2-((4-((3-ethynylphenyl)amino)-6-(2-methoxyethoxy)quinazolin-7-yl)oxy)ethyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoate

• 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: 2-((4-((3-ethynylphenyl)amino)-6-(2-methoxyethoxy)quinazolin-7-yl)oxy)ethyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoate
• 英文别名: 2-[4-(3-Ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethyl 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoate；2-[4-(3-ethynylanilino)-6-(2-methoxyethoxy)quinazolin-7-yl]oxyethyl 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoate
• 化学式: C₄₃H₄₄N₄O₆
• 分子量: 712.846
• InChiKey: BOCGDIORWNNYOP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9
• 重原子数：
  53
• 可旋转键数：
  15
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  他米巴罗汀 在 氯化亚砜 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 2-((4-((3-ethynylphenyl)amino)-6-(2-methoxyethoxy)quinazolin-7-yl)oxy)ethyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoate
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents

  摘要：

  A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.

  DOI：

  10.1021/acsmedchemlett.5b00286

文献信息

• COUPLING COMPOUNDS OF NSAID ANTI-INFLAMMATORY AND ANALGESIC DRUGS AND EGFR KINASE INHIBITORS, SYNTHESIS METHODS AND APPLICATIONS THEREOF
  申请人：Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

  公开号：US20160175453A1

  公开（公告）日：2016-06-23

  The present invention discloses coupling compounds of a structure as shown in Formula I, II or III formed by connecting NSAID anti-inflammatory and analgesic drugs and EGFR inhibitors by ester bonds or pharmaceutically acceptable salts or stereoisomers thereof or prodrug molecules thereof: where R is a NSAID anti-inflammatory and analgesic drug. In the present invention, the coupling compounds obtained by coupling NSAID anti-inflammatory and analgesic drugs with EGFR inhibitors have excellent therapeutic effects of tumors and provide new drugs for clinic treatment options.

  本发明揭示了一种结构如公式I、II或III所示的偶联化合物，通过酯键或药用可接受的盐或其立体异构体或其前药分子连接非甾体类抗炎镇痛药和EGFR抑制剂而形成：其中R为非甾体类抗炎镇痛药。在本发明中，通过将非甾体类抗炎镇痛药与EGFR抑制剂偶联而获得的偶联化合物具有出色的肿瘤治疗效果，并为临床治疗提供了新的药物选择。
• US9452220B2
  申请人：——

  公开号：US9452220B2

  公开（公告）日：2016-09-27
• Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents
  作者：Yanmei Zhang、Micky D. Tortorella、Jinxi Liao、Xiaochu Qin、Tingting Chen、Jinfeng Luo、Jiantong Guan、John J. Talley、Zhengchao Tu

  DOI：10.1021/acsmedchemlett.5b00286

  日期：2015.10.8

  A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.