選擇性毒蕈素受體拮抗劑-Liriodenine 之化學合成研究
Synthesis of Liriodenine, a selective muscarinic antagonist
中文摘要選擇性毒蕈素受體拮抗劑-Liriodenine 之化學合成研究
Liriodenine (20)屬於 7-oxoaporphine 生物鹼，經藥理篩選發現對於 carbachol 誘發 天竺鼠支氣管及迴腸平滑肌之收縮具有鬆弛作用，但對心臟強心作用之活性僅為 平滑肌鬆弛作用之十分之一而已，表示 liriodenine (20)對毒蕈素 M3 亞型受體具 有選擇性之拮抗作用。由於 liriodenine (20)於化學結構與已知選擇性 M3 拮抗物 (4-DAMP ) 不同而具構造特殊性。為提昇毒蕈素 M3 亞型受體之拮抗作用並改善 其化學性狀，經化學構造修飾並探討 liriodenine 之化學構造與藥效關係是唯一途 逕。本論文係研究 liriodenine 簡易且有效之化學合成方法，以期將來用於製備 liriodenine 類似物，做為設計支氣管擴張劑之前導藥物重要依據。
Liriodenine 之化學製備方法乃以 piperonal 為起始物，經與 aminoacetaldehyde dimethyl acetal 縮和後，利用 Pomeranz-Fritsch 反應製成
6,7-methylenedioxyisoquinoline(26)後，再與 benzoyl chloride 及 trimethylsilyl cyanide 製成 isoquinoline Reissert compound 27。與各種鄰位碘及溴取代之苯醛類 進行縮合反應後，形成各種 benzylisoquinoline 之酯類 31,32，再水解成醇類 33,34，再氧化成酮類 35,36 衍生物，最後經由分子內環化形成 liriodenine(20)； 環化合成反應採用光化學、tributyltin hydride 或 Psychorr 等三種反應，其全程合 成產率各為 19 %， 17% 及 6%。其中以 tributyltin hydride 環化反應最為適宜未 來擴量製備之用。
英文摘要
Synthesis of Liriodenine, A Selective Muscarinic Antagonist
Liriodenine, an 7-oxoaporphine alkaloid was found to inhibit tracheal and ileum contraction of guinea-pig induced by carbachol. It also showed to have cardiotonic effect but only one tenth potency compared with smooth muscle relaxation effect. The pharmacological activity was demonstrated that liriodenine is a selective muscarinic M3 subtype receptor antagonist. The structure of liriodenine is completely different from the known M3 antagonist (eg. 4-DAMP). To enhance the selectivity on
muscarinic M3 antagonist activity, structural modification and SAR study is essential for liriodenine. In this thesis, we like to focus on the development of a new and facile synthesis of liriodenine. Application of the proposed synthetic method will be
beneficial to design new lead as potential bronchodilators.
Liriodenine was prepared by condensation of piperonal and aminoacetaldehyde dimethyl acetal, and then to form the 6, 7-methylenedioxyisoquinoline (27) via
Pomeranz-Fritsch reaction. Then it was reacted with benzoyl chloride and
trimethylsilyl cyanide to yield isoquinoline Reissert compound 28. The Reissert 28 was condensed with o-bromo- or o-iodobenzaldehydes to form the corresponding benzylisoquinoline esters 32 and 33, and then hydrolyzed to alcohols 34 and 35 and oxidized to ketone 36 and 37. Finally, intramolecular cyclization of the alcohols 34 and 35 react either by photo irradiation or tributyltin hydride or Pschorr reaction to finish the total synthesis of liriodenine. The yields of total synthesis of liriodenine were 19% for photocyclization, 17% for organotin hydride cyclization, and 6% for Pschorr cyclization. Cyclization by tributyltin hydride is the most effective way to prepare liriodenine with high yield and it should be able to apply in large scale synthesis.
