衍自Pavinane架構之中樞神經藥物研發

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。

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.