新穎性四氫異喹啉化合物之合成研究

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。

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.