N4-(2-carboxyphenyl)-N2-(4-ethoxycarbonylphenyl)-5,6-dichloropyrimidine-2,4-diamine hydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N4-(2-carboxyphenyl)-N2-(4-ethoxycarbonylphenyl)-5,6-dichloropyrimidine-2,4-diamine hydrochloride
• 英文别名: 2-[[5,6-Dichloro-2-(4-ethoxycarbonylanilino)pyrimidin-4-yl]amino]benzoic acid;hydrochloride；2-[[5,6-dichloro-2-(4-ethoxycarbonylanilino)pyrimidin-4-yl]amino]benzoic acid;hydrochloride
• 化学式: C₂₀H₁₆Cl₂N₄O₄*(x)ClH
• 分子量: 483.7
• InChiKey: KMEGHXNPWFAPJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.57
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  113
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N4-(2-carboxyphenyl)-N2-(4-ethoxycarbonylphenyl)-5,6-dichloropyrimidine-2,4-diamine hydrochloride 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以32%的产率得到N⁴-(2-carboxyphenyl)-N²-(4-carboxyphenyl)-5,6-dichloropyrimidine-2,4-diamine hydrochloride
  参考文献：
  名称：

  Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors

  摘要：

  The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 +/- 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.

  DOI：

  10.1021/jm300334d
• 作为产物：
  描述：

  邻氨基苯甲酸 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 96.5h， 生成 N4-(2-carboxyphenyl)-N2-(4-ethoxycarbonylphenyl)-5,6-dichloropyrimidine-2,4-diamine hydrochloride
  参考文献：
  名称：

  Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors

  摘要：

  The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 +/- 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.

  DOI：

  10.1021/jm300334d

文献信息

• [EN] AURORA KINASE INHIBITORS AND METHODS OF MAKING AND USING THEREOF<br/>[FR] INHIBITEURS DE KINASE AURORA ET PROCÉDÉS POUR LES FABRIQUER ET LES UTILISER
  申请人：H LEE MOFFITT CANCER CT AND RES INST

  公开号：WO2012135641A3

  公开（公告）日：2012-12-27
• Development of <i>o</i>-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors
  作者：Harshani R. Lawrence、Mathew P. Martin、Yunting Luo、Roberta Pireddu、Hua Yang、Harsukh Gevariya、Sevil Ozcan、Jin-Yi Zhu、Robert Kendig、Mercedes Rodriguez、Roy Elias、Jin Q. Cheng、Saïd M. Sebti、Ernst Schonbrunn、Nicholas J. Lawrence

  DOI：10.1021/jm300334d

  日期：2012.9.13

  The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 +/- 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.