1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)urea | 1305852-34-9

• 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: 1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)urea
• CAS: 1305852-34-9
• 化学式: C₁₄H₁₄N₂O₃
• 分子量: 258.277
• InChiKey: QVCKFZUQUCTTTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  70.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)urea 、 4-氯-1H-吡唑并[3,4-d]嘧啶 在 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 1-(3-Methoxyphenyl)-3-[4-(1-methylpyrazolo[3,4-d]pyrimidin-4-yl)oxyphenyl]urea
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo

  摘要：

  We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo [3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.

  DOI：

  10.1021/jm301537p
• 作为产物：
  描述：

  间氨基苯甲醚 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)urea
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Pyrazolo[3,4-d]pyrimidine Derivatives Leading to the Discovery of a Novel Multikinase Inhibitor That Potently Inhibits FLT3 and VEGFR2 and Evaluation of Its Activity against Acute Myeloid Leukemia in Vitro and in Vivo

  摘要：

  We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo [3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.

  DOI：

  10.1021/jm301537p

文献信息

• Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations
  作者：Eman Z. Elrazaz、Rabah A.T. Serya、Nasser S.M. Ismail、Amgad Albohy、Dalal A. Abou El Ella、Khaled A.M. Abouzid

  DOI：10.1016/j.bioorg.2021.105019

  日期：2021.8

  angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the

  血管内皮生长因子受体 (VEGFR) 是众所周知的控制血管生成和癌症进展的靶标之一。在这项研究中，我们报告了一系列 4-取代的噻吩并[2,3- d ]嘧啶衍生物作为 VEGFR-2 抑制剂的设计、合成和生物学评价。这些化合物的设计基于从有效吡咯并[3,2- d ]嘧啶抑制剂VIII与 VEGFR-2 (PDB: 3VHE) 的晶体结构中提取的相互作用。除了这些相互作用之外，新化合物还被设计为与溶剂可及区域中的残基相互作用，例如 Asn923。因此，合成噻吩并嘧啶目标化合物并进行VEGFR-2酶抑制测定。几种目标化合物（7d-f、8b-c、8e-g和15c ) 表现出对 VEGFR-2 的有效抑制活性，IC 50值在低纳摩尔范围内。化合物8b和8e显示出异常有效的抑制活性，IC 50 分别为5和3.9  nM。还进行了分子对接分析和分子动力学模拟，以进一步研究这些发现。
• Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof
  申请人：BEIJING SCITECH-MQ PHARMACEUTICALS LIMITED

  公开号：US10980809B2

  公开（公告）日：2021-04-20

  The present invention relates to a urea-substituted aromatic ring-linked dioxinoquinazoline and a urea-substituted aromatic ring-linked dioxinoquinoline of Formula (I), or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided are the preparation of the compound as shown in Formula (I) and the pharmaceutically acceptable salt thereof and the use thereof as a drug. The drug is used as an inhibitor of tyrosine kinases (e.g., VEGFR-2, C-RAF, B-RAF) for treating tyrosine kinase-related diseases.

  本发明涉及一种脲取代的芳环连二噁喹唑啉和一种脲取代的芳环连二噁喹唑啉的式(I)，或其药学上可接受的盐或其水合物。还提供了式 (I) 所示化合物及其药学上可接受的盐的制备方法及其作为药物的用途。该药物用作酪氨酸激酶（如VEGFR-2、C-RAF、B-RAF）的抑制剂，用于治疗酪氨酸激酶相关疾病。
• Scaffold hopping and redesign approaches for quinazoline based urea derivatives as potent VEGFR-2 inhibitors
  作者：Soha R. Abd El Hadi、Deena S. Lasheen、Dalia H. Soliman、Eman Z. Elrazaz、Khaled A.M. Abouzid

  DOI：10.1016/j.bioorg.2020.103961

  日期：2020.8

  In our attempt to discover effective anticancer agents, three series of novel quinazoline-based compounds have been designed, synthesized and tested as VEGFR-2 inhibitors. Five quinazoline -2-carboxamide derivatives (5d, 5e, 5 h, 5i, 5j) revealed potent nanomolar VEGFR-2 inhibition with IC50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of the reference drug sorafenib (IC50 78.9 nM). Additionally, the qui-nazoline 2-carboxylate derivative bearing a fluorine substituent in middle ring (7a) showed IC50 values of 14.8 nM. Most of the new synthesized compounds are examined on NCI sixty cell lines of human cancer cells. Furthermore, molecular modeling study was administered to realize any clarification of the binding mode in the inactive VEGFR-2 conformation that demonstrates compatible binding modes similar to those of sorafenib and regorafenib. Finally, several ADME descriptors were calculated through a predictive kinetic study.
• UREA-SUBSTITUTED AROMATIC RING-LINKED DIOXANE-QUINAZOLINE AND -LINKED DIOXANE-QUINOLINE COMPOUNDS, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：BEIJING SCITECH-MQ PHARMACEUTICALS LIMITED

  公开号：US20200061065A1

  公开（公告）日：2020-02-27

  The present invention relates to a urea-substituted aromatic ring-linked dioxinoquinazoline and a urea-substituted aromatic ring-linked dioxinoquinoline of Formula (I), or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided are the preparation of the compound as shown in Formula (I) and the pharmaceutically acceptable salt thereof and the use thereof as a drug. The drug is used as an inhibitor of tyrosine kinases (e.g., VEGFR-2, C-RAF, B-RAF) for treating tyrosine kinase-related diseases.