3-(4-Amino-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]-pyrimidine hydrochloride

• 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: 3-(4-Amino-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]-pyrimidine hydrochloride
• 英文别名: 3-N-(4-aminophenyl)-4-N-(3-chlorophenyl)-2H-pyrazolo[3,4-d]pyrimidine-3,4-diamine;hydrochloride
• 化学式: C₁₇H₁₄ClN₇*ClH
• 分子量: 388.259
• InChiKey: RRWXNZYBSKSJGM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  105
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  特定基氨基甲酸脂酶 在 盐酸 、 甲醇 、 一水合肼 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 为溶剂， 反应 52.0h， 生成 3-(4-Amino-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]-pyrimidine hydrochloride
  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

• Pyrazole derivatives and processes for the preparation thereof
  申请人：Novartis AG

  公开号：US05981533A1

  公开（公告）日：1999-11-09

  4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula I ##STR1## wherein the symbols are as defined in claim 1, and intermediates for their manufacture are described. The compounds of formula I inhibit especially the tyrosine kinase activity of the receptor for epidermal growth factor and can be used, for example, in the case of epidermal hyperproliferation (psoriasis) and as anti-tumor agents.

  公式I的4-氨基-1H-吡唑并[3,4-d]嘧啶衍生物如下所示：其中符号如权利要求1中所定义，并描述了其制备的中间体。公式I的化合物特别抑制表皮生长因子受体的酪氨酸激酶活性，例如，在表皮过度增生（银屑病）和作为抗肿瘤剂中可以使用。
• PYRAZOLE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF
  申请人：Novartis AG

  公开号：EP0819129B1

  公开（公告）日：2000-08-02
• US5981533A
  申请人：——

  公开号：US5981533A

  公开（公告）日：1999-11-09
• Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-<i>d</i>]pyrimidines
  作者：Peter Traxler、Guido Bold、Joerg Frei、Marc Lang、Nicholas Lydon、Helmut Mett、Elisabeth Buchdunger、Thomas Meyer、Marcel Mueller、Pascal Furet

  DOI：10.1021/jm970124v

  日期：1997.10.1

  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.