4-[4-(6'-Chloro-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-butyl]-4-aza-tricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione | 110944-39-3

• 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-[4-(6'-Chloro-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-butyl]-4-aza-tricyclo[5.2.1.0^2,6]dec-8-ene-3,5-dione
• 英文别名: 4-[4-[4-(6-Chloropyrazin-2-yl)piperazin-1-yl]butyl]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione
• CAS: 110944-39-3
• 化学式: C₂₁H₂₆ClN₅O₂
• 分子量: 415.923
• InChiKey: ZNFZAYDULOCKNB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  69.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-降冰片烯-2,3-二甲酰亚胺 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-[4-(6'-Chloro-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-butyl]-4-aza-tricyclo[5.2.1.0^2,6]dec-8-ene-3,5-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

• 2-Oxa-bicyclo[2.2.1]heptanderivate und diese Verbindungen enthaltende Arzneimittel
  申请人：SCHERING AKTIENGESELLSCHAFT

  公开号：EP0358290A1

  公开（公告）日：1990-03-14

  Die Erfindung betrifft 2-Oxa-bicyclo[2.2.1]heptanderivate der For­mel I, sowie deren Enantiomere, worin z.B. A -(CH₂)n-, (E)-oder(Z)-CH=CH-, -C≡C, -O- oder -S-, B Wasserstoff, C₁-C₁₀-Alkyl, -OR², Halogen, -C≡N, -N₃, -COOR³, R¹ Sauerstoff oder eine -CH₂-Gruppe, R⁴ -COOR⁵ Z -(CH₂)p-, (E)-CH=CH-, -C≡C-, W eine Direktbindung, eine freie oder funktionell abgewandelte Hy­droxymethylengruppe oder eine freie oder funktionell abgewandelte wobei die OH-Gruppe jeweils α- oder β-ständig sein kann D eine Direktbindung, eine gesättigte Alkylengruppe mit 1 - 5 C-Atomen, eine verzweigte ge­sättigte oder eine geradkettige oder verzweigte ungesättigte Alkylen­gruppe mit 2 - 5 C-Atomen. E eine Direktbindung, -C≡C- oder -CH=CR⁷- R⁸ Wasserstoff, C₁-C₁₀-Alkyl, C₃-C₁₀-Cycloalkyl, gegebenenfalls sub­stituiertes C₆-C₁₂-Aryl oder einen 5- oder 6-gliedrigen hetero­cyclischen Rest und falls R⁵ Wasserstoff bedeutet, deren Salze mit physiologisch verträg­lichen Basen bedeuten, sowie die α-, β- oder γ-Cyclodextrinclathrate, sowie mit die Liposomen verkapselten Verbindungen der Formel I, Ver­fahren zu ihrer Herstellung und diese Verbindungen enthaltende Arz­neimittel.

  本发明涉及式 I 的 2-氧杂双环[2.2.1]庚烷衍生物、 及其对映体、 其中，例如 A -(CH₂)n-, (E)- 或 (Z)-CH=CH-, -C≡C, -O- 或 -S-、 B 氢、C₁-C₁₀-烷基、-OR²、卤素、-C≡N、-N₃、-COOR³、 R¹氧或-CH₂基团、 R⁴ -COOR⁵ Z -(CH₂)p-, (E)-CH=CH-, -C≡C-、 W 是直接键、游离或功能修饰的羟甲基或游离或功能修饰的羟甲基。 其中 OH 基团可以是 α- 或 β-末端，在每种情况下 D 为直接键、 具有 1 - 5 个 C 原子的饱和亚烷基、具有 2 - 5 个 C 原子的支链饱和亚烷基或直链或支链不饱和亚烷基。 E 是直接键、-C≡C- 或 -CH=CR⁷- R⁸ 是氢、C₁-C₁₀-烷基、C₃-C₁₀-环烷基、任选取代的 C₆-C₁₂-芳基或 5 或 6 元杂环基，且 如果 R⁵ 是氢，它们与生理学上可耐受的碱的盐，以及 α-、β- 或 γ-环糊精凝块，和包裹有脂质体的式 I 化合物，它们的制备过程和含有这些化合物的药物。
• 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.