5-[4-(3-chloropropoxy)phenyl]-6-methyl-2-(3-methylpyridin-2-yl)-2H-pyridazin-3-one | 1364250-12-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-[4-(3-chloropropoxy)phenyl]-6-methyl-2-(3-methylpyridin-2-yl)-2H-pyridazin-3-one
• CAS: 1364250-12-3
• 化学式: C₂₀H₂₀ClN₃O₂
• 分子量: 369.851
• InChiKey: NLLAYKYMXUEAOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.92
• 重原子数：
  26.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  57.01
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  5-[4-(3-chloropropoxy)phenyl]-6-methyl-2-(3-methylpyridin-2-yl)-2H-pyridazin-3-one 在 盐酸 、 potassium carbonate 、 sodium iodide 作用下， 以 甲醇 、 乙醇 、 乙腈 为溶剂， 反应 24.0h， 生成 6-methyl-2-(3-methylpyridin-2-yl)-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one hydrochloride
  参考文献：
  名称：

  Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H₃ Receptor Antagonists with Potent Cognition Enhancing Activity

  摘要：

  Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K-i = 2.8 nM) and rat H(3)Rs (rH(3)R K-i = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R-2 and R-6 positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH3R K-i = 1.7 nM, rH(3)R K = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H3R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

  DOI：

  10.1021/jm201295j
• 作为产物：
  描述：

  5-(4-methoxyphenyl)-6-methyl-2H-pyridazin-3-one 在 copper(l) iodide 、 三溴化硼 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 生成 5-[4-(3-chloropropoxy)phenyl]-6-methyl-2-(3-methylpyridin-2-yl)-2H-pyridazin-3-one
  参考文献：
  名称：

  Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H₃ Receptor Antagonists with Potent Cognition Enhancing Activity

  摘要：

  Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K-i = 2.8 nM) and rat H(3)Rs (rH(3)R K-i = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R-2 and R-6 positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH3R K-i = 1.7 nM, rH(3)R K = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H3R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

  DOI：

  10.1021/jm201295j