficient,Serotonin receptors, | en |
| dc.relation.page | 111 | - |
| dc.identifier.doi | 10.6342/NTU201803845 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-08-17 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 藥學研究所 | - |
| 顯示於系所單位： | 藥學系 | |
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