4-(4-(2-methoxy)phenylpiperazin-1-yl)-trans-but-2-en-1-amine | 144009-85-8

• 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-(2-methoxy)phenylpiperazin-1-yl)-trans-but-2-en-1-amine
• 英文别名: 4-(4-(2-methoxyphenyl)piperazin-1-yl)-trans-but-2-en-1-amine；4-(4-(2-methoxyphenyl)piperazin-1-yl)-trans-but-2-enylamine；4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine；trans-4-[4-(2-methyloxyphenyl)piperazinyl]-2-buten-1-yl-amine；E-1-amino-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-butene；(E)-4-[4-(2-methoxyphenyl)piperazin-1-yl]but-2-en-1-amine
• CAS: 144009-85-8
• 化学式: C₁₅H₂₃N₃O
• 分子量: 261.367
• InChiKey: OBKXILSZNIKPPO-SNAWJCMRSA-N

物化性质

• 沸点：
  417.3±45.0 °C(Predicted)
• 密度：
  1.068±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  41.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-(2-methoxy)phenylpiperazin-1-yl)-trans-but-2-en-1-amine 、 苯并噻吩-2-羧酸 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以51%的产率得到benzo[b]thiophene-2-carboxylic acid (4-[4-(2-methoxyphenyl)piperazin-1-yl]-trans-butenyl)amide
  参考文献：
  名称：

  N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists

  摘要：

  In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K-i = 1 nM) for D3 and similar to 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.

  DOI：

  10.1021/jm900095y
• 作为产物：
  描述：

  2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)-trans-but-2-enyl)isoindoline-1,3-dione 在 肼 作用下， 以 乙醇 为溶剂， 反应 5.0h， 以42%的产率得到4-(4-(2-methoxy)phenylpiperazin-1-yl)-trans-but-2-en-1-amine
  参考文献：
  名称：

  Synthesis and Pharmacological Evaluation of Fluorine-Containing D₃ Dopamine Receptor Ligands

  摘要：

  A series of fluorine-containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized, and their affinities for human dopamine D-2, D-3, and D-4 receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e, and 21e, which bind with high affinity at D-3 (K-i = 0.17-5 nM) and moderate to high selectivity for D-3 VS D-2 receptors (ranging from similar to 25-to 163-fold). These compounds were also evaluated for intrinsic activity at D-2 and D3 receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D-2 VS D-3 receptors. These compounds may be useful for behavioral pharmacology studies on the role of D-2-like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D-3 receptor (K-i = 0.17 nM for D-3, 163-fold selectivity for D-3 VS D-2 receptors), represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D-3 receptor expression.

  DOI：

  10.1021/jm101323b

文献信息

• Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands
  作者：Zhude Tu、Shihong Li、Aixiao Li、Michelle Taylor、David Ho、Maninder Malik、Robert R. Luedtke、Robert H. Mach

  DOI：10.1039/c3md00098b

  日期：——

  A series of substituted 1H-indolyl carboxylic acid amides that contain a N-(2-methoxyphenyl)piperazine or N-(2-fluoroethoxy)piperazine group were synthesized and their affinities for human dopamine D2, D3, and D4 receptors were determined. Two of these compounds, 14a and 14b, displayed high binding affinity at D3 (Ki = 0.18 and 0.4 nM, respectively), and selectivity for D3vs. D2 receptors (87-fold and 60-fold, respectively). These two compounds had low binding affinity at D4 receptors and σ receptor sites. The intrinsic activity of these compounds at D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay; both 14a and 14b were found to be partial agonists. Furthermore, for compound 14a, the log D value of 2.85 suggested it has suitable lipophilicity for crossing the blood–brain-barrier.

