4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]cyclohexylamine | 847860-17-7

• 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-[4-(3-trifluoromethylphenyl)piperazin-1-yl]cyclohexylamine
• 英文别名: 4-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]cyclohexan-1-amine
• CAS: 847860-17-7
• 化学式: C₁₇H₂₄F₃N₃
• 分子量: 327.393
• InChiKey: IHMNKDCXZCCTLA-UHFFFAOYSA-N

物化性质

• 沸点：
  409.6±45.0 °C(Predicted)
• 密度：
  1.195±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  32.5
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]cyclohexylamine 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 氯仿 、 水 为溶剂， 反应 9.0h， 生成 trans-1-{4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]cyclohexyl}pyrrolidin-2-one
  参考文献：
  名称：

  1-酰亚胺/酰胺基取代的4-（4-芳基哌嗪-1-基）环己烷衍生物的结构-本征活性关系研究；具有抗焦虑活性的新型有效5-HT1A受体药物。

  摘要：

  在柔性长链芳基哌嗪的结构中引入1,4-二取代的环己烷环导致线性约束的有效5-羟色胺（5-HT）（1A）配体。为了追踪该组中的结构-本征活性关系，合成了具有不同环酰亚胺/酰胺末端的一系列新的1-取代的4-（4-芳基哌嗪-1-基）环己烷衍生物，以及它们的柔性四亚甲基类似物，并药理学评估的5-HT（1A）受体。体外结合实验表明，所有化合物均为有效的5-HT（1A）受体试剂（K（i）= 1.9-74 nM）。另外测试的某些衍生物还显示出对α（1）-肾上腺素能受体（K（i）= 2.9-101 nM）和5-HT（7）受体的高亲和力。体内功能检查发现，刚性配体的o-OCH（3）基团在芳基部分和对端末端的环状酰亚胺系统表现得像突触后5-HT（1A）受体拮抗剂。另一方面，未取代的，m-Cl或m-CF（3）取代的衍生物以及在末端片段中具有环状酰胺基的衍生物表现出激动或部分激动活性。测试的四种衍生物中的三种，即

  DOI：

  10.1016/j.bmc.2005.09.060
• 作为产物：
  描述：

  4-[1-(3-trifluoromethylphenyl)piperazin-4-yl]cyclohexanone oxime 在 platinum(IV) oxide 氢气 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 6.0h， 以78%的产率得到4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]cyclohexylamine
  参考文献：
  名称：

  1-Aryl-4-(4-succinimidobutyl)piperazines and their conformationally constrained analogues: synthesis, binding to serotonin (5-HT1A, 5-HT2A, 5-HT7), α1-adrenergic, and dopaminergic D2 receptors, and in vivo 5-HT1A functional characteristics

  摘要：

  Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D-1, and D-2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19-25 were found to be highly active 5-HT1A receptor ligands (K-i = 4-44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7) or controlled by substituents in the aromatic ring (alpha(1)), or influenced by both those structural modifications (5-HT2A), or very low (D-2, K-i = 5.3-31 mu M). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.Several in vivo models were used to asses functional activity of 19-25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki = 4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested. (c) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.12.041

文献信息

• Conformational Restriction in Novel NAN-190 and MP3022 Analogs and Their 5-HT1A Receptor Activity
  作者：Maria H. Paluchowska、Ryszard Bugno、Sijka Charakchieva-Minol、Andrzej J. Bojarski、Ewa Tatarczyńska、Ewa Chojnacka-Wójcik

  DOI：10.1002/ardp.200600009

  日期：2006.9

  postsynaptic 5‐HT1A receptors, respectively. Rigidification of MP3022 and its 5,6‐dimethyl analog structures resulted in cis and trans stereoisomers 6b–9b with a 1‐ and 2‐substituted benzotriazole moiety. In both series, in vitro experiments showed that the cis configurations of the compounds were better tolerated by 5‐HT1A receptor sites than the trans ones. The conformational analysis revealed various

  新合成的 NAN-190 类似物在芳基哌嗪部分含有 m-Cl 和 m-CF3 取代基及其构象限制对应物显示出非常高的 5-HT1A 受体亲和力。在 LLR 测试中，柔性化合物 4a 和 5a 分别显示出部分激动剂和激动剂的特征。测试结构中的构象限制导致观察到的体内效应发生变化；化合物 4b 和 5b 分别被归类为非活性剂和突触后 5-HT1A 受体拮抗剂。MP3022 及其 5,6-二甲基类似物结构的刚性化产生具有 1- 和 2- 取代苯并三唑部分的顺式和反式立体异构体 6b – 9b。在这两个系列中，体外实验表明，化合物的顺式构型比反式构型对5-HT1A受体位点的耐受性更好。构象分析揭示了可以通过这些结构中的末端苯并三唑片段探索的各种空间区域。与之前描述的 cis-6b 一样，新配体 cis-7b 显示出突触后 5-HT1A 受体激动剂的特征，而 cis-8b 则被表征为这些受体位点的部
• Novel, flexible, and conformationally defined analogs of gepirone: synthesis and 5-HT1A, 5-HT2A, and D2 receptor activity
  作者：Maria H. Paluchowska、Ryszard Bugno、Andrzej J. Bojarski、Sijka Charakchieva-Minol、Beata Duszyńska、Ewa Tatarczyńska、Aleksandra Kłodzińska、Katarzyna Stachowicz、Ewa Chojnacka-Wójcik

  DOI：10.1016/j.bmc.2004.11.019

  日期：2005.2

  Novel, flexible arylpiperazine gepirone analogs (1a-3a) with a mixed 5-HT1A/5-HT2A receptor profile, low D2 receptor affinity, and agonistic (2a) or partial agonistic (1a, 3a) activity toward 5-HT1A receptor sites were synthesized. Their conformationally restricted counterparts (1b-3b) were selective 5-HT1A ligands (over 5-HT2A and D2 receptors), which turned out to be agonists (2b, 3b), or partial

  具有混合的5-HT1A / 5-HT2A受体特征，低D2受体亲和力和对5-HT1A受体位点的激动（2a）或部分激动（1a，3a）活性的新型灵活的芳基哌嗪吉哌隆类似物（1a-3a）是合成的。其构象受限的对应物（1b-3b）是选择性的5-HT1A配体（超过5-HT2A和D2受体），结果证明是5-HT1A受体的激动剂（2b，3b）或部分激动剂（1b）。