4,4a,5,5a,6,6a-hexahydro-2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]4,6-ethenocycloprop[f]isoindole-1,3(2H,3AH)-dione | 114222-46-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4,4a,5,5a,6,6a-hexahydro-2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]4,6-ethenocycloprop[f]isoindole-1,3(2H,3AH)-dione
• 英文别名: 4-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione
• CAS: 114222-46-7
• 化学式: C₂₆H₃₃N₃O₃
• 分子量: 435.566
• InChiKey: YNJVCNKZQNAPMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  53.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1,3-dioxo-2H-4,6-etheno-1,3,3a,6a-tetrahydrocyclopropisoindole 在 sodium hydride 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4,4a,5,5a,6,6a-hexahydro-2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]4,6-ethenocycloprop[f]isoindole-1,3(2H,3AH)-dione
  参考文献：
  名称：

  Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies

  摘要：

  A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.

  DOI：

  10.1021/jm00402a023

文献信息

• US4892943A
  申请人：——

  公开号：US4892943A

  公开（公告）日：1990-01-09
• Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies
  作者：Magid Abou-Gharbia、Usha R. Patel、Michael B. Webb、John A. Moyer、Terrance H. Andree、Eric A. Muth

  DOI：10.1021/jm00402a023

  日期：1988.7

  A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.