2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-1,2,4,5-tetrahydro-1H-benzisoquinolin-1-one | 135729-57-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-1,2,4,5-tetrahydro-1H-benzisoquinolin-1-one
• 英文别名: (R)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one；2-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one；2-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-5,6-dihydro-4H-benzo[de]isoquinolin-1-one
• CAS: 135729-57-6
• 化学式: C₁₉H₂₂N₂O
• 分子量: 294.396
• InChiKey: DIDFYSQVOPVZQB-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  23.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-1,2,4,5-tetrahydro-1H-benzisoquinolin-1-one 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 360.0h， 生成 (3aS)-2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-2,3,3a,4,5,6-hexahydro-1H-benzisoquinolin-1-one 、 (3aR)-2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-2,3,3a,4,5,6-hexahydro-1H-benzisoquinolin-1-one
  参考文献：
  名称：

  2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

  摘要：

  Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pK(i) values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pK(i) 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 mug/kg iv), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

  DOI：

  10.1021/jm00070a008
• 作为产物：
  描述：

  2-(R)-1-Aza-bicyclo[2.2.2]oct-3-yl-3-hydroxy-2,3,3a,4,5,6-hexahydro-benzo[de]isoquinolin-1-one 在 盐酸 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 生成 2-<(R)-1-azabicyclo<2.2.2>oct-3-yl>-1,2,4,5-tetrahydro-1H-benzisoquinolin-1-one
  参考文献：
  名称：

  2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists

  摘要：

  Several series of N-(quinuclidin-3-yl)aryl and heteroaryl-fused pyridones were synthesized and evaluated for 5-HT3 receptor affinity. In the heteroaryl series, 2-(quinuclidin-3-yl)tetrahydropyrido-[4,3-b]indol-1-one (8a) and the 4,5-alkano-bridged analogues (14 and 15) displayed high 5-HT3 receptor affinity with pK(i) values > 9. The (3S)-quinuclidinyl isomers had > 10 fold higher affinity than the (3R)-isomers. In a series of 2-quinuclidin-3-yl)isoquinolin-1-ones, derivatives substituted with small lipophilic groups (25b-e) and with 4,5-alkano-bridges (34-36) also displayed high affinity. In particular, the hexahydro-1H-benz[de]isoquinolinone (S,S)-37 was the highest affinity 5-HT3 receptor ligand prepared (pK(i) 10.4). A number of the high affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the B-J reflex in the anesthetized rat. Again, (S,S)-37 was the most active agent tested (ID50 0.02 mug/kg iv), and this compound was also potent in blocking cisplatin-induced emesis in both the ferret and the dog. Computer modeling studies were performed, and previously reported 5-HT3 receptor antagonist pharmacophore models were refined to include a key lipophilic binding domain.

  DOI：

  10.1021/jm00070a008

文献信息

• New tricyclic compounds
  申请人：SYNTEX (U.S.A.) INC.

  公开号：EP0430190B1

  公开（公告）日：1995-07-05
• US5202333A
  申请人：——

  公开号：US5202333A

  公开（公告）日：1993-04-13