R-PG648 | 1092953-74-6

• 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: R-PG648
• 英文别名: (R)-N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide；N-[(3R)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-3-hydroxybutyl]-1H-indole-2-carboxamide
• CAS: 1092953-74-6
• 化学式: C₂₃H₂₆Cl₂N₄O₂
• 分子量: 461.391
• InChiKey: NABHHUMHJIHHIX-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  71.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (R)-2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)isoindoline-1,3-dione 在 1,1′-carbonyldiimidazole 、 肼 作用下， 以 乙醇 为溶剂， 反应 6.0h， 生成 R-PG648
  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

文献信息

• 4-PHENYLPIPERAZINE DERIVATIVES WITH FUNCTIONALIZED LINKERS AS DOPAMINE D3 RECEPTOR SELECTIVE LIGANDS AND METHODS OF USE
  申请人：The United States of America, as Represented by the Secretary, Department of Health and Human Serv

  公开号：US20140296249A1

  公开（公告）日：2014-10-02

  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, OAc, and cis or trans-cyclopropyl 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由可卡因和其他滥用物质引起的加强和寻药效应。通过在4-苯基哌嗪配体的丁酰胺连接链中引入功能基团，可以实现改善的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、OAc和顺式或反式环丙基基团等功能基团。总的来说，这些修饰在D3受体上耐受性良好，并且在D2和D4受体上实现了高选择性。
• US8748608B2
  申请人：——

  公开号：US8748608B2

  公开（公告）日：2014-06-10
• 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).