4-(piperazin-1-yl)phenol dihydrochloride

• 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-(piperazin-1-yl)phenol dihydrochloride
• 英文别名: 1-(4-Hydroxyphenyl)piperazine hydrochloride；4-piperazin-1-ylphenol;hydrochloride
• 化学式: C₁₀H₁₄N₂O*2ClH
• 分子量: 251.156
• InChiKey: HOQZYXZHPXPKCX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.22
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  35.5
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(piperazin-1-yl)phenol dihydrochloride 在 lithium hydroxide monohydrate 、 水 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium iodide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 (E)-(2-((4-(4-hydroxyphenyl)piperazin-1-yl)methyl)-3-phenylacryloyl)leucine
  参考文献：
  名称：

  具有肉桂基的阿片样物质受体调节剂

  摘要：

  为了获得选择性和有效的阿片样物质受体配体，我们合成了alvimopan的脱氢衍生物，并发现了化合物（28f），它是一种选择性但中等亲和力的MOR拮抗剂，比alvimopan（1）弱。我们用芳基哌嗪取代了芳基哌啶单元，从而获得了1-（α-羧肉桂基）-4-芳基哌嗪，如13h，令我们惊讶的是它没有MOR或DOR活性，但却是具有中等亲和力的KOR激动剂。相反，文献报道的芳基哌嗪4和5的文献实例是泛阿片受体拮抗剂，而6是MOR激动剂。两种化合物（13l和11b）在甩尾试验中显示出镇痛反应，该反应被降冰片碱（norBNI）预处理所阻断。在10种1-（α-羧基肉桂基）-4-芳基哌啶中，化合物28g和其他5种是特异性MOR拮抗剂。有趣的是，发现该系列化合物26b比纳洛酮更有效，但比1弱。对接研究解释了上述哌嗪和哌啶的不同活性。

  DOI：

  10.1021/acs.jmedchem.7b00643
• 作为产物：
  描述：

  1-乙酰基-4-(4-羟基苯基)哌嗪 在 盐酸 、 水 作用下， 反应 3.0h， 生成 4-(piperazin-1-yl)phenol dihydrochloride
  参考文献：
  名称：

  苯磺酰哌嗪系列抗克氏锥虫的合成、设计及构效关系

  摘要：

  开始了针对克氏锥虫的新型苯磺酰基哌嗪系列的早期命中至先导优化过程。进行了合成、设计、生物学评价和 SAR 研究，并确定了具有良好效力水平 (IC 50 ∼ 5 μM)、选择性 (>50) 和有希望的预测 ADMET 特征的化合物，作为进一步开发治疗药物的候选者南美锥虫病。

  DOI：

  10.1002/cmdc.202200211

文献信息

• Hit-to-lead optimization of a pyrazinylpiperazine series against Leishmania infantum and Leishmania braziliensis
  作者：Thibault Joseph William Jacques Dit Lapierre、Mariza Gabriela Faleiro de Moura Lodi Cruz、Nícolas Peterson Ferreira Brito、Daniela de Melo Resende、Felipe de Oliveira Souza、Eduardo Jorge Pilau、Meryck Felipe Brito da Silva、Bruno Junior Neves、Silvane Maria Fonseca Murta、Celso de Oliveira Rezende Júnior

  DOI：10.1016/j.ejmech.2023.115445

  日期：2023.8

  An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series

  在针对命中的苯甲酰片段进行广泛的 SAR 后，针对L. infantum和L. braziliensis对新型吡嗪基哌嗪系列进行了早期命中至先导优化( 4 )。删除( 4 ) 的间位-Cl导致获得对位羟基衍生物 ( 12 )，SAR 的大多数单取代衍生物的设计均基于此。该系列的进一步优化，涉及双取代的苯甲酰基片段和 ( 12 )的羟基取代基，允许获得总共 15 种抗利什曼原虫效力增强的化合物 (IC 50 < 10 μM)，其中九个在低微摩尔范围内显示活性 (IC 50  < 5 μM)。该优化最终确定了邻位、间位二羟基衍生物 ( 46 ) 作为该系列的早期先导化合物（IC 50 ( L. infantum ) = 2.8 μM，IC 50 ( L. braziliensis ) = 0.2 μM）。对一些选定的化合物对其他锥虫寄生虫的额外评估表明，该系列对利什曼原虫寄生虫具有选择性，并且计算机ADMET
• An efficient scale up process for synthesis of N-arylpiperazines
  作者：Lokesh Ravilla、N. Venkata Subba Naidu、Kuppuswamy Nagarajan

  DOI：10.1016/j.tetlet.2015.06.003

  日期：2015.7

  An efficient protocol for the synthesis of various substituted phenylpiperazines was developed using sulfolane as solvent. The protocol was clean, high yielding and products were obtained in high purities (>= 99%). It was also fast and convenient, as the final products were precipitated as hydrochloride salts and could be obtained by filtration. Sulfolane, an aprotic, dipolar, high boiling and recoverable solvent was used as a substitute for common organic solvents. (C) 2015 Elsevier Ltd. All rights reserved.
• Indolebutylamines as Selective 5-HT_1A Agonists
  作者：Timo Heinrich、Henning Böttcher、Gerd D. Bartoszyk、Hartmut E. Greiner、Christoph A. Seyfried、Christoph van Amsterdam

  DOI：10.1021/jm040792y

  日期：2004.9.1

  A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT1A agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT1A receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT1A affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D-2 binding and increased selectivity for the 5-HT1A receptor. Agonistic 5-HT1A receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-4-[4-(4-Carbamoylphenyl)piperazin-1-yl}butyl}-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT1A receptor agonist [GTPgammaS, ED50 = 4.7 nM] with nanomolar 5-HT1A affinity [IC50 = 0.9 nM] and selectivity [D-2, IC50 > 850 nM]. 3-4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl}-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT1A agonists known [5-HT1A, IC50 = 0.09 nM; D-2, IC50 = 140 nM].