1-Benzyl-4-chloro-3-phenylpyrazolo[3,4-d]pyrimidine | 196505-06-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-Benzyl-4-chloro-3-phenylpyrazolo[3,4-d]pyrimidine
• CAS: 196505-06-3
• 化学式: C₁₈H₁₃ClN₄
• 分子量: 320.781
• InChiKey: SECCTPOQLMQLKF-UHFFFAOYSA-N

物化性质

• 沸点：
  528.6±50.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-Benzyl-4-chloro-3-phenylpyrazolo[3,4-d]pyrimidine 在 三氯化铝 作用下， 以 乙醇 、 苯 为溶剂， 反应 2.5h， 生成 N-(3-氯苯基)-3-苯基-2H-吡唑并[3,4-d]嘧啶-4-胺
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-d]pyrimidines

  摘要：

  In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, upsilon-Abl) and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 mu M, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 mu M. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.

  DOI：

  10.1021/jm970124v
• 作为产物：
  描述：

  二硫代苯甲酸甲酯 在 sodium methylate 、 三氯氧磷 作用下， 以 水 为溶剂， 反应 40.25h， 生成 1-Benzyl-4-chloro-3-phenylpyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-d]pyrimidines

  摘要：

  In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, upsilon-Abl) and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 mu M, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 mu M. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.

  DOI：

  10.1021/jm970124v

文献信息

• ANTI-INFLAMMATORY PYRAZOLOPYRIMIDINES
  申请人：Shokat Kevan M.

  公开号：US20090124638A1

  公开（公告）日：2009-05-14

  The present invention provides anti-inflammatory compounds useful in the treatment of diseases and conditions in which inflammation is involved in disease progression or the manifestation of symptoms of the disease or condition.
• Anti-Inflammatory Pyrazolopyrimndines
  申请人：Shokat Kevan M.

  公开号：US20110144134A1

  公开（公告）日：2011-06-16

  The present invention provides anti-inflammatory compounds useful in the treatment of diseases and conditions in which inflammation is involved in disease progression or the manifestation of symptoms of the disease or condition.
• US9512125B2
  申请人：——

  公开号：US9512125B2

  公开（公告）日：2016-12-06