3-bromo-5-(piperazin-1-yl)pyrazolo[1.5-a]pyrimidine | 1454558-22-5

• 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: 3-bromo-5-(piperazin-1-yl)pyrazolo[1.5-a]pyrimidine
• 英文别名: 3-Bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine；3-bromo-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine
• CAS: 1454558-22-5
• 化学式: C₁₀H₁₂BrN₅
• 分子量: 282.143
• InChiKey: MFINLMYILJJJND-UHFFFAOYSA-N

物化性质

• 密度：
  1.80±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  45.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-bromo-5-(piperazin-1-yl)pyrazolo[1.5-a]pyrimidine 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (S)-2-amino-1-(4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one
  参考文献：
  名称：

  [EN] PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
  [FR] COMPOSÉS À BASE DE PYRAZOLO[1,5-A] PYRIMIDINE, COMPOSITIONS LES COMPRENANT ET UTILISATIONS DE CEUX-CI

  摘要：

  基于吡唑并[1,5-a]嘧啶的化合物的公式如下：其中R1、R2和R3在此处被定义。还公开了包含这些化合物的组合物以及它们的使用方法，用于治疗、管理和/或预防由适配器相关激酶1活性介导的疾病和紊乱。

  公开号：

  WO2013134228A1
• 作为产物：
  描述：

  5-氯吡唑并[1,5-a]嘧啶 在 N-溴代丁二酰亚胺(NBS) 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 5.0h， 生成 3-bromo-5-(piperazin-1-yl)pyrazolo[1.5-a]pyrimidine
  参考文献：
  名称：

  [EN] INHIBITORS OF ADAPTER ASSOCIATED KINASE 1, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
  [FR] INHIBITEURS DE LA KINASE 1 ASSOCIÉE À UN ADAPTATEUR, COMPOSITIONS LES COMPORTANT ET LEURS PROCÉDÉS D'UTILISATION

  摘要：

  揭示了与适配器相关激酶1（AAK1）抑制剂3-甲氧基氧杂环戊烷-3-基-4-(3-(2-甲氧基吡啶-3-基)吡唑并[1,5-a]嘧啶-5-基)哌嗪-1-羧酸酯相关的药物：以及其药用盐和固体形式。还揭示了包含该化合物的组合物以及使用它们治疗、管理和/或预防由AAK1活性介导的疾病和疾病的方法。

  公开号：

  WO2015142714A1

文献信息

• Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
  作者：W. Kostich、B. D. Hamman、Y.-W. Li、S. Naidu、K. Dandapani、J. Feng、A. Easton、C. Bourin、K. Baker、J. Allen、K. Savelieva、J. V. Louis、M. Dokania、S. Elavazhagan、P. Vattikundala、V. Sharma、M. L. Das、G. Shankar、A. Kumar、V. K. Holenarsipur、M. Gulianello、T. Molski、J. M. Brown、M. Lewis、Y. Huang、Y. Lu、R. Pieschl、K. OMalley、J. Lippy、A. Nouraldeen、T. H. Lanthorn、G. Ye、A. Wilson、A. Balakrishnan、R. Denton、J. E. Grace、K. A. Lentz、K. S. Santone、Y. Bi、A. Main、J. Swaffield、K. Carson、S. Mandlekar、R. K. Vikramadithyan、S. J. Nara、C. Dzierba、J. Bronson、J. E. Macor、R. Zaczek、R. Westphal、L. Kiss、L. Bristow、C. M. Conway、B. Zambrowicz、C. F. Albright

  DOI：10.1124/jpet.116.235333

  日期：2016.8.1

  To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

  为了找出治疗神经性疼痛的新靶点，我们在急性和持续性疼痛行为试验中测试了 3097 个小鼠基因敲除品系。筛选出的其中一个品系含有转接蛋白-2相关激酶1（AAK1）基因的无效等位基因，在急性疼痛试验（热板、福尔马林一期）中反应正常，但在福尔马林二期中对持续性疼痛的反应明显减弱。AAK1 基因敲除小鼠在接受脊神经结扎（SNL）的 Chung 程序后也不会出现触觉过敏。基于这些发现，人们发现了 AAK1 的强效小分子抑制剂。对小鼠的研究表明，其中一种抑制剂 LP-935509 可降低小鼠对二期福尔马林的疼痛反应，并能逆转小鼠在脊神经结扎术后完全建立的疼痛行为。进一步的研究表明，这种抑制剂还能降低大鼠慢性收缩损伤（CCI）模型和大鼠链脲佐菌素糖尿病周围神经病变模型中的诱发疼痛反应。通过使用非脑穿透性 AAK1 抑制剂和局部给药 AAK1 抑制剂，发现与抗神经病变作用相关的 AAK1 库位于脊髓。与这些结果一致的是，AAK1抑制剂剂量依赖性地减少了CCI引起的脊髓自发神经活动的增加，并阻断了反复电刺激爪子引起的绞痛的发展。研究人员使用α2肾上腺素能受体和阿片受体抑制剂进一步研究了AAK1抗痛觉的机制。这些研究表明，α2肾上腺素能受体抑制剂（而非阿片受体抑制剂）不仅能阻止AAK1抑制剂在行为实验中的抗神经病理性作用，还能阻止AAK1抑制剂诱导的大鼠CCI模型中脊髓神经活动的减少。因此，AAK1抑制剂是一种新型的神经病理性疼痛治疗方法，它在动物模型中的活性与α2肾上腺素能信号传导（行为学和电生理学）有机理联系，而α2肾上腺素能信号传导是人类已知的抗痛觉途径。
• PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
  申请人：BI Yingzhi

  公开号：US20130253194A1

  公开（公告）日：2013-09-26

  Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R 1 , R 2 and R 3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

  本发明揭示了基于吡唑并[1,5-a]嘧啶的化合物，其化学式为：其中R1、R2和R3在本文中有定义。本发明还揭示了包含该化合物的组合物以及使用该化合物治疗、管理和/或预防适配器关联激酶1活性介导的疾病和障碍的方法。
• Pyrazolo[1,5-a]pyrimidine-based compounds, compositions comprising them, and methods of their use
  申请人：Bi Yingzhi

  公开号：US08946415B2

  公开（公告）日：2015-02-03

  Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by adaptor associated kinase 1 activity are also disclosed.

  公开了基于Pyrazolo[1,5-a]pyrimidine的化合物的公式：其中R1，R2和R3在此定义。还公开了包含这些化合物的组合物以及使用它们治疗，管理和/或预防由适配器相关激酶1活性介导的疾病和紊乱的方法。
• INHIBITORS OF ADAPTER ASSOCIATED KINASE 1, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
  申请人：Lexicon Pharmaceuticals, Inc.

  公开号：EP3119783A1

  公开（公告）日：2017-01-25
• US8946415B2
  申请人：——

  公开号：US8946415B2

  公开（公告）日：2015-02-03