N-(bis-methylsulfanyl-methylidene)-3,4-dichloromethylbenzenesulfonamide | 93487-83-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(bis-methylsulfanyl-methylidene)-3,4-dichloromethylbenzenesulfonamide
• 英文别名: N-(3,4-dichlorophenylsulfonyl)imidodithiocarbonic acid dimethyl ester；N-[bis(methylsulfanyl)methylidene]-3,4-dichlorobenzenesulfonamide
• CAS: 93487-83-3
• 化学式: C₉H₉Cl₂NO₂S₃
• 分子量: 330.28
• InChiKey: OMRNAZABQRCIQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  106
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(bis-methylsulfanyl-methylidene)-3,4-dichloromethylbenzenesulfonamide 、 4-ethyl-4,5-dihydro-1H-pyrazole 在 吡啶 作用下， 以75%的产率得到N-[(4-ethyl-4,5-dihydro-1H-pyrazol-1-yl)-methylsulfanyl-methylidene]-3,4-dichlorobenzenesulfonamide
  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：

  二硫化碳 、 3,4-二氯苯磺酰胺 、 碘甲烷 在 sodium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 以86%的产率得到N-(bis-methylsulfanyl-methylidene)-3,4-dichloromethylbenzenesulfonamide
  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

文献信息

• US4200578A
  申请人：——

  公开号：US4200578A

  公开（公告）日：1980-04-29
• US4250316A
  申请人：——

  公开号：US4250316A

  公开（公告）日：1981-02-10
• US4282363A
  申请人：——

  公开号：US4282363A

  公开（公告）日：1981-08-04
• US4289876A
  申请人：——

  公开号：US4289876A

  公开（公告）日：1981-09-15
• <i>N</i>′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features
  作者：Arnold van Loevezijn、Jennifer Venhorst、Wouter I. Iwema Bakker、Cor G. de Korte、Wouter de Looff、Stefan Verhoog、Jan-Willem van Wees、Martijn van Hoeve、Rob P. van de Woestijne、Martina A. W. van der Neut、Alice J. M. Borst、Maria J. P. van Dongen、Natasja M. W. J. de Bruin、Hiskias G. Keizer、Chris G. Kruse

  DOI：10.1021/jm200466r

  日期：2011.10.27

  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.