(11bS)-1,6,7,11b-tetrahydro-9,10-dimethoxy-3-(2-methylpropyl)-4H-benzo[a]quinolizine | 1215167-80-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (11bS)-1,6,7,11b-tetrahydro-9,10-dimethoxy-3-(2-methylpropyl)-4H-benzo[a]quinolizine
• 英文别名: (11bS)-9,10-dimethoxy-3-(2-methylpropyl)-4,6,7,11b-tetrahydro-1H-benzo[a]quinolizine
• CAS: 1215167-80-8
• 化学式: C₁₉H₂₇NO₂
• 分子量: 301.429
• InChiKey: VHLATFMZPWYSEZ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (11bS)-1,6,7,11b-tetrahydro-9,10-dimethoxy-3-(2-methylpropyl)-4H-benzo[a]quinolizine 在 高氯酸 、 间氯过氧苯甲酸 作用下， 以 甲醇 为溶剂， 反应 38.0h， 生成 (8aR,9aS,10aS)-5,8,8a,9a,10,10a-hexahydro-2,3-dimethoxy-8a-(2-methylpropyl)-6H-benz[a]oxireno[g]quinolizine
  参考文献：
  名称：

  Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

  摘要：

  Tetrabenazine (TBZ) ((+/-)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (+/-)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (K-i = 4.47 nM) was 8000-fold more potent than ()-1 (K-i = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: K-i= 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.02.046
• 作为产物：
  描述：

  丁苯那嗪 在 乙醇 、 五氯化磷 、 左旋樟脑磺酸 、 L-Selectride 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 为溶剂， 反应 1.17h， 生成 (11bS)-1,6,7,11b-tetrahydro-9,10-dimethoxy-3-(2-methylpropyl)-4H-benzo[a]quinolizine
  参考文献：
  名称：

  Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

  摘要：

  Tetrabenazine (TBZ) ((+/-)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (+/-)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (K-i = 4.47 nM) was 8000-fold more potent than ()-1 (K-i = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: K-i= 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.02.046

文献信息

• [EN] DIHYDROTETRABENAZINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM<br/>[FR] DIHYDROTETRABENAZINES ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT
  申请人：CAMBRIDGE LAB LTD

  公开号：WO2005077946A1

  公开（公告）日：2005-08-25

  The invention provides novel isomers of dihydrotetrabenazine, individual enantiomers and mixtures thereof wherein the dihydrotetrabenazine is a 3,11 b-cis- dihydrotetrabenazine. Also provided are methods for the preparation of the novel isomers, pharmaceutical compositions containing them and their use in treating hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette's syndrome.

  该发明提供了二氢四甲基单胺的新异构体、单体对映体和混合物，其中二氢四甲基单胺是3,11 b-顺式-二氢四甲基单胺。还提供了制备新异构体的方法、含有它们的药物组合物以及它们在治疗高动力性运动障碍如亨廷顿病、半球动作障碍、老年舞蹈症、抽动症、迟发性运动障碍和抽动症候群中的用途。
• Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors
  作者：Zhangyu Yao、Xueying Wei、Xiaoming Wu、Jonathan L. Katz、Theresa Kopajtic、Nigel H. Greig、Hongbin Sun

  DOI：10.1016/j.ejmech.2011.02.046

  日期：2011.5

  Tetrabenazine (TBZ) ((+/-)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (+/-)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (K-i = 4.47 nM) was 8000-fold more potent than ()-1 (K-i = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: K-i= 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders. (C) 2011 Elsevier Masson SAS. All rights reserved.