N-[(4-ethyl-4,5-dihydro-1H-pyrazol-1-yl)-methylsulfanyl-methylidene]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide | 1337565-02-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻吩类
• 英文名称: N-[(4-ethyl-4,5-dihydro-1H-pyrazol-1-yl)-methylsulfanyl-methylidene]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide
• CAS: 1337565-02-2
• 化学式: C₁₆H₁₈ClN₃O₂S₃
• 分子量: 415.989
• InChiKey: PWVSALJAUQMEMW-UHFFFAOYSA-N

物化性质

• 沸点：
  579.4±60.0 °C(predicted)
• 密度：
  1.48±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  62.1
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  乙胺 、 N-[(4-ethyl-4,5-dihydro-1H-pyrazol-1-yl)-methylsulfanyl-methylidene]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide 以 甲醇 、 水 为溶剂， 反应 1.0h， 以83%的产率得到N-[(5-chloro-3-methyl-1-benzothiophen-2-yl)sulfonyl]-N',4-diethyl-3,4-dihydropyrazole-2-carboximidamide
  参考文献：
  名称：

  N′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features

  摘要：

  The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT6R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT6R antagonist showing good human in vitro metabolic stability. Rat pharrnacokinetic data were sufficiently good to enable further in vivo profiling.

  DOI：

  10.1021/jm200466r
• 作为产物：
  描述：

  2-乙基丙烯醛 在 吡啶 、 一水合肼 作用下， 以 甲醇 为溶剂， 生成 N-[(4-ethyl-4,5-dihydro-1H-pyrazol-1-yl)-methylsulfanyl-methylidene]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide
  参考文献：
  名称：

  N′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features

  摘要：

  The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT6R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT6R antagonist showing good human in vitro metabolic stability. Rat pharrnacokinetic data were sufficiently good to enable further in vivo profiling.

  DOI：

  10.1021/jm200466r