1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-3-(2-chloro-ethyl)-1-methyl-urea | 898910-47-9

• 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: 1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-3-(2-chloro-ethyl)-1-methyl-urea
• 英文别名: 1-[4-(3-Bromoanilino)quinazolin-6-yl]-3-(2-chloroethyl)-1-methylurea
• CAS: 898910-47-9
• 化学式: C₁₈H₁₇BrClN₅O
• 分子量: 434.723
• InChiKey: DYTIKWBBBIWLSY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 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：

  1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-3-(2-chloro-ethyl)-1-methyl-urea 在 nitrosonium tetrafluoroborate 、 溶剂黄146 作用下， 以 乙腈 为溶剂， 以49%的产率得到1-[4-(3-Bromoanilino)quinazolin-6-yl]-3-(2-chloroethyl)-1-methyl-3-nitrosourea
  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 吡啶 、 lithium aluminium tetrahydride 、 铁粉 、 溶剂黄146 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 3.5h， 生成 1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-3-(2-chloro-ethyl)-1-methyl-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