心血管藥物螺旋芐基異奎琳類似物之合成研究
Synthesis of Spirobenzylisoquinoline Analogues as Potential
中文摘要
JKL1067 ( 2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquinoline ) (33)是一個 合成的螺旋芐基異奎琳,研究發現其可增加心收縮力和減緩自發性的心跳速率,除 此之外,對於 ouabain 所引起的心律不整有抑制的作用.為了要進一步研究其化學 結構與心臟作用藥效的關係,我們利用化學合成的方法合成了八個螺旋芐基異 奎琳之類似化合物33, 34, 36, 37, 39, 40, 42 和 43.化學合成方法係先合成原小蘗 鹼型衍生物為關鍵性中間化合物,再與 CH3I 反應生成 N-methiodide salts 32, 35, 38 和 42 之後,利用 stevens 之重排反應,在 dimsylsodium 強鹼催化下,反應生成螺 旋芐基異奎琳類似物33, 36, 39 和 42. 接著再將螺旋芐基異奎琳類似物 33, 36, 39 和 42 與 CH3I 反應生成四級之螺旋芐基異奎琳類似物 34, 37, 40 和 43.
八個螺旋芐基異奎琳類似物是以大白鼠之離體心臟作有關心收縮力與心跳速率 之藥理活性測試.結果顯示,三級的螺旋芐基異奎琳類似物 36 和 42 可增加心收縮 力和減緩心跳速率作用.至於四級的螺旋芐基異奎琳類似物 34, 37, 40 和 43 對心 臟組織並沒有任何作用.
英文摘要
JKL1067 ( 2,3-methylenedioxy-9,10-dimethoxyspirobenzylisoquinoline )(33).a synthetic spirobenzylisoquinoline, exhibited a positive inotropic effectand negative chronotropic effect. Besides the positive inotropic effect, it
alsopossessed antiarrhythmic activity against cardiac arrhythmia induced by oua- bain. In order to
study the relationship between the structure and activity oncardiovascular
system, several spirobenzylisoquinoline analogues, such as 33,34, 36, 37, 39, 40, 42 and 43, have been prepared by chemical synthesis. Protoberberine
derivativbes were used as key intermediates. Treatment ofprotoberbines with methiodide afforded N-methyltetrahydroprotoberberimiumiodide32,35, 38 and 41.
The preparations of spirobenzylisoquinolines 33,36, 39 and42 were accomplished by the Stevens rearrangement of the N-methylquarternary salts 32, 35, 38 and 41 catalyzed by
dimsyl sodium in dimethyl sulfoxide. N-Methylation of spirobenzylisoquinolines 33, 36, 39 and 42 with methiodideafforded N,N-dimethylspirobenzylisoquinolinium iodides 34, 37, 40 and 43. Eight spirobenzylisoquinoline analogues were evaluated with the isolatedheart preparation from rats to determine the chronotropic and inotropiceffects.The results indicated that tertiary
spirobenzylisoquinoline analogues 36 and42 have equal effects in positive
inotropic and negative
chronotropic activi-ties with JKL1067 33 in cardiac tissues. Compound 39 showeda stronger intropiceffect and a weaker chronotropic effect than that of JKL1067 (33).
Howevernone of the quarternary spirobenzylisoquinoline ana-logues was active incardiac preparations.
