4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine | 1615714-10-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine
• CAS: 1615714-10-7
• 化学式: C₇H₇ClF₂N₂O
• 分子量: 208.595
• InChiKey: HVQFBFXQBIDURS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine 、 6-methyl-1H-benzoimidazole-4-carboxylic acid methyl ester 在 caesium carbonate 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.17h， 生成
  参考文献：
  名称：

  Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity

  摘要：

  We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

  DOI：

  10.1021/acsmedchemlett.9b00343
• 作为产物：
  描述：

  草酰丙酸二乙酯 在 sodium tetrahydroborate 、 氯化亚砜 、 sodium ethanolate 、 sodium carbonate 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 48.0h， 生成 4-(chloromethyl)-6-(difluoromethoxy)-5-methylpyrimidine
  参考文献：
  名称：

  AZAINDOLE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING THE SAME

  摘要：

  该发明提供了式（I）的化合物以及用于治疗结核分枝杆菌感染或肺结核，或者用于抑制DprE1的方法。

  公开号：

  US20150025087A1

文献信息

• Azaindole compounds, synthesis thereof, and methods of using the same
  申请人：Global Alliance for TB Drug Development

  公开号：US09163020B2

  公开（公告）日：2015-10-20

  The invention provides compounds of formula (I) and methods of treating a Mycobacterium infection or tuberculosis, or inhibiting DprE1 with the same.

  本发明提供了式(I)的化合物以及用于治疗分枝杆菌感染或结核病，或抑制DprE1的方法。
• Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
  作者：Pravin S. Shirude、Radha K. Shandil、M. R. Manjunatha、Claire Sadler、Manoranjan Panda、Vijender Panduga、Jitendar Reddy、Ramanatha Saralaya、Robert Nanduri、Anisha Ambady、Sudha Ravishankar、Vasan K. Sambandamurthy、Vaishali Humnabadkar、Lalit K. Jena、Rudrapatna S. Suresh、Abhishek Srivastava、K. R. Prabhakar、James Whiteaker、Robert E. McLaughlin、Sreevalli Sharma、Christopher B. Cooper、Khisi Mdluli、Scott Butler、Pravin S. Iyer、Shridhar Narayanan、Monalisa Chatterji

  DOI：10.1021/jm500571f

  日期：2014.7.10

  In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
• US9163020B2
  申请人：——

  公开号：US9163020B2

  公开（公告）日：2015-10-20
• [EN] AZAINDOLE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING THE SAME<br/>[FR] COMPOSÉS D'AZA-INDOLE, LEUR SYNTHÈSE ET PROCÉDÉS POUR LES UTILISER
  申请人：GLOBAL ALLIANCE FOR TB DRUG DEV

  公开号：WO2015009525A1

  公开（公告）日：2015-01-22

  The invention provides compounds of formula (I) and methods of treating a Mycobacterium infection or tuberculosis, or inhibiting DprE1 with the same.