N-(5-chlorothiophen-2-yl)sulfonyl-N',4-diethyl-3,4-dihydropyrazole-2-carboximidamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: N-(5-chlorothiophen-2-yl)sulfonyl-N',4-diethyl-3,4-dihydropyrazole-2-carboximidamide
• 化学式: C₁₂H₁₇ClN₄O₂S₂
• 分子量: 348.878
• InChiKey: SBCKDJZRMMRMDJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  111
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-乙基丙烯醛 在 一水合肼 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 48.0h， 生成 N-(5-chlorothiophen-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

文献信息

• SULFONYLPYRAZOLE AND SULFONYLPYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS
  申请人：Van Loevezijn Arnold

  公开号：US20080311179A1

  公开（公告）日：2008-12-18

  This invention concerns compounds of the general formula (1). and derivatives thereof, which are antagonists of 5-HT 6 receptors, wherein the symbols have the meanings given in the description. The invention also concerns methods for the preparation of these compounds, to novel intermediates useful for their synthesis, and to uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in treating at least on disease or condition chosen from Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes.

  本发明涉及通式（1）的化合物及其衍生物，它们是5-HT6受体拮抗剂，其中符号的含义如说明书所示。本发明还涉及制备这些化合物的方法，对于其合成有用的新型中间体，以及这些化合物和组合物的用途，特别是将它们用于向患者施用以达到治疗帕金森病、亨廷顿舞蹈症、精神分裂症、焦虑、抑郁症、躁郁症、精神病、癫痫、强迫症、情绪障碍、偏头痛、阿尔茨海默病、与年龄相关的认知衰退、轻度认知障碍、睡眠障碍、进食障碍、厌食症、贪食症、暴食症、惊恐发作、不安定症、注意力缺陷多动障碍、注意力缺陷障碍、戒断可卡因、乙醇、尼古丁或苯二氮平的滥用、疼痛、与脊髓损伤或头部损伤有关的疾病、脑积水、功能性肠道障碍、肠易激综合征、肥胖症和2型糖尿病等至少一种疾病或症状的治疗效果。
• US7728018B2
  申请人：——

  公开号：US7728018B2

  公开（公告）日：2010-06-01
• US8722887B2
  申请人：——

  公开号：US8722887B2

  公开（公告）日：2014-05-13
• [EN] SULFONYLPYRAZOLE AND SULFONYLPYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS<br/>[FR] DÉRIVÉS CARBOXAMIDINE DE SULFONYLPYRAZOLE ET SULFONYLPYRAZOLINE EN TANT QU'ANTAGONISTES DE 5-HT6
  申请人：SOLVAY PHARM BV

  公开号：WO2008034863A2

  公开（公告）日：2008-03-27

  [EN] This invention concerns sulfonylpyrazoline carboxamidine derivatives as antagonists of 5-HT₆ receptors, to methods for the preparation of these compounds and to novel intermediates useful for their synthesis. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes. The compounds have the general formula (1), wherein the symbols have the meanings given in the description.
  [FR] La présente invention concerne des dérivés carboxamidine de sulfonylpyrazoline en tant qu'antagonistes des récepteurs 5-HT₆, les procédés de préparation de ces composés et de nouveaux intermédiaires utiles pour leur synthèse. L'invention concerne également les utilisations de tels composés et compositions, en particulier leur utilisation pour leur administration à des patients de façon à obtenir un effet thérapeutique sur la maladie de Parkinson, la chorée de Huntington, la schizophrénie, l'anxiété, la dépression, la psychose maniacodépressive, les psychoses, l'épilepsie, les troubles compulsifs obsessifs, les troubles de l'humeur, la migraine, la maladie d'Alzheimer, le déclin cognitif relatif à l'âge, la déficience cognitive modérée, les troubles du sommeil, les troubles de l'alimentation, l'anorexie, la boulimie, l'hyperphagie boulimique, les crises de panique, l'acathésie, le trouble déficitaire de l'attention avec hyperactivité, le trouble déficitaire de l'attention, le retrait de l'abus de cocaïne, d'éthanol, de nicotine ou de benzodiazépines, la douleur, les troubles liés au trauma rachidien ou blessures de la tête, l'hydrocéphalie, le trouble fonctionnel de l'intestin, le syndrome de l'intestin irritable, l'obésité et le diabète de type-2. Les composés répondent à la formule générale (1), dans laquelle les symboles ont les significations données dans la description.
• <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.