3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propan-1-ol | 1221965-74-7

• 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-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propan-1-ol
• 英文别名: M 527301；N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-hydroxypropoxy)-quinazolin-4-amine；Gefitinib metabolite M-527301；3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypropan-1-ol
• CAS: 1221965-74-7
• 化学式: C₁₈H₁₇ClFN₃O₃
• 分子量: 377.803
• InChiKey: AMLVQRCDTNBYLW-UHFFFAOYSA-N

物化性质

• 沸点：
  524.7±50.0 °C(Predicted)
• 密度：
  1.395±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  76.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  双(2-氯乙基)氨基磷酰二氯 、 3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propan-1-ol 在 正丁基锂 、 氨 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 4.5h， 生成 3-((4-((3-chloro-4-fluorophenylamino))-7-methoxyquinazolin-6-yl)oxy)propyl N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

  摘要：

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.12.055
• 作为产物：
  描述：

  4-(3-氯-4-氟苯氨基)-7-甲氧基喹唑啉-6-醇乙酸酯 在 ammonium hydroxide 、 potassium carbonate 、 potassium iodide 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 14.0h， 生成 3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propan-1-ol
  参考文献：
  名称：

  Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

  摘要：

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.12.055

文献信息

• Spiro compounds and methods of use
  申请人：Chen Paul Guoqing

  公开号：US20070167470A1

  公开（公告）日：2007-07-19

  The present invention relates to spiro compounds of formula I, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states such as cancers associated with protein tyrosine kinases, especially epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), to their method of use as medicaments and to their method of use in the manufacture of medicaments for use in the production of inhibition of tyrosine kinase reducing effects in warm-blooded animals such as humans.

  本发明涉及式I的螺环化合物，其制备方法，含有其作为活性成分的药物组合物，用于治疗与蛋白酪氨酸激酶相关的疾病状态，特别是表皮生长因子（EGF）和血管内皮生长因子（VEGF）相关的癌症等疾病状态的方法，以及它们作为药物的使用方法，以及用于制造用于在温血动物（如人类）中减少酪氨酸激酶抑制效果的药物的使用方法。
• Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
  作者：Songwen Lin、Yingbo Li、Yufen Zheng、Laichun Luo、Qi Sun、Zemei Ge、Tieming Cheng、Runtao Li

  DOI：10.1016/j.ejmech.2016.12.055

  日期：2017.2

  A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose). (C) 2017 Elsevier Masson SAS. All rights reserved.