N-(3-chlorophenyl)-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | 1338789-23-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: N-(3-chlorophenyl)-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: N-(3-chlorophenyl)-6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine；N-(3-chlorophenyl)-6-methylsulfanyl-1-(2-phenylethyl)pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1338789-23-3
• 化学式: C₂₀H₁₈ClN₅S
• 分子量: 395.915
• InChiKey: YQKKZNSKOPPFHY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(3-chlorophenyl)-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 在 10 wt% Pd(OH)2 on carbon 、 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以67%的产率得到N-(3-chlorophenyl)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  探索特权吡唑并[3,4- d ]嘧啶支架周围的化学空间：寻求新型的T315I突变型Abl的变构抑制剂

  摘要：

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。

  DOI：

  10.1021/co500004e
• 作为产物：
  描述：

  苯乙肼 在 N,N-二甲基甲酰胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 、 水 、 甲苯 为溶剂， 反应 58.17h， 生成 N-(3-chlorophenyl)-6-(methylthio)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells

  摘要：

  Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for cSrc. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC50 of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.07.079

文献信息

• Prodrugs of Pyrazolo[3,4-<i>d</i>]pyrimidines: From Library Synthesis to Evaluation as Potential Anticancer Agents in an Orthotopic Glioblastoma Model
  作者：Giulia Vignaroli、Giulia Iovenitti、Claudio Zamperini、Federica Coniglio、Pierpaolo Calandro、Alessio Molinari、Anna Lucia Fallacara、Andrea Sartucci、Alessia Calgani、David Colecchia、Andrea Mancini、Claudio Festuccia、Elena Dreassi、Massimo Valoti、Francesca Musumeci、Mario Chiariello、Adriano Angelucci、Maurizio Botta、Silvia Schenone

  DOI：10.1021/acs.jmedchem.7b00637

  日期：2017.7.27

  Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a−8a and 9a−e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME

  吡唑并[3,4- d ]嘧啶是有效的蛋白激酶抑制剂，具有有希望的抗肿瘤活性，但水溶性较差，因此值得进一步优化。在这里，我们提出了一锅两步程序，用于合成一组具有较高水溶性和增强的药代动力学和治疗特性的吡唑并[3,4- d ]嘧啶前药（1a - 8a和9a - e）。ADME研究表明，最有前途的前药具有更好的水溶性，在人和鼠血清中具有良好的水解作用，并且相对于母体药物而言，其跨细胞膜的能力增强，这说明了它们在体外24小时的性能更好对人胶质母细胞瘤U87细胞系的细胞毒性。最后，还对体内的4–4a药物/前药进行了评估，揭示了前药具有良好疗效的有利的药代动力学特征。事实证明，前药方法的应用是提高母体药物水溶性的成功策略，对它们的生物学功效也产生了积极影响。
• COMPOUNDS AND USES THEREOF
  申请人：LEAD DISCOVERY SIENA S.R.L.

  公开号：US20180186796A1

  公开（公告）日：2018-07-05

  The present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivatives of formula I and IV able to target the Src family kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine kinase and uses and method of preparation thereof. In particular, the compounds of the invention are for use in the treatment and/or prevention of cancer, such as neuroblastoma (NB) or glioblastoma multiforme (GBM) or for use in the treatment and/or prevention of neurodegenerative diseases such as taupathies.
• Exploring the Chemical Space around the Privileged Pyrazolo[3,4-<i>d</i>]pyrimidine Scaffold: Toward Novel Allosteric Inhibitors of T315I-Mutated Abl
  作者：Giulia Vignaroli、Martina Mencarelli、Deborah Sementa、Emmanuele Crespan、Miroslava Kissova、Giovanni Maga、Silvia Schenone、Marco Radi、Maurizio Botta

  DOI：10.1021/co500004e

  日期：2014.4.14

  screening of this “privileged scaffold”-based compound collection, validated the use of a diversity-oriented approach in a field characteristically explored by target-oriented synthesis. In fact, several compounds showed high activity against the selected kinases (i.e., Src, Abl wt, and T315I mutated-form), furthermore and interestingly a new compound has emerged as an allosteric inhibitor of the T315I mutated-form

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。
• Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells
  作者：Marco Radi、Chiara Brullo、Emmanuele Crespan、Cristina Tintori、Francesca Musumeci、Mariangela Biava、Silvia Schenone、Elena Dreassi、Claudio Zamperini、Giovanni Maga、Dafne Pagano、Adriano Angelucci、Mauro Bologna、Maurizio Botta

  DOI：10.1016/j.bmcl.2011.07.079

  日期：2011.10

  Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for cSrc. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC50 of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment. (C) 2011 Elsevier Ltd. All rights reserved.