FD-110 | 153437-71-9

• 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: FD-110
• 英文别名: 6-methylamino-4-(3'-methylanilino)quinazoline；4-[(3-Methylphenyl)amino]-6-(methylamino)quinazoline；6-N-methyl-4-N-(3-methylphenyl)quinazoline-4,6-diamine
• CAS: 153437-71-9
• 化学式: C₁₆H₁₆N₄
• 分子量: 264.33
• InChiKey: IWBVCRRXSCJLQC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  49.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  FD-110 在 nitrosonium tetrafluoroborate 、 溶剂黄146 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 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， 20.0~160.0 ℃ 、200.0 kPa 条件下， 反应 5.0h， 生成 FD-110
  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

• Quinazoline derivatives useful for treatment of neoplastic disease
  申请人：Zeneca Limited

  公开号：US05457105A1

  公开（公告）日：1995-10-10

  The invention concerns quinazoline derivatives of the formula I ##STR1## wherein m is 1, 2 or 3 and each R.sup.1 includes hydroxy, amino, carboxy, carbamoyl, ureido, (1-4C)alkoxycarbonyl, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, hydroxyamino, (1-4C)alkoxyamino, (2-4C)alkanoyloxyamino, trifluoromethoxy, (1-4C)alkyl, (1-4C)alkoxy and (1-3C)alkylenedioxy; n is 1 or 2 and each R.sup.2 includes hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano and (1-4C)alkyl; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them; and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of cancer.

  该发明涉及式I的喹唑啉衍生物 其中m为1、2或3，每个R.sup.1包括羟基、氨基、羧基、氨基甲酰基、脲基、(1-4C)烷氧羰基、N-(1-4C)烷基氨甲酰基、N,N-二[(1-4C)烷基]氨甲酰基、羟胺基、(1-4C)烷氧胺基、(2-4C)烷酰氧胺基、三氟甲氧基、(1-4C)烷基、(1-4C)烷氧基和(1-3C)烷二氧基；n为1或2，每个R.sup.2包括氢、羟基、卤素、三氟甲基、氨基、硝基、氰基和(1-4C)烷基；或其药学上可接受的盐；制备它们的方法；含有它们的药物组合物；以及利用这些化合物的受体酪氨酸激酶抑制特性治疗癌症。
• Quinazoline derivatives
  申请人：ZENECA LIMITED

  公开号：EP0566226B1

  公开（公告）日：1995-11-08
• US5457105A
  申请人：——

  公开号：US5457105A

  公开（公告）日：1995-10-10
• US5616582A
  申请人：——

  公开号：US5616582A

  公开（公告）日：1997-04-01
• US7572798B2
  申请人：——

  公开号：US7572798B2

  公开（公告）日：2009-08-11