N-(4-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]urea | 819056-61-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(4-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]urea
• 英文别名: 1-(4-Fluorophenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea
• CAS: 819056-61-6
• 化学式: C₁₉H₂₂BFN₂O₃
• 分子量: 356.205
• InChiKey: UIGZUASHNMPWJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.77
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  59.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(4-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]urea 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.5h， 生成 N-(6-(4-(3-(4-fluorophenyl)ureido)phenyl)pyridin-2-yl)acrylamide
  参考文献：
  名称：

  Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1 H -indazole-3-amine as multi-target RTKs inhibitors

  摘要：

  VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.10.008
• 作为产物：
  描述：

  4-氟苯胺 以 二氯甲烷 为溶剂， 反应 0.25h， 生成 N-(4-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]urea
  参考文献：
  名称：

  Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1 H -indazole-3-amine as multi-target RTKs inhibitors

  摘要：

  VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.10.008

文献信息

• 氨基嘧啶并吡唑/吡咯类衍生物及其制备方法和用途
  申请人：四川大学华西医院

  公开号：CN112961158B

  公开（公告）日：2022-07-01

  本发明涉及氨基嘧啶并吡唑/吡咯类衍生物及其制备方法和用途，属于医药领域。本发明提供了式Ⅰ所示的化合物、其光学异构体、化合物或其光学异构体在药学上可接受的盐。生物学实验证明，本发明化合物能够不仅可以显著抑制乳腺癌、肺癌、结直肠癌、胃癌、胆管癌、尿路上皮癌等多种癌细胞的增殖，具有广谱的抗癌作用，对成纤维细胞和肝星状细胞的增殖也表现出抑制作用，而且能够在体内抑制肿瘤的生长，为抗肿瘤、抗纤维化药物的开发提供了新的选择。
• Design, synthesis and biological evaluation of a series of novel pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as FGFRs-dominant multi-target receptor tyrosine kinase inhibitors for the treatment of gastric cancer
  作者：Xiuli Wu、Zhihao Liu、Cailin Gan、Wei Wei、Qianyu Zhang、Hongyao Liu、Hanyun Que、Xingping Su、Lin Yue、Hualong He、Liang Ouyang、Tinghong Ye

  DOI：10.1016/j.bioorg.2022.105965

  日期：2022.10

  have recently been suggested as potential targets for gastric cancer treatment. We herein report the discovery of pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as a new class of FGFRs-dominant multi-target receptor tyrosine kinase inhibitors. SAR assessment identified the most active compounds 8f and 8k, which showed excellent inhibitory activity against a variety of receptor tyrosine

  胃癌是全球第二大致命癌症。随着治疗手段的进步，早期胃癌的5年生存率可达95%以上。然而，晚期胃癌的预后和生存时间仍然很严峻。因此，迫切需要更有效的胃癌治疗靶向疗法。FGFR、VEGFR 和其他受体酪氨酸激酶最近被建议作为胃癌治疗的潜在靶标。我们在此报告了吡咯并[2,3 - d ]嘧啶/吡唑并[3,4- d ]嘧啶-4-胺衍生物作为一类新型FGFRs-显性多靶受体酪氨酸激酶抑制剂的发现。SAR 评估确定了最活跃的化合物8f和8k，对多种受体酪氨酸激酶显示出极好的抑制活性。此外，8f和8k在 SNU-16 胃癌细胞系中表现出优异的效力。此外，8f和8k可以抑制 FGFR1 磷酸化和下游信号通路以及诱导细胞凋亡。在体内，8f和8k在 SNU-16 异种移植模型中抑制肿瘤生长，而不会引起明显的毒性。这些发现提高了化合物8f和8k可能作为治疗胃癌的潜在药物的可能性。
• Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4
  作者：Chuansheng Li、Yuanyuan Shan、Ying Sun、Ru Si、Liyuan Liang、Xiaoyan Pan、Binghe Wang、Jie Zhang

  DOI：10.1016/j.ejmech.2017.10.030

  日期：2017.12

  Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a 'triplet' inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Discovery of <i>N</i>-(4-(3-Amino-1<i>H</i>-indazol-4-yl)phenyl)-<i>N</i>‘-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-Aminoindazole-Based Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitor
  作者：Yujia Dai、Kresna Hartandi、Zhiqin Ji、Asma A. Ahmed、Daniel H. Albert、Joy L. Bauch、Jennifer J. Bouska、Peter F. Bousquet、George A. Cunha、Keith B. Glaser、Christopher M. Harris、Dean Hickman、Jun Guo、Junling Li、Patrick A. Marcotte、Kennan C. Marsh、Maria D. Moskey、Ruth L. Martin、Amanda M. Olson、Donald J. Osterling、Lori J. Pease、Niru B. Soni、Kent D. Stewart、Vincent S. Stoll、Paul Tapang、David R. Reuter、Steven K. Davidsen、Michael R. Michaelides

  DOI：10.1021/jm061280h

  日期：2007.4.1

  In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.
• Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1 H -indazole-3-amine as multi-target RTKs inhibitors
  作者：Ying Sun、Yuanyuan Shan、Chuansheng Li、Ru Si、Xiaoyan Pan、Binghe Wang、Jie Zhang

  DOI：10.1016/j.ejmech.2017.10.008

  日期：2017.12

  VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4. (C) 2017 Elsevier Masson SAS. All rights reserved.