  合成了一系列取代的1H-吲哚羧酸酰胺，这些化合物包含N-(2-甲氧基苯基)哌嗪或N-(2-氟乙氧基)哌嗪基团，并确定了它们对人类多巴胺D2、D3和D4受体的亲和力。其中两个化合物，14a和14b，在D3受体上显示出高结合亲和力（Ki分别为0.18和0.4 nM），并且在D3与D2受体之间具有选择性（分别为87倍和60倍）。这两个化合物在D4受体和σ受体位点的结合亲和力较低。通过使用依赖于福斯可林的腺苷酸酰化酶抑制测定，确定了这些化合物在D2和D3受体上的内在活性；发现14a和14b都是部分激动剂。此外，对于化合物14a，其log D值为2.85，表明其具有适合穿越血脑屏障的脂溶性。
• Heterocyclic Analogues of <i>N</i>-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with Functionalized Linking Chains as Novel Dopamine D3 Receptor Ligands:  Potential Substance Abuse Therapeutic Agents
  作者：Peter Grundt、Katherine M. Prevatt、Jianjing Cao、Michelle Taylor、Christina Z. Floresca、Ji-Kyung Choi、Bruce G. Jenkins、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm0704200

  日期：2007.8.1

  Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylben zamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding

  多巴胺D3受体拮抗剂和部分激动剂已显示出可卡因和其他滥用药物引起的药物寻找作用。化合物6 [PG01037，（N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）-反式-丁-2-烯基）-4-吡啶-2-基苯甲酰胺）]及相关类似物目前正在对成瘾性动物模型进行评估。在这些研究中，已观察到体外结合亲和力，体内占有率和行为效能之间的差异。这项研究的目的是检查（1）丁基酰胺连接链上的2-吡啶基苯基部分的修饰和（2）与2-芴基酰胺或2-吡啶基苯基酰胺和2-甲氧基系统偶联的丁基酰胺连接链上的羟基，乙酰基和环丙基取代基-或2,3-二氯取代的苯基哌嗪来测量对结合亲和力，D2 / D3选择性的影响，亲脂性和功能。通常，如在竞争结合测定中所测量的，这些修饰在人多巴胺D3（hD3）受体（Ki = 1-5 nM）上具有良好的耐受性。几种类似物对多巴胺D3的选择性比D2和D4受体高100倍以上。此外，尽管所有带有烯烃连接
• 4-PHENYLPIPERAZINE DERIVATIVES WITH FUNCTIONALIZED LINKERS AS DOPAMINE D3 RECEPTOR SELECTIVE LIGANDS AND METHODS OF USE
  申请人：Newman Amy Hauck

  公开号：US20100267737A1

  公开（公告）日：2010-10-21

  Dopamine D 3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D 3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D 3 receptors and achieve high selectivity over D 2 and D 4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知可以调节可卡因和其他滥用物质引起的强化和寻药效应。通过在4-苯基哌嗪类配体的丁酰胺链中引入功能基团，可以获得改进的D3受体亲和力和选择性，以及水溶性。公开了一系列链连接衍生物，其中引入了OH或OAc基团等功能基团。一般来说，这些修饰在D3受体上很好地耐受，并实现了对D2和D4受体的高选择性。
• 1-piperazinyl-2-butenes and -2-butynes
  申请人：Wittekind; Raymond R.

  公开号：US05130315A1

  公开（公告）日：1992-07-14

  Novel 1-piperazinyl-2-butenes and -2-butynes, intermediates and processes for the preparation thereof, and methods of treating psychoses utilizing compounds or compositions thereof are disclosed.

  本发明公开了1-哌嗪基-2-丁烯和2-丁炔及其中间体和制备方法，以及利用这些化合物或组合物治疗精神病的方法。
• Dopamine D3 receptor ligands and preparation and medical uses of the same
  申请人：Li Jin

  公开号：US08829001B2

  公开（公告）日：2014-09-09

  The present invention relates to a novel piperazine derivative represented by Formula I having an activity for regulating dopamine D3 receptor, stereoisomers thereof, pharmaceutically acceptable salts or solvates, and a pharmaceutical composition comprising the compound, a process for preparing the same, and use thereof in the prevention or treatment of a disease associated with central nervous system dysfunction, such as Parkinson's disease, schizophrenia, drug addiction and relapse, as well as kidney protection and immunoregulation, or as a tool for researching D3R function or diseases associated with D3R dysfunction.

  本发明涉及一种新的哌嗪衍生物，其化学式为I式，具有调节多巴胺D3受体的活性，其立体异构体，药学上可接受的盐或溶剂，以及包含该化合物的制药组合物，制备该化合物的方法，以及在预防或治疗与中枢神经系统功能障碍有关的疾病，如帕金森病、精神分裂症、药物成瘾和复发，以及肾脏保护和免疫调节方面的用途，或作为研究D3R功能或与D3R功能障碍相关疾病的工具。