8-(1-benzylpiperidin-4-yl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 8-(1-benzylpiperidin-4-yl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione
• 英文别名: 8-(1-benzylpiperidin-4-yl)-1,3-dimethyl-7,9-dihydro-6H-purino[7,8-a]pyrazine-2,4-dione
• 化学式: C₂₂H₂₈N₆O₂
• 分子量: 408.503
• InChiKey: AAMNASYCNXHMJG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  64.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  7-(2-bromoethyl)-8-(hydroxymethyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione 在 三溴化磷 、 N,N-二异丙基乙胺 作用下， 以 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 8-(1-benzylpiperidin-4-yl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione
  参考文献：
  名称：

  8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors

  摘要：

  Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A(2A) adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A(1) ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A(1) and A(2A)ARs at similar concentrations representing dual A(1)/A(2A) antagonists with high selectivity versus the other AR subtypes. Among the best dual A(1)/A(2A)AR antagonists were 8-(3-(4-chlorophenyl)propy1)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-flpurine-2,4(1H,3H)-dione (41,K-i human A(1): 65.5 nM, A(2A): 230 nM; K-1 rat A(1): 352 nM, A(2A): 316 nM) and 1,3-dimethy1-84(2(thiophen-2-yl)thiazol-4-y1)methyl)-6,7,8,9-tetrahydropyrazino[2,1-fjpurine-2,4(1H,3H)-dione (57, K-i human A(1): 642 nM, A(2A): 203 nM; K-i rat A(1): 166 nM, A(2A): 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple -target inhibition: (R)-1,3-dimethy1-8-(2,1,3,4-tetrahydronaphthalen-1-y1)-6,7,8,9-tetrahydropyrazino[2,1-Apurine-2,4(1H,3H)-dione (49) was about equipotent at A(1) and A(2A)ARs and at MAO-B (K-i human A(1): 393 nM, human A(2A): 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.09.003

文献信息

• 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors
  作者：Andreas Brunschweiger、Pierre Koch、Miriam Schlenk、Muhammad Rafehi、Hamid Radjainia、Petra Küppers、Sonja Hinz、Felipe Pineda、Michael Wiese、Jörg Hockemeyer、Jag Heer、Frédéric Denonne、Christa E. Müller

  DOI：10.1016/j.bmc.2016.09.003

  日期：2016.11

  Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A(2A) adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A(1) ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A(1) and A(2A)ARs at similar concentrations representing dual A(1)/A(2A) antagonists with high selectivity versus the other AR subtypes. Among the best dual A(1)/A(2A)AR antagonists were 8-(3-(4-chlorophenyl)propy1)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-flpurine-2,4(1H,3H)-dione (41,K-i human A(1): 65.5 nM, A(2A): 230 nM; K-1 rat A(1): 352 nM, A(2A): 316 nM) and 1,3-dimethy1-84(2(thiophen-2-yl)thiazol-4-y1)methyl)-6,7,8,9-tetrahydropyrazino[2,1-fjpurine-2,4(1H,3H)-dione (57, K-i human A(1): 642 nM, A(2A): 203 nM; K-i rat A(1): 166 nM, A(2A): 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple -target inhibition: (R)-1,3-dimethy1-8-(2,1,3,4-tetrahydronaphthalen-1-y1)-6,7,8,9-tetrahydropyrazino[2,1-Apurine-2,4(1H,3H)-dione (49) was about equipotent at A(1) and A(2A)ARs and at MAO-B (K-i human A(1): 393 nM, human A(2A): 595 nM, IC50 human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach. (C) 2016 Elsevier Ltd. All rights reserved.