4-(benzylamino)-7-methoxyquinazolin-6-ol

• 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: 4-(benzylamino)-7-methoxyquinazolin-6-ol
• 化学式: C₁₆H₁₅N₃O₂
• 分子量: 281.314
• InChiKey: ARGNVJPDKVQMDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  67.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-溴庚酸乙酯 、 4-(benzylamino)-7-methoxyquinazolin-6-ol 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以62%的产率得到ethyl 7-(4-(benzylamino)-7-methoxyquinazolin-6-yloxy)heptanoate
  参考文献：
  名称：

  Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer

  摘要：

  By incorporating historic deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series OF compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug Candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, respectively. In most tumor Cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results Suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.

  DOI：

  10.1021/jm901453q
• 作为产物：
  描述：

  4-氯-6,7-二甲氧基喹唑啉 在 m-bromoaniline hydrochloride 、 sodium thiomethoxide 作用下， 以 二甲胺 、 异丙醇 为溶剂， 反应 4.5h， 生成 4-(benzylamino)-7-methoxyquinazolin-6-ol
  参考文献：
  名称：

  酪氨酸激酶抑制剂。5.作为表皮生长因子受体的酪氨酸激酶结构域的有效的腺苷5'-三磷酸结合位点抑制剂的4-[（（苯基甲基）氨基]-和4-（苯基氨基）喹唑啉的合成与构效关系。

  摘要：

  已经制备了一系列的4-取代的喹唑啉和相关化合物，并评估了它们在磷脂酶C-γ1衍生的底物上抑制表皮生长因子受体的酪氨酸激酶活性的能力。结果表明基本环系统的结构-活性关系（SAR）狭窄，喹唑啉是优选的生色团，苄基氨基和苯胺基是优选的侧链。在4-苯胺基系列中，苯环的3-位被小的亲脂性吸电子基团取代提供了具有增强效价的类似物。研究了两个系列的化合物[4-（苯甲基）氨基和4-（3-溴苯基）氨基]，以确定喹唑啉取代基的SAR。在更具活性的4-（3-溴苯基）氨基系列中，给电子基团（NH2，OMe）在6或7位的活性增加，其模式与对喹唑啉环的8位附近的高电子密度的要求一致。6,7-二甲氧基衍生物是这两个系列中最有效的，而4-（3-溴苯基）氨基衍生物（3）的IC50为0.029 nM，是迄今为止最有效的酪氨酸激酶活性抑制剂。表皮生长因子受体酶的作用。

  DOI：

  10.1021/jm00018a008

文献信息

• TARTRATE SALTS OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Cai Xiong

  公开号：US20090076022A1

  公开（公告）日：2009-03-19

  The present invention relates to tartrate salts of quinazoline containing zinc-binding moiety based derivatives that are inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The tartrate salts may further act as HDAC inhibitors.

  本发明涉及含有锌结合基团的喹唑啉酸盐衍生物，这些衍生物是表皮生长因子受体酪氨酸激酶（EGFR-TK）的抑制剂，以及它们在治疗EGFR-TK相关疾病和疾病如癌症中的用途。这些酒石酸盐还可能作为HDAC抑制剂。
• FORMULATION OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Cai Xiong

  公开号：US20090111772A1

  公开（公告）日：2009-04-30

  The present invention relates to a composition comprising an inclusion complex of a cyclodextrin and quinazoline containing zinc-binding moiety based derivatives. The cyclodextrin is preferable a β-cyclodextrin or a derivative thereof. The quinazolines have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及一种包含环糊精和喹唑啉含锌结合基团衍生物的包含复合物的组合物。环糊精最好是β-环糊精或其衍生物。喹唑啉具有增强和意想不到的性质，作为表皮生长因子受体酪氨酸激酶（EGFR-TK）的抑制剂，以及它们在治疗EGFR-TK相关疾病和疾病如癌症中的用途。所述衍生物还可以作为HDAC抑制剂。
• QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Qian Changgeng

  公开号：US20080194578A1

  公开（公告）日：2008-08-14

  The present invention relates to quinazoline containing zinc-binding moiety based derivatives that have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及含有锌结合基团的喹唑啉衍生物，具有增强和意外的抑制表皮生长因子受体酪氨酸激酶（EGFR-TK）的性质，并可用于治疗EGFR-TK相关的疾病和疾病，如癌症。所述衍生物还可以作为HDAC抑制剂。
• Multi-Functional Small Molecules as Anti-Proliferative Agents
  申请人：Cai Xiong

  公开号：US20080221132A1

  公开（公告）日：2008-09-11

  The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.

  本发明涉及一种新型选择性抑制多种细胞或分子靶点的组合物、方法和应用。更具体地说，本发明涉及多功能小分子，其中一种功能能够抑制组蛋白去乙酰化酶（HDAC），另一种功能能够抑制与异常细胞增殖、分化或存活有关的不同细胞或分子途径。
• Quinazoline based EGFR inhibitors containing a zinc binding moiety
  申请人：Curis, Inc.

  公开号：US07547781B2

  公开（公告）日：2009-06-16

  The present invention relates to quinazoline containing zinc-binding moiety based derivatives that have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及含有锌结合基团的喹嗪衍生物，其具有增强和意外的抑制表皮生长因子受体酪氨酸激酶（EGFR-TK）的性质，并且可用于治疗EGFR-TK相关疾病和疾病，如癌症。所述衍生物还可能作为HDAC抑制剂。