(R)-2-[9-Isopropyl-6-(pyridin-2-ylamino)-9H-purin-2-ylamino]-butan-1-ol | 1404306-81-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (R)-2-[9-Isopropyl-6-(pyridin-2-ylamino)-9H-purin-2-ylamino]-butan-1-ol
• 英文别名: (2R)-2-[[9-propan-2-yl-6-(pyridin-2-ylamino)purin-2-yl]amino]butan-1-ol
• CAS: 1404306-81-5
• 化学式: C₁₇H₂₃N₇O
• 分子量: 341.416
• InChiKey: SZQLGGOIDGLQBH-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,6-二氯-9-异丙基-9h-嘌呤 在 palladium diacetate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三乙胺 作用下， 以 二甲基亚砜 、 甲苯 为溶剂， 反应 6.17h， 生成 (R)-2-[9-Isopropyl-6-(pyridin-2-ylamino)-9H-purin-2-ylamino]-butan-1-ol
  参考文献：
  名称：

  Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling

  摘要：

  Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 mu M on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.141

文献信息

• 2,6,9-Substituted purine derivatives and their use in the treatment of proliferative disorders
  申请人：Fischer Martin Peter

  公开号：US20050009846A1

  公开（公告）日：2005-01-13

  The present invention relates to compounds of formula I or a pharmaceutically acceptable salt thereof wherein R 2 is 2-hydroxymethylpyrrolidin- 1 -yl, or NHCH(R 4 )CH(R 3 )OH, wherein R 3 is hydrogen or methyl and R 4 is methyl, ethyl or isopropyl; R 6 is 3-nitrophenylamino, 3,4-dimethoxybenzylamino, 3-iodobenzyl-amino, pyrid-2-yl-methylamino, pyrid-4-yl-methylamino or indan-5-amino; R 9 is isopropyl or cyclopentanyl. In a further aspect, the invention relates to pharmaceutical compositions comprising said compounds, and the use thereof in treating antiproliferative disorders and or viral disorders.

  本发明涉及式I的化合物或其药学上可接受的盐，其中R2为2-羟甲基吡咯烷-1-基或NHCH（R4）CH（R3）OH，其中R3为氢或甲基，R4为甲基、乙基或异丙基；R6为3-硝基苯胺基、3,4-二甲氧基苯甲基氨基、3-碘苯甲基氨基、吡啶-2-基甲基氨基、吡啶-4-基甲基氨基或茚-5-基氨基；R9为异丙基或环戊基。在进一步方面，本发明涉及包括所述化合物的制药组合物及其在治疗抗增殖性疾病和/或病毒性疾病中的用途。
• 2,6,9-substituted purine derivatives and their use in the treatment of proliferative disorders
  申请人：Cyclacel Limited

  公开号：US07612079B2

  公开（公告）日：2009-11-03

  The present invention relates to compounds of formula I or a pharmaceutically acceptable salt thereof wherein R2 is 2-hydroxymethylpyrrolidin-1-yl, or NHCH(R4)CH(R3)OH, wherein R3 is hydrogen or methyl and R4 is methyl, ethyl or isopropyl; R6 is 3-nitrophenylamino, 3,4-dimethoxybenzylamino, 3-iodobenzyl-amino, pyrid-2-yl-methylamino, pyrid-4-yl-methylamino or indan-5-amino; R9 is isopropyl or cyclopentanyl. In a further aspect, the invention relates to pharmaceutical compositions comprising said compounds, and the use thereof in treating antiproliferative disorders and or viral disorders.

  本发明涉及式I的化合物或其药学上可接受的盐，其中： R2为2-羟甲基吡咯烷-1-基，或NHCH（R4）CH（R3）OH，其中R3为氢或甲基，R4为甲基、乙基或异丙基； R6为3-硝基苯胺基、3,4-二甲氧基苯甲氨基、3-碘苯甲氨基、吡啶-2-甲基氨基、吡啶-4-甲基氨基或茚-5-氨基； R9为异丙基或环戊基。 在另一个方面，本发明涉及包括所述化合物的制药组合物，以及在治疗抗增殖性疾病和/或病毒性疾病中使用它们的用途。
• 2,6,9-SUBSTITUTED PURINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：Cyclacel Limited

  公开号：EP1399446B1

  公开（公告）日：2005-08-03
• US7612079B2
  申请人：——

  公开号：US7612079B2

  公开（公告）日：2009-11-03
• Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling
  作者：Luc Demange、Fatma Nait Abdellah、Olivier Lozach、Yoan Ferandin、Nohad Gresh、Laurent Meijer、Hervé Galons

  DOI：10.1016/j.bmcl.2012.10.141

  日期：2013.1

  Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 mu M on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). (C) 2012 Elsevier Ltd. All rights reserved.