2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione | 944344-35-8

• 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: 2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione
• 英文别名: 2-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-hydroxybutyl]isoindoline-1,3-dione；2-(4-(4-(2,3-dichlorophenyl)-piperazin-1-yl)-3-hydroxybutyl)-isoindoline-1,3-dione；2-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-hydroxybutyl]isoindole-1,3-dione
• CAS: 944344-35-8
• 化学式: C₂₂H₂₃Cl₂N₃O₃
• 分子量: 448.349
• InChiKey: LLBNIHMRUBRMLU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione 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 3-(4-(2,3-dichlorophenyl)piperazin-1-yl)-4-fluorobutan-1-amine
  参考文献：
  名称：

  Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  摘要：

  The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin- I -yl) -3-hydroxybutyl)1H-indole-2carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutylproduct (8).

  DOI：

  10.1021/ml500006v
• 作为产物：
  描述：

  potassium phtalimide 以 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 0.66h， 生成 2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione
  参考文献：
  名称：

  N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）丁基）芳基羧酰胺的杂环类似物，具有功能化的连接链，作为新的多巴胺D3受体配体：潜在的药物滥用治疗剂。

  摘要：

  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

  DOI：

  10.1021/jm0704200

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。
• 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。
• 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：US08748608B2

  公开（公告）日：2014-06-10

  Dopamine D3 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 D3 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 D3 receptors and achieve high selectivity over D2 and D4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知能够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连接链中引入功能基团，可以获得改良的D3受体亲和力和选择性，以及水溶性。披露了一系列连接链衍生物，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受体上很容易耐受，并实现了对D2和D4受体的高选择性。
• 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。
• High Affinity Dopamine D₃ Receptor (D₃R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D₃R Knockout Mice
  作者：Comfort A. Boateng、Oluyomi M. Bakare、Jia Zhan、Ashwini K. Banala、Caitlin Burzynski、Elie Pommier、Thomas M. Keck、Prashant Donthamsetti、Jonathan A. Javitch、Rana Rais、Barbara S. Slusher、Zheng-Xiong Xi、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.5b00776

  日期：2015.8.13

  The dopamine D-3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (K-i = 0.12 nM) and 32 (K-i = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing selfadministration of heroin in wild-type but not D3R knockout mice.