6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid | 1269421-64-8

• 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: 6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid
• 英文别名: 4-Hydroxy-6-methylquinazoline-8-carboxylic acid；6-methyl-4-oxo-3H-quinazoline-8-carboxylic acid
• CAS: 1269421-64-8
• 化学式: C₁₀H₈N₂O₃
• 分子量: 204.185
• InChiKey: NUPNSFDWUSHPCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  78.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid 在 吡啶 、 草酰氯 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢溴酸 、 溶剂黄146 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.67h， 生成 tert-butyl ((1,4-trans)-4-((8-((6-chloro-3-(2,5-difluorophenylsulfonamido)-2-fluorophenyl)carbamoyl)-6-methylquinazolin-4-yl)amino)cyclohexyl)carbamate
  参考文献：
  名称：

  Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

  摘要：

  Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.

  DOI：

  10.1021/acsmedchemlett.0c00344
• 作为产物：
  描述：

  methyl 6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylate 在 甲醇 、 水 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以710 mg的产率得到6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid
  参考文献：
  名称：

  [EN] ARYLAMIDE COMPOUND, PHARMACEUTICAL COMPOSITION COMPRISING SAME, AND PREPARATION METHOD THEREFOR AND USE THEREOF
  [FR] COMPOSÉ ARYLAMIDE, COMPOSITION PHARMACEUTIQUE LE COMPRENANT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
  [ZH] 芳基酰胺化合物、包含其的药物组合物及其制备方法和用途

  摘要：

  本发明涉及式（I'）的芳基酰胺化合物、包含其的药物组合物、其制备方法及其用于预防或治疗肿瘤相关的疾病或病况。

  公开号：

  WO2022089219A1

文献信息

• RAF INHIBITOR COMPOUNDS AND METHODS OF USE THEREOF
  申请人：Aliagas Ignacio

  公开号：US20130018033A1

  公开（公告）日：2013-01-17

  Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

  公式I的化合物对于抑制Raf激酶非常有用。本文揭示了使用公式I的化合物及其立体异构体、互变异构体、前药和其药学上可接受的盐，在哺乳动物细胞的体外、体内或原位诊断、预防或治疗相关病理条件的方法。
• [EN] RAF INHIBITOR COMPOUNDS AND METHODS OF USE THEREOF<br/>[FR] COMPOSÉS INHIBITEURS DE Raf ET LEURS PROCÉDÉS D'UTILISATION
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2011025938A3

  公开（公告）日：2011-05-05
• Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity
  作者：Ramsay E. Beveridge、Heidi Ackerly Wallweber、Avi Ashkenazi、Maureen Beresini、Kevin R. Clark、Paul Gibbons、Elise Ghiro、Susan Kaufman、Alexandre Larivée、Melissa Leblanc、Jean-Philippe Leclerc、Alexandre Lemire、Cuong Ly、Joachim Rudolph、Jacob B. Schwarz、Sanjay Srivastava、Weiru Wang、Liang Zhao、Marie-Gabrielle Braun

  DOI：10.1021/acsmedchemlett.0c00344

  日期：2020.12.10

  Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.
• [EN] ARYLAMIDE COMPOUND, PHARMACEUTICAL COMPOSITION COMPRISING SAME, AND PREPARATION METHOD THEREFOR AND USE THEREOF<br/>[FR] COMPOSÉ ARYLAMIDE, COMPOSITION PHARMACEUTIQUE LE COMPRENANT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION<br/>[ZH] 芳基酰胺化合物、包含其的药物组合物及其制备方法和用途
  申请人：SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD

  公开号：WO2022089219A1

  公开（公告）日：2022-05-05

  本发明涉及式（I'）的芳基酰胺化合物、包含其的药物组合物、其制备方法及其用于预防或治疗肿瘤相关的疾病或病况。