2-(3-fluoro-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-isoindoline-1,3-dione | 1301178-77-7

• 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: 2-(3-fluoro-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-isoindoline-1,3-dione
• 英文别名: 2-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-fluorobutyl]isoindoline-1,3-dione；2-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]-3-fluorobutyl]isoindole-1,3-dione
• CAS: 1301178-77-7
• 化学式: C₂₂H₂₂Cl₂FN₃O₂
• 分子量: 450.34
• InChiKey: ADPBLMNKJHDION-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 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：
  43.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(3-fluoro-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-isoindoline-1,3-dione 在 sodium hydroxide 、 肼 作用下， 以 乙醇 、 氯仿 、 水 为溶剂， 反应 6.0h， 生成 N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-fluorobutyl)-9H-fluorene-2-carboxamide
  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：

  N-(3,4-环氧基丁基)邻苯二甲酰亚胺 在 三乙胺 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 72.0h， 生成 2-(3-fluoro-4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-isoindoline-1,3-dione
  参考文献：
  名称：

  [EN] PHENYL CARBAMATES AND THEIR USE AS INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE (FAAH) ENZYME AND MODULATORS OF THE D3 DOPAMINE RECEPTOR (D3DR)
  [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)

  摘要：

  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。

  公开号：

  WO2015007615A1

文献信息

• 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。
• Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66
  作者：Vivek Kumar、Ashwini K. Banala、Erick G. Garcia、Jianjing Cao、Thomas M. Keck、Alessandro Bonifazi、Jeffery R. Deschamps、Amy Hauck Newman

  DOI：10.1021/ml500006v

  日期：2014.6.12

  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).
• US9828352B2
  申请人：——

  公开号：US9828352B2

  公开（公告）日：2017-11-28