6-hydroxy-2-(3-nitrophenyl)pyrimidin-4(3H)-one | 873663-34-4

• 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: 6-hydroxy-2-(3-nitrophenyl)pyrimidin-4(3H)-one
• 英文别名: 6-Hydroxy-2-(3-nitrophenyl)-4(3h)-pyrimidinone；4-hydroxy-2-(3-nitrophenyl)-1H-pyrimidin-6-one
• CAS: 873663-34-4
• 化学式: C₁₀H₇N₃O₄
• mdl: MFCD11218494
• 分子量: 233.183
• InChiKey: KWMJUMMRGSJOAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-hydroxy-2-(3-nitrophenyl)pyrimidin-4(3H)-one 在 三乙胺 、 三溴氧磷 作用下， 以 乙腈 为溶剂， 反应 2.0h， 生成 4,6-二溴-2-(3-硝基苯基)嘧啶
  参考文献：
  名称：

  [EN] 2, 4, 6-TRISUBSTITUTED PYRIMIDINES AS PHOSPHOTIDYLINOSITOL (PI) 3-KINASE INHIBITORS AND THEIR USE IN THE TREATMENT OF CANCER
  [FR] PYRIMIDINES A SUBSTITUTION TRIPLE AUX POSITIONS 2, 4, 6 UTILISES EN TANT QU'INHIBITEURS DE PHOSPHOTIDYLINOSITOL (PI) 3-KINASE ET UTILISATIONS DE CELLES-CI POUR TRAITER UN CANCER

  摘要：

  该发明涉及式（I）中的嘧啶衍生物，其中p、R1、R2、q、R3、r、R4、X1和Q1中的每一个具有描述中定义的任何含义；其制备过程，含有它们的药物组合物以及它们在制造用于在温血动物（如人类）中产生抗增殖效应的药物的用途。

  公开号：

  WO2006005914A1
• 作为产物：
  描述：

  3-硝基苯甲脒 盐酸盐 在 盐酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 6-hydroxy-2-(3-nitrophenyl)pyrimidin-4(3H)-one
  参考文献：
  名称：

  Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

  摘要：

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

  DOI：

  10.1021/acs.jmedchem.5b01082

文献信息

• [EN] 2, 4, 6-TRISUBSTITUTED PYRIMIDINES AS PHOSPHOTIDYLINOSITOL (PI) 3-KINASE INHIBITORS AND THEIR USE IN THE TREATMENT OF CANCER<br/>[FR] PYRIMIDINES A SUBSTITUTION TRIPLE AUX POSITIONS 2, 4, 6 UTILISES EN TANT QU'INHIBITEURS DE PHOSPHOTIDYLINOSITOL (PI) 3-KINASE ET UTILISATIONS DE CELLES-CI POUR TRAITER UN CANCER
  申请人：ASTRAZENECA AB

  公开号：WO2006005914A1

  公开（公告）日：2006-01-19

  The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R1, R2, q, R3, r, R4, X1 and Q1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

  该发明涉及式（I）中的嘧啶衍生物，其中p、R1、R2、q、R3、r、R4、X1和Q1中的每一个具有描述中定义的任何含义；其制备过程，含有它们的药物组合物以及它们在制造用于在温血动物（如人类）中产生抗增殖效应的药物的用途。
• 2,4,6-Trisubstituted Pyrimidines as Phosphotidylinositol (Pi) 3-Kinase Inhibitors and Their Use in the Treatment of Cancer
  申请人：Bailey Peter John

  公开号：US20080058332A1

  公开（公告）日：2008-03-06

  The invention concerns pyrimidine derivatives of Formula (I) wherein each of p, R 1 , R 2 , q, R 3 , r, R 4 , X 1 and Q 1 have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

  本发明涉及式(I)的嘧啶衍生物，其中p、R1、R2、q、R3、r、R4、X1和Q1中的每一个具有描述中定义的任何含义；制备它们的过程，含有它们的制药组合物以及它们在制造用于在诸如人类等恒温动物中产生抗增殖效应的药物的制剂中的使用。
• 2,4,6-TRISUBSTITUTED PYRIMIDINES AS PHOSPHOTIDYLINOSITOL (PI) 3-KINASE INHIBITORS AND THEIR USE IN THE TREATMENT OF CANCER
  申请人：AstraZeneca AB

  公开号：EP1768978A1

  公开（公告）日：2007-04-04
• US7893063B2
  申请人：——

  公开号：US7893063B2

  公开（公告）日：2011-02-22
• Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach
  作者：Julian Engel、André Richters、Matthäus Getlik、Stefano Tomassi、Marina Keul、Martin Termathe、Jonas Lategahn、Christian Becker、Svenja Mayer-Wrangowski、Christian Grütter、Niklas Uhlenbrock、Jasmin Krüll、Niklas Schaumann、Simone Eppmann、Patrick Kibies、Franziska Hoffgaard、Jochen Heil、Sascha Menninger、Sandra Ortiz-Cuaran、Johannes M. Heuckmann、Verena Tinnefeld、René P. Zahedi、Martin L. Sos、Carsten Schultz-Fademrecht、Roman K. Thomas、Stefan M. Kast、Daniel Rauh

  DOI：10.1021/acs.jmedchem.5b01082

  日期：2015.9.10

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.