6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one | 859173-00-5

• 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-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one
• 英文别名: 6-chloro-7-(4-chlorophenyl)-8-pyridin-4-yl-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one
• CAS: 859173-00-5
• 化学式: C₁₆H₉Cl₂N₅O
• 分子量: 358.186
• InChiKey: BRFORIPGDGLNGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  70
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one 在 potassium trimethylsilonate 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.25h， 生成 4-((7-(4-chlorophenyl)-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile
  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：

  4-(4-chlorophenyl)-3-(pyridin-4-yl)furan-2(5H)-one 在 盐酸 、 potassium tert-butylate 、 氧气 、 一水合肼 、 肼 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 23.0h， 生成 6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one
  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

文献信息

• Azabicyclic heterocycles as cannabinoid receptor modulators
  申请人：Yu Guixue

  公开号：US20050171110A1

  公开（公告）日：2005-08-04

  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. including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are described herein.

  本申请描述了符合公式I的化合物，包括所有的前药、药学上可接受的盐和立体异构体，以及包含至少一种符合公式I的化合物和可选的一种或多种其他治疗剂的制药组合物，以及使用符合公式I的化合物进行治疗的方法，包括单独使用和与一种或多种其他治疗剂的组合使用。公式I的化合物包括R1、R2、R3、R4、R5、m和n。
• AZABICYCLIC HETEROCYCLES AS CANNABINOID RECEPTOR MODULATORS
  申请人：Bristol-Myers Squibb Company

  公开号：EP1697371A1

  公开（公告）日：2006-09-06
• US7816357B2
  申请人：——

  公开号：US7816357B2

  公开（公告）日：2010-10-19
• [EN] AZABICYCLIC HETEROCYCLES AS CANNABINOID RECEPTOR MODULATORS<br/>[FR] HETEROCYCLES AZABICYCLIQUES EN TANT QUE MODULATEURS DE RECEPTEUR CANABINOIDES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005063762A1

  公开（公告）日：2005-07-14

  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. including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3, R4, R5, m and n are described herein.
• 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.