5-amino-1-benzyl-3-phenyl-1H-pyrazole-4-carbonitrile | 196504-90-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-amino-1-benzyl-3-phenyl-1H-pyrazole-4-carbonitrile
• 英文别名: 5-amino-1-benzyl-3-phenylpyrazole-4-carbonitrile；5-amino-1-benzyl-4-cyano-3-phenyl-1H-pyrazole
• CAS: 196504-90-2
• 化学式: C₁₇H₁₄N₄
• 分子量: 274.325
• InChiKey: WKRJANVMIXALQQ-UHFFFAOYSA-N

物化性质

• 沸点：
  552.4±50.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  67.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-amino-1-benzyl-3-phenyl-1H-pyrazole-4-carbonitrile 在 三氯氧磷 作用下， 以 水 为溶剂， 反应 19.0h， 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
• 作为产物：
  描述：

  二硫代苯甲酸甲酯 在 sodium methylate 作用下， 反应 21.25h， 生成 5-amino-1-benzyl-3-phenyl-1H-pyrazole-4-carbonitrile
  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

• Regioselective Synthesis of Highly Functionalized Pyrazoles from <i>N</i>-Tosylhydrazones
  作者：Qian Zhang、Meng Tang

  DOI：10.1021/acs.orglett.9b00561

  日期：2019.3.15

  A regioselective synthesis of highly functionalized pyrazoles from N-tosylhydrazones was developed. The reaction was general for a wide range of substrates and demonstrated excellent tolerance to a variety of substituents, and the method has been successfully applied to the formal synthesis of ibrutinib.

  开发了从N-甲苯磺酰腙区域选择性合成高功能化吡唑的方法。该反应对多种底物具有通用性，对多种取代基表现出优异的耐受性，该方法已成功应用于依鲁替尼的正式合成。
• Highly specific modulators of GTPases for target validation
  申请人：IRM, LLC

  公开号：US20040241706A1

  公开（公告）日：2004-12-02

  This invention provides methods and compositions related to modified GTPase sequences and GTPase modulators.

  本发明提供了与改性GTP酶序列和GTP酶调节剂有关的方法和组合物。
• Late‐Stage Diversification of Pyrazoles as Antileishmanial Agents
  作者：Tobias Winge、Ben Perry、An Matheeussen、Guy Caljon、Bernhard Wünsch

  DOI：10.1002/cmdc.202400028

  日期：2024.4.16

  N‐Pyrazolylcarboxamides and N‐pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late‐stage diversification of 3‐bromopyrazoles 10 A/B and 14 A by Pd‐catalyzed Sonogashira and Suzuki‐Miyaura cross coupling reactions. The electron‐withdrawing properties of the cyano moiety in 4‐position of the pyrazole ring limited the acylation of the primary amino moiety in 5‐position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3‐position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4‐position and containing the large 4‐benzylpiperidinoo moiety exhibited a modest antileishmanial (IC₅₀=19 μM) and antitrypanosomal activity (IC₅₀=7.9 μM)). However, its considerable toxicity against the PMM and MRC‐5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2‐ to 4‐fold.

  摘要N-吡唑羧酰胺和 N-吡唑脲类是开发新型抗利什曼病药物的有前途的先导化合物。在此，我们报告了通过钯催化的 Sonogashira 和 Suzuki-Miyaura 交叉偶联反应对 3-溴吡唑 10 A/B 和 14 A 进行后期多样化的情况。吡唑环 4 位氰基的吸电子特性限制了 5 位伯氨基的酰化。我们制备了一大批在 3 位具有不同芳基和炔基取代基的吡唑，并记录了它们的抗利什曼病和抗锥虫活性。脲 38 在 4-位上缺少撤电子氰基，但含有大的 4-苄基哌啶基，具有适度的抗利什曼病活性（IC50=19 μM）和抗锥虫活性（IC50=7.9 μM）。然而，它对 PMM 和 MRC-5 细胞的毒性相当大，这表明它的选择性很低，也就是说，在所需的抗寄生虫活性与 2-4 倍的非预期细胞毒性之间存在着很小的差距。
• [EN] HIGHLY SPECIFIC MODULATORS OF GTPASES FOR TARGET VALIDATION<br/>[FR] MODULATEURS HAUTEMENT SPECIFIQUES DE GTPASES POUR VALIDATION DE CIBLES
  申请人：IRM LLC

  公开号：WO2004024082A2

  公开（公告）日：2004-03-25

  This invention provides methods and compositions related to modified GTPase sequences and GTPase modulators.