3-(2-Chloro-ethyl)-1-methyl-1-(4-m-tolylamino-quinazolin-6-yl)-urea | 454685-99-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 3-(2-Chloro-ethyl)-1-methyl-1-(4-m-tolylamino-quinazolin-6-yl)-urea
• 英文别名: 3-(2-Chloroethyl)-1-methyl-1-[4-(3-methylanilino)quinazolin-6-yl]urea
• CAS: 454685-99-5
• 化学式: C₁₉H₂₀ClN₅O
• 分子量: 369.854
• InChiKey: XRKQHEYLROMICO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(2-Chloro-ethyl)-1-methyl-1-(4-m-tolylamino-quinazolin-6-yl)-urea 在 nitrosonium tetrafluoroborate 、 溶剂黄146 作用下， 以 乙腈 为溶剂， 以50%的产率得到FD-137
  参考文献：
  名称：

  The Combi-Targeting Concept:  Synthesis of Stable Nitrosoureas Designed to Inhibit the Epidermal Growth Factor Receptor (EGFR)

  摘要：

  According to the "combi-targeting" concept, the EGFR tyrosine kinase ( TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds ( 3'-Cl and Br series) with small angles ( 0.5-3 degrees) were generally stronger EGFR TK inhibitors than those with large angles ( 18-21 degrees). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line ( Pearson r = 0.8). On the basis of stability ( t(1/2)), EGFR TK inhibitory potency ( IC50), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

  DOI：

  10.1021/jm0600390
• 作为产物：
  描述：

  2-氰基-4-硝基苯胺 在 palladium on activated charcoal 吡啶 、 lithium aluminium tetrahydride 、 五氯化磷 、 硫酸 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 异丙醇 为溶剂， 160.0 ℃ 、200.0 kPa 条件下， 反应 5.0h， 生成 3-(2-Chloro-ethyl)-1-methyl-1-(4-m-tolylamino-quinazolin-6-yl)-urea
  参考文献：
  名称：

  The Combi-Targeting Concept:  Synthesis of Stable Nitrosoureas Designed to Inhibit the Epidermal Growth Factor Receptor (EGFR)

  摘要：

  According to the "combi-targeting" concept, the EGFR tyrosine kinase ( TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds ( 3'-Cl and Br series) with small angles ( 0.5-3 degrees) were generally stronger EGFR TK inhibitors than those with large angles ( 18-21 degrees). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line ( Pearson r = 0.8). On the basis of stability ( t(1/2)), EGFR TK inhibitory potency ( IC50), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.

  DOI：

  10.1021/jm0600390

文献信息

• Combi-molecules having signal transduction inhibitory properties and dna damaging properties
  申请人：——

  公开号：US20040086907A1

  公开（公告）日：2004-05-06

  The present invention relates to a series of new chemical agents that demonstrate anti-tumor activity. More particularly, the present invention relates to molecules, referred to as “combi-molecules”, that combine two major mechanisms of anti-tumor action. A combi-molecule is capable of degrading to a ligand involved in cell signaling pathways and to an agent capable of damaging DNA. More specifically, the present invention relates to molecules capable of blocking epidermal growth factor receptor (EGFR) mediated signal transduction and capable of damaging DNA. The present invention also relates to a general method of synthesis of these combi-molecules.

  本发明涉及一系列新的化学药剂，具有抗肿瘤活性。更具体地说，本发明涉及分子，称为“组合分子”，它们结合了两种主要的抗肿瘤作用机制。组合分子能够降解为细胞信号通路中涉及的配体和能够损伤DNA的药剂。更具体地说，本发明涉及能够阻止表皮生长因子受体（EGFR）介导的信号转导并能够损伤DNA的分子。本发明还涉及这些组合分子的一般合成方法。
• COMBI-MOLECULES HAVING SIGNAL TRANSDUCTION INHIBITORY PROPERTIES AND DNA DAMAGING PROPERTIES
  申请人：McGill University

  公开号：EP1366027B1

  公开（公告）日：2006-09-20
• US7572798B2
  申请人：——

  公开号：US7572798B2

  公开（公告）日：2009-08-11
• [EN] COMBI-MOLECULES HAVING SIGNAL TRANSDUCTION INHIBITORY PROPERTIES AND DNA DAMAGING PROPERTIES<br/>[FR] COMBI-MOLECULES POSSEDANT DES PROPRIETES INHIBITRICES DE TRANSDUCTION DE SIGNAUX ET D'ENDOMMAGEMENT DE L'ADN
  申请人：UNIV MCGILL

  公开号：WO2002068396A1

  公开（公告）日：2002-09-06

  The present invention relates to a series of new chemical agents that demonstrate anti-tumor activity. More particularly, the present invention relates to molecules, referred to as 'combi-molecules', that combine two major mechanisms of anti-tumor action. A combi-molecule is capable of degrading to a ligand involved in cell signaling pathways and to an agent capable of damaging DNA. More specifically, the present invention relates to molecules capable of blocking epidermal growth factor receptor (EGFR) mediated signal transduction and capable of damaging DNA. The present invention also relates to a general method of synthesis of these combi-molecules.
• The Combi-Targeting Concept:  Synthesis of Stable Nitrosoureas Designed to Inhibit the Epidermal Growth Factor Receptor (EGFR)
  作者：Juozas Domarkas、Fabienne Dudouit、Christopher Williams、Qiu Qiyu、Ranjita Banerjee、Fouad Brahimi、Bertrand Jacques Jean-Claude

  DOI：10.1021/jm0600390

  日期：2006.6.1

  According to the "combi-targeting" concept, the EGFR tyrosine kinase ( TK) inhibitory potency of compounds termed "combi-molecules" is critical for selective growth inhibition of tumor cells with disordered expression of EGFR or its closest family member erbB2. Here we report on the optimization of the EGFR TK inhibitory potency of the combi-molecules of the nitrosourea class by comparison with their aminoquinazoline and ureidoquinazoline precursors. This led to the discovery of a new structural parameter that influences their EGFR TK inhibitory potency, i.e., the torsion angle between the plane of the quinazoline ring and the ureido or the nitrosoureido moiety of the synthesized drugs. Compounds ( 3'-Cl and Br series) with small angles ( 0.5-3 degrees) were generally stronger EGFR TK inhibitors than those with large angles ( 18-21 degrees). This was further corroborated by ligand-receptor van der Waals interaction calculations that showed significant binding hindrance imposed by large torsion angles in the narrow ATP cleft of EGFR. Selective antiproliferative studies in a pair of mouse fibroblast NIH3T3 cells, one of which NIH3T3/neu being transfected with the erbB2 oncogene, showed that IC50 values for inhibition of EGFR TK could be good predictors of their selective potency against the serum-stimulated growth of the erbB2-tranfected cell line ( Pearson r = 0.8). On the basis of stability ( t(1/2)), EGFR TK inhibitory potency ( IC50), and selective erbB2 targeting, compound 23, a stable nitrosourea, was considered to have the structural requirements for further development.