6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one | 917481-90-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one
• 英文别名: 6-Chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol；3-chloro-4-(4-chlorophenyl)-5-pyridin-4-yl-1H-pyridazin-6-one
• CAS: 917481-90-4
• 化学式: C₁₅H₉Cl₂N₃O
• 分子量: 318.162
• InChiKey: IFHDGUQCUNBDNR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one 在 吡啶 、 potassium carbonate 、 肼 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.25h， 生成 8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione
  参考文献：
  名称：

  Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

  摘要：

  Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

  DOI：

  10.1021/jm4010835
• 作为产物：
  描述：

  3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine 在 lithium hydroxide 作用下， 以 水 、 乙腈 为溶剂， 反应 4.0h， 以48%的产率得到6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one
  参考文献：
  名称：

  Azabicyclic heterocycles as cannabinoid receptor modulators

  摘要：

  本申请描述了符合式I的化合物，包括至少一种符合式I的化合物和可选地一种或多种额外治疗剂的药物组合物，以及使用符合式I的化合物进行治疗的方法，无论是单独使用还是与一种或多种额外治疗剂结合使用。这些化合物具有一般的式I和式II：包括所有的前药、药用盐和立体异构体，R1、R2、R3和R4在此处描述。

  公开号：

  US20060287323A1

文献信息

• AZABICYCLIC HETEROCYCLES AS CANNABINOID RECEPTOR MODULATORS
  申请人：Bristol-Myers Squibb Company

  公开号：EP1891074A1

  公开（公告）日：2008-02-27
• US7629342B2
  申请人：——

  公开号：US7629342B2

  公开（公告）日：2009-12-08
• [EN] AZABICYCLIC HETEROCYCLES AS CANNABINOID RECEPTOR MODULATORS<br/>[FR] HÉTÉROCYCLES AZABICYCLIQUES EN TANT QUE RÉGULATEURS DE RÉCEPTEUR CANNABINOÏDE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2006138682A1

  公开（公告）日：2006-12-28

  [EN] The present application describes compounds according to Formula: (I) or (II); wherein R¹ and R² are aryl or heteroaryl. These compounds are useful as cannabinoid receptor modulators, particulary for the treatment of obesity and smoking abuse.
  [FR] La présente demande de brevet décrit des composés de Formule : (I) ou (II) ; où R¹ et R² représentent des groupements aryle ou hétéroaryle. Ces composés peuvent être employés en tant que régulateurs de récepteur cannabinoïde, en particulier dans le traitement de l'obésité et de la dépendance à la nicotine.
• Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties
  作者：Bruce A. Ellsworth、Philip M. Sher、Ximao Wu、Gang Wu、Richard B. Sulsky、Zhengxiang Gu、Natesan Murugesan、Yeheng Zhu、Guixue Yu、Doree F. Sitkoff、Kenneth E. Carlson、Liya Kang、Yifan Yang、Ning Lee、Rose A. Baska、William J. Keim、Mary Jane Cullen、Anthony V. Azzara、Eva Zuvich、Michael A. Thomas、Kenneth W. Rohrbach、James J. Devenny、Helen E. Godonis、Susan J. Harvey、Brian J. Murphy、Gerry G. Everlof、Paul I. Stetsko、Olafur Gudmundsson、Susan Johnghar、Asoka Ranasinghe、Kamelia Behnia、Mary Ann Pelleymounter、William R. Ewing

  DOI：10.1021/jm4010835

  日期：2013.12.12

  Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.
• Azabicyclic heterocycles as cannabinoid receptor modulators
  申请人：Ewing R. William

  公开号：US20060287323A1

  公开（公告）日：2006-12-21

  The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I and Formula II: including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R 1 , R 2 , R 3 and R 4 are described herein.

  本申请描述了符合式I的化合物，包括至少一种符合式I的化合物和可选地一种或多种额外治疗剂的药物组合物，以及使用符合式I的化合物进行治疗的方法，无论是单独使用还是与一种或多种额外治疗剂结合使用。这些化合物具有一般的式I和式II：包括所有的前药、药用盐和立体异构体，R1、R2、R3和R4在此处描述。