Aporphines. 9. Synthesis and Pharmacological Evaluation of (±) 9, 10-Dihydroxyaporphine [(±)-Isoapomorphine], (±)-,(-)-, and (±)-1,2-Dihydroxyaporphine, and (+)-1, 2, 9, 10 - Tetrahydroxyaporphine.
Aporphines. 9. Synthesis and Pharmacological Evaluation of (±) 9, 10-Dihydroxyaporphine [(±)-Isoapomorphine], (±)-,(-)-, and (±)-1,2-Dihydroxyaporphine, and (+)-1, 2, 9, 10 - Tetrahydroxyaporphine.
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9. (±) 9, 10-二羟基阿朴啡[(±)-异扑吗啡]、(±)-、(-)-、(±)-1,2-二羟基阿朴啡和(+)的合成和药理学评价-1,2,9,10-四羟基阿朴啡。
DOI：
10.1021/jm00269a602
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发表时间：
1973
影响因子：
7.3
通讯作者：
D. Teiger
中科院分区：
文献类型：
--
作者：
J. Neumeyer;M. McCarthy;S. Battista;F. Rosenberg;D. Teiger
描述了标题化合物2-4的合成和初步药理学评价，并与(-)-荷叶碱和(-)-阿扑吗啡[(-)-!]进行比较。用于合成(±)-2的方法涉及对先前用于合成阿扑吗啡和阿扑可待因的Reissert烷基化-Pschorr环化路线的修改。研究了两种可供选择的反应顺序（9a-10a-13a 13b-* 13c 或 9a-* 9b-10b-13c）来制备 Pschorr 前体 13c。 (±)-6、荷叶碱和海藻氨酸的O-去甲基化是用Ac2O中的57% HI完成的，得到所需的羟基阿朴啡2-4。药理学结果表明，催吐和中枢神经系统活性主要在于10和11位被酚羟基取代的阿朴啡。将羟基转移至位置 9、10 或位置 1.2 会显着降低药理效力。同样，与阿扑吗啡相比，1、2、9、10位取代的四羟基阿朴啡也显着降低了活性。在我们之前的研究中，我们描述了在氮原子和10位和11位上功能取代的五种外消旋阿朴啡的成功全合成。该程序适用于非天然鸦片生物碱（即吗啡和可待因）衍生的阿朴啡的合成。 (-)-阿扑吗啡和(±)-阿扑吗啡及其相应的JV-丙基同系物的初步药理学评价
The synthesis and preliminary pharmacological evaluation of the title compounds2-4 are described and compared with those of (-)-nuciferine and (-)-apomorphine [(-)-!]. The method used for the synthesis of (±)-2 involved modifications of the Reissert alkylation-Pschorr cyclization route previously employed for the synthesis of apomorphine and apocodeine. Two alternative sequences of reactions (9a— 10a—13a 13b—* 13c or 9a—* 9b—10b—13c) were investigated for the preparation of the Pschorr precursor 13c. O-Demethylation of (±)-6, nuciferine, and glaucine was accomplished with 57% HI in Ac20 to givethe desired hydroxyaporphines 2-4. The pharmacological results indicatedthat emetic and CNS activity resides principally in those aporphines that are substituted with phenolic hydroxyl groups in the 10 and 11 positions. Shifting the hydroxyl groups to positions 9, 10 or to positions 1.2 markedly reduced pharmacological potency. Similarly, the tetrahydroxyaporphine substituted in the 1, 2, 9, 10 positions also markedly reduced the activity in comparison with apomorphine.In our previous study1 we described the successful total synthesis of five racemic aporphines functionally substituted on the nitrogen atom and on the 10 and 11 posi-tions. The procedure was applicable to the synthesis of aporphines not derivable from the naturally occurring opium alkaloids (ie, morphine and codeine). Preliminary pharmacological evaluation of (-)-apomorphine and (±)-apomorphine and their corresponding JV-propyl homologs