4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-fluorobutan-1-amine | 1301178-79-9

• 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-(2,3-dichlorophenyl)piperazin-1-yl]-3-fluorobutan-1-amine
• CAS: 1301178-79-9
• 化学式: C₁₄H₂₀Cl₂FN₃
• 分子量: 320.237
• InChiKey: COIGHUIQJZKIAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  32.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-fluorobutan-1-amine 在 sodium tetrahydroborate 、 三乙酰氧基硼氢化钠 作用下， 以 甲醇 、 水 、 1,2-二氯乙烷 为溶剂， 反应 24.5h， 生成 N-((9H-fluoren-2-yl)methyl)-4-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-3-fluoro-N-methylbutan-1-amine
  参考文献：
  名称：

  N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity

  摘要：

  N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, > 1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by > 100-fold (e.g., D3R K-i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.

  DOI：

  10.1021/jm200288r
• 作为产物：
  描述：

  1-(2,3-二氯苯基)哌嗪 在 二乙胺基三氟化硫 、 肼 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 15.0h， 生成 4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-fluorobutan-1-amine
  参考文献：
  名称：

  N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity

  摘要：

  N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, > 1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by > 100-fold (e.g., D3R K-i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.

  DOI：

  10.1021/jm200288r

文献信息

• [EN] PHENYL CARBAMATES AND THEIR USE AS INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME AND MODULATORS OF THE D3 DOPAMINE RECEPTOR (D3DR)<br/>[FR] PHENYL CARBAMATES ET LEUR UTILISATION COMME INHIBITEURS DE L'ENZYME HYDROLASE D'AMIDES D'ACIDES GRAS (FAAH) ET MODULATEURS DU RÉCEPTEUR D3 DE LA DOPAMINE (D3DR)
  申请人：FOND ISTITUTO ITALIANO DI TECNOLOGIA

  公开号：WO2015007615A1

  公开（公告）日：2015-01-22

  The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof wherein Ar', R1, R2, R3, R4, X, Y are as defined in the description of invention, as multi-target directed ligands (MTDLs) that are at the same time inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR), their methods of preparation, formulations and therapeutic applications thereof.

  该发明提供了式（I）的化合物或其药用可接受的盐，其中Ar'，R1，R2，R3，R4，X，Y如发明描述中所定义，作为多靶点定向配体（MTDLs），同时是脂肪酸酰胺水解酶（FAAH）酶的抑制剂和D3多巴胺受体（D3DR）的调节剂，以及它们的制备方法、配方和治疗应用。
• Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders
  作者：Alessandro Bonifazi、Amy H. Newman、Thomas M. Keck、Silvia Gervasoni、Giulio Vistoli、Fabio Del Bello、Gianfabio Giorgioni、Pegi Pavletić、Wilma Quaglia、Alessandro Piergentili

  DOI：10.1021/acschemneuro.1c00368

  日期：2021.10.6

  multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, respectively, which displayed potent D2R antagonism, 5-HT1AR and D4R agonism, as well as potent D3R partial agonism. They also behaved as low-potency 5-HT2AR antagonists and 5-HT2CR partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents

  在寻找靶向多巴胺 D 3受体 (D 3 R) 的新型双位化合物时，N -(2,3-二氯苯基)哌嗪核（主要药效团）已与 6,6- 或 5,5-二苯基连接-1,4-二恶烷-2-甲酰胺或 1,4-苯并二恶烷-2-甲酰胺支架（二级药效团）由未取代或 3-F-/3-OH-取代的丁基链构成。这种支架杂交策略导致发现了可能对中枢神经系统疾病有用的有效的 D 3 R 选择性或多靶标配体。特别地，6,6-二苯基-1,4-二恶烷衍生物3显示出D 3R 优先分布，而 5,5-二苯基-1,4-二恶烷和 1,4-苯二恶烷衍生物6和9分别显示出有效的 D 2 R 拮抗作用，5-HT 的多靶点行为1A R 和 D 4 R 激动，以及有效的 D 3 R 部分激动。它们还表现为低效 5-HT 2A R 拮抗剂和 5-HT 2C R 部分激动剂。这样的概况可能是发现新型抗精神病药物的一个有希望的起点。
• PHENYL CARBAMATES AND THEIR USE AS INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME AND MODULATORS OF THE D3 DOPAMINE RECEPTOR (D3DR)
  申请人：FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA

  公开号：US20160194296A1

  公开（公告）日：2016-07-07

  The invention provides compounds of Formula (I) or pharmaceutically acceptable salts thereof wherein Ar′, R 1 , R 2 , R 3 , R 4 , X, Y are as defined in the description of invention, as multi-target directed ligands (MTDLs) that are at the same time inhibitors of the fatty acid amide hydrolase (FAAH) enzyme and modulators of the D3 dopamine receptor (D3DR), their methods of preparation, formulations and therapeutic applications thereof.

  本发明提供了化合物I或其药学上可接受的盐，其中Ar′、R1、R2、R3、R4、X、Y的定义如本发明描述中所述，作为多靶点定向配体（MTDLs），同时作为脂肪酸酰胺水解酶（FAAH）酶的抑制剂和D3多巴胺受体（D3DR）的调节剂，以及它们的制备方法、配方和治疗应用。
• US9828352B2
  申请人：——

  公开号：US9828352B2

  公开（公告）日：2017-11-28
• <i>N</i>-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity
  作者：Ashwini K. Banala、Benjamin A. Levy、Sameer S. Khatri、Cheryse A. Furman、Rebecca A. Roof、Yogesh Mishra、Suzy A. Griffin、David R. Sibley、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm200288r

  日期：2011.5.26

  N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, > 1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by > 100-fold (e.g., D3R K-i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.