N-<1-azabicyclo<2.2.2>octan-3(S)-yl>-8-chloro-2(R),6(S)-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin-10-carboxamide | 141979-78-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: N-<1-azabicyclo<2.2.2>octan-3(S)-yl>-8-chloro-2(R),6(S)-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin-10-carboxamide
• 英文别名: (1S,9R)-N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-4-chloro-8-oxatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-6-carboxamide
• CAS: 141979-78-4
• 化学式: C₂₀H₂₅ClN₂O₂
• 分子量: 360.884
• InChiKey: ZIAMDRHEQRSMSY-JCKWVBRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-chloro-cis-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid 在 氯化亚砜 、 硫酸 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 1.75h， 生成 N-<1-azabicyclo<2.2.2>octan-3(S)-yl>-8-chloro-2(R),6(S)-methano-3,4,5,6-tetrahydro-2H-1-benzoxocin-10-carboxamide
  参考文献：
  名称：

  Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides

  摘要：

  Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (K(i) = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1-mu-g/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4-mu-g/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.

  DOI：

  10.1021/jm00083a015

文献信息

• Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides
  作者：Raymond D. Youssefyeh、H. F. Campbell、J. E. Airey、S. Klein、M. Schnapper、M. Powers、R. Woodward、W. Rodriguez、S. Golec

  DOI：10.1021/jm00083a015

  日期：1992.3

  Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (K(i) = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1-mu-g/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4-mu-g/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.