N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-quinolin-4-yloxy)phenyl)semicarbazide | 1428788-19-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-quinolin-4-yloxy)phenyl)semicarbazide
• 英文别名: N¹-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-quinolin-4-yloxy)phenyl)semicarbazide；N¹-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)semicarbazide；4-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)semicarbazide
• CAS: 1428788-19-5
• 化学式: C₂₄H₂₈FN₅O₄
• 分子量: 469.516
• InChiKey: QPJHTYWSVSSFAV-UHFFFAOYSA-N

物化性质

• 密度：
  1.313±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.03
• 重原子数：
  34.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  110.97
• 氢给体数：
  3.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-quinolin-4-yloxy)phenyl)semicarbazide 在 四氯化硅 、 溶剂黄146 作用下， 以 异丙醇 为溶剂， 反应 0.6h， 生成 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)urea
  参考文献：
  名称：

  Identification of novel N-(2-aryl-1, 3-thiazolidin-4-one)-N-aryl ureas showing potent multi-tyrosine kinase inhibitory activities

  摘要：

  A total of 29 novel compounds bearing N-1-(2-aryl-1, 3-thiazolidin-4-one)-N-3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.01.061
• 作为产物：
  描述：

  4-氯-6-甲氧基-7-(3-吗啉丙氧基)喹啉 在 吡啶 、 盐酸 、 铁粉 、 一水合肼 、 溶剂黄146 、 三氯氧磷 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 二氯甲烷 、 水 、 氯苯 、 乙腈 为溶剂， 反应 11.0h， 生成 N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-quinolin-4-yloxy)phenyl)semicarbazide
  参考文献：
  名称：

  Identification of novel N-(2-aryl-1, 3-thiazolidin-4-one)-N-aryl ureas showing potent multi-tyrosine kinase inhibitory activities

  摘要：

  A total of 29 novel compounds bearing N-1-(2-aryl-1, 3-thiazolidin-4-one)-N-3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.01.061

文献信息

• NOVEL QUINOLINE DERIVATIVES AND THEIR APPLICATIONS
  申请人：Shenyang Pharmaceutical University

  公开号：US20150307453A1

  公开（公告）日：2015-10-29

  The invention relates to a series of quinoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs. Thereof M, R 1 , R 2 , X, Y and n are defined as claims. And the compounds of general formula I show potent inhibitory activity against c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.

  该发明涉及一系列喹啉衍生物，其一般式为I，包括药学上可接受的盐、水合物、溶剂合物或前药。其中M、R1、R2、X、Y和n的定义如索取权所述。一般式I的化合物显示出对c-Met激酶的强效抑制活性。本发明还涉及这些化合物、药学上可接受的盐和水合物的用途，用于制备用于治疗和/或预防由c-Met激酶异常表达引起的疾病的药物，特别是用于治疗和/或预防癌症。
• Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors
  作者：Baohui Qi、Bin Mi、Xin Zhai、Ziyi Xu、Xiaolong Zhang、Zeru Tian、Ping Gong

  DOI：10.1016/j.bmc.2013.06.026

  日期：2013.9

  synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50 = 1

  合成了一系列新的N 1-（3-氟-4-（6,7-二取代-喹啉-4-基氧基）苯基）-N 4-芳基半碳酰肼衍生物，并评估了它们对c- Met激酶的抑制作用和对A549的细胞毒性，HT-29，MKN-45和MDA-MB-231癌细胞系在体外。进一步针对几种其他癌细胞系（U87MG，NCI-H460和SMMC7721）评估了几种有效的化合物。所测试的大多数化合物均表现出中等至优异的活性。SAR的研究确定了最有前途的化合物28（c -Met IC 50  = 1.4 nM）作为c -Met激酶抑制剂。在这项研究中，有前途的化合物28 鉴定出，与Foretinib相比，对A549，HT-29，U87MG和NCI-H460细胞系分别显示出2.1倍，3.3倍，48.4倍和3.6倍的增长。
• Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors
  作者：Xin Zhai、Guanglong Bao、Limei Wang、Mingke Cheng、Meng Zhao、Sijia Zhao、Hongyang Zhou、Ping Gong

  DOI：10.1016/j.bmc.2016.02.003

  日期：2016.3

  In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a–w, 26a–d and 30a–d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer

  在继续努力确定能够抑制c-Met激酶的小分子的过程中，研究了三个系列的带有（硫）半卡巴zone骨架的新型6,7-二取代-4-苯氧基喹啉衍生物（23a – w，26a – d和30a – d）。设计，合成并评估其细胞毒性。生物学数据表明，大多数化合物对HT-29，MKN-45，A549癌细胞系表现出中等至优异的活性，对MDA-MB-231细胞的效力相对较差，并且在正常PBL细胞中几乎没有任何细胞毒性。进一步检查了11种化合物对c-Met激酶的抑制活性和3种化合物（23h，23n和26a）显示出良好的抑制活性。这项工作导致发现了一种有效的c-Met抑制剂23n，它在R 2部分带有2-羟基-3-烯丙基苯基，它是有价值的先导分子，对A549和HT-29细胞系具有显着的细胞毒性和高选择性。 IC 50值为11 nM和27 nM。此外，它在单数字纳摩尔水平（IC 50  = 1.54 nM）上表现出出