| Summary: | 碩士 === 台北醫學院 === 藥學類 === 84 === 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.
JKL1067 ( 2,3-methylenedioxy-9,10-
dimethoxyspirobenzylisoquinoline )(33).a synthetic
spirobenzylisoquinoline, exhibited a positive inotropic
effectand negative chronotropic effect. Besides the posittive
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.
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