N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylidene]-3-chlorobenzenesulfonamide | 1337565-41-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylidene]-3-chlorobenzenesulfonamide
• 英文别名: methyl 8-benzyl-N-(3-chlorophenyl)sulfonyl-2,3,8-triazaspiro[4.5]dec-3-ene-2-carboximidothioate
• CAS: 1337565-41-9
• 化学式: C₂₂H₂₅ClN₄O₂S₂
• 分子量: 477.051
• InChiKey: GTJYYVKRYCJNRN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.33
• 重原子数：
  31.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  65.34
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylidene]-3-chlorobenzenesulfonamide 在 1-氯乙基氯甲酸酯 作用下， 以 甲醇 、 水 、 1,2-二氯乙烷 为溶剂， 反应 1.0h， 生成 N-[ethylamino-(2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)methylidene]-3-chlorobenzenesulfonamide
  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：

  溴甲苯 在 吡啶 、 sodium hypochlorite 、 lithium aluminium tetrahydride 、 双氧水 、 potassium carbonate 作用下， 以 甲醇 、 环戊基甲醚 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 26.0h， 生成 N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylidene]-3-chlorobenzenesulfonamide
  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