4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine | 1062174-25-7

• 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: 4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine
• 英文别名: 1-(1-benzylpiperidin-4-yl)-6-chloro-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidine；1-(1-Benzyl-piperidin-4-yl)-6-chloro-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidine；4-[1-(1-benzylpiperidin-4-yl)-6-chloropyrazolo[3,4-d]pyrimidin-4-yl]morpholine
• CAS: 1062174-25-7
• 化学式: C₂₁H₂₅ClN₆O
• 分子量: 412.922
• InChiKey: LCBRXPQEPPIAAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  59.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine 在 1-氯乙基氯甲酸酯 、 potassium carbonate 作用下， 以 DCE 为溶剂， 反应 5.5h， 以100%的产率得到6-chloro-4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride
  参考文献：
  名称：

  雷帕霉素哺乳动物靶标的ATP竞争性抑制剂：高强度和选择性吡唑并嘧啶的设计和合成

  摘要：

  雷帕霉素（mTOR）的哺乳动物靶标是生长，存活和代谢的主要调节剂，是经过验证的癌症治疗靶标。雷帕霉素及其类似物（mTOR的变构抑制剂）仅部分抑制一种mTOR蛋白复合物。描述了具有增强抗癌功​​效潜力的ATP竞争性mTOR整体抑制剂。鉴定并完善了导致效价和选择性的结构特征，从而在肿瘤异种移植模型中产生了具有体内功效的化合物。

  DOI：

  10.1021/jm900851f
• 作为产物：
  描述：

  4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine hydrochloride 在 sodium hydroxide 、 水 作用下， 生成 4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine
  参考文献：
  名称：

  PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS

  摘要：

  本发明涉及吡唑吡嘧啶类似物，制备吡唑吡嘧啶类似物的方法，包含吡唑吡嘧啶类似物的组合物，以及治疗mTOR相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。该发明还涉及治疗PI3K相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。

  公开号：

  US20080234262A1

文献信息

• Discovery of 4-Morpholino-6-aryl-1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidines as Highly Potent and Selective ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin (mTOR): Optimization of the 6-Aryl Substituent
  作者：Jeroen C. Verheijen、David J. Richard、Kevin Curran、Joshua Kaplan、Mark Lefever、Pawel Nowak、David J. Malwitz、Natasja Brooijmans、Lourdes Toral-Barza、Wei-Guo Zhang、Judy Lucas、Irwin Hollander、Semiramis Ayral-Kaloustian、Tarek S. Mansour、Ker Yu、Arie Zask

  DOI：10.1021/jm9013828

  日期：2009.12.24

  6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC50 against mTOR and greater than 1000-fold selectivity over PI3K-α. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds

  设计和合成了一系列4-吗啉代-6-芳基-1 H-吡唑并[3,4- d ]嘧啶，它们是雷帕霉素（mTOR）哺乳动物靶标的有效和选择性抑制剂。优化6-芳基取代基导致发现带有6-脲基苯基的抑制剂，这是第一个报道的具有亚纳摩尔抑制浓度的mTOR活性位点抑制剂。本文提供的数据表明，6-芳基脲基苯基取代基可产生有效的mTOR和磷脂酰肌醇3-激酶α（PI3K-α）混合抑制剂，而6-烷基脲基苯基附肢则具有高度选择性的mTOR抑制剂。6-烷基脲基苯基与1-氨基甲酰基哌啶取代的组合产生具有亚纳摩尔级IC 50的化合物对mTOR的抗性和对PI3K-α的选择性大于1000倍。另外，基于结构的药物设计导致制备了几种6-芳基脲基苯基-1H-吡唑并[3，4- d ]嘧啶，其在芳基脲基部分的4-位被水溶性基团取代。这些化合物将有效的mTOR抑制（IC 50 <1 nM）与细胞增殖试验（IC 50 <1 nM）中前所未有的活性结合在一起。
• Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase
  作者：Pawel Nowak、Derek C. Cole、Natasja Brooijmans、Matthew G. Bursavich、Kevin J. Curran、John W. Ellingboe、James J. Gibbons、Irwin Hollander、YongBo Hu、Joshua Kaplan、David J. Malwitz、Lourdes Toral-Barza、Jeroen C. Verheijen、Arie Zask、Wei-Guo Zhang、Ker Yu

  DOI：10.1021/jm9012642

  日期：2009.11.26

  The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3K gamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3K alpha IC50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORCl (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.
• Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-α: Hit to lead studies
  作者：Adam M. Gilbert、Pawel Nowak、Natasja Brooijmans、Matthew G. Bursavich、Christoph Dehnhardt、Efren Delos Santos、Larry R. Feldberg、Irwin Hollander、Stephen Kim、Sabrina Lombardi、Kaapjoo Park、Aranapakam M. Venkatesan、Robert Mallon

  DOI：10.1016/j.bmcl.2009.11.051

  日期：2010.1

  Series of purine and pyrazolo[3,4-d] pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110 alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110 gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells. (C) 2009 Elsevier Ltd. All rights reserved.
• [EN] PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS<br/>[FR] ANALOGUES DE PYRAZOLOPYRIMIDINE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE KINASE MTOR ET KINASE PI3
  申请人：WYETH CORP

  公开号：WO2008115974A2

  公开（公告）日：2008-09-25

  [EN] The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K -related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.
  [FR] La présente invention concerne des analogues de pyrazolopyrimidine, des procédés de préparation d'analogues de pyrazolopyrimidine et des compositions comprenant un analogue de pyrazolopyrimidine et des procédés de traitement de troubles liés au mTOR comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine. L'invention concerne également le traitement de troubles liés au PI3K comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine.