N-[2-methyl-4-[(3S)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]oxolane-2-carboxamide | 1146700-08-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: N-[2-methyl-4-[(3S)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]oxolane-2-carboxamide
• CAS: 1146700-08-4
• 化学式: C₂₁H₃₁N₃O₂
• 分子量: 357.496
• InChiKey: BSAKAGUSLYMSNM-WWKKGYIRSA-N

物化性质

• 沸点：
  561.3±50.0 °C(predicted)
• 密度：
  1.181±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  44.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-四氢呋喃甲酸 、 2-methyl-4-(2-(2S)-methyl-[1,3'(3'S)]bipyrrolidinyl-1'-yl)-phenylamine 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-[2-methyl-4-[(3S)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]oxolane-2-carboxamide
  参考文献：
  名称：

  Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep–wake disorders

  摘要：

  Previous studies have shown that compound 1 displayed high affinity towards histamine H-3 receptor (H3R), (human (h-H3R), K-i = 8.6 nM, rhesus monkey (rh-H3R), K-i = 1.2 nM, and rat (r-H3R), K-i = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.006

文献信息

• [EN] SUBSTITUTED N-PHENYL-BIPYRROLIDINE CARBOXAMIDES AND THERAPEUTIC USE THEREOF<br/>[FR] CARBOXAMIDES DE N-PHÉNYL-BIPYRROLIDINE SUBSTITUÉS ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI AVENTIS

  公开号：WO2009052065A1

  公开（公告）日：2009-04-23

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I), Wherein R, R1, R2, R3 and R4 are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor.

  本发明公开并声明了一系列式(I)的取代N-苯基-双吡咯烷羧酰胺，其中R、R1、R2、R3和R4如本文所述。更具体地说，本发明的化合物是H3受体调节剂，因此在制药方面特别有用，尤其是在治疗和/或预防通过H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。此外，本发明还公开了取代N-苯基-双吡咯烷羧酰胺及其中间体的制备方法。
• SUBSTITUTED N-PHENYL-BIPYRROLIDINE CARBOXAMIDES AND THERAPEUTIC USE THEREOF
  申请人：CZECHTIZKY Werngard

  公开号：US20100173897A1

  公开（公告）日：2010-07-08

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). Wherein R, R 1 , R 2 , R 3 and R 4 are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor.

  本发明揭示和声明了一系列取代的N-苯基双吡咯烷羧酰胺化合物，其化学式为(I)，其中R、R1、R2、R3和R4如本文所述。更具体地，本发明的化合物是H3受体调节剂，因此在治疗和/或预防包括与中枢神经系统相关的多种H3受体调节的疾病方面，特别是作为药物剂量是有用的。此外，本发明还揭示了取代的N-苯基双吡咯烷羧酰胺及其中间体的制备方法。
• Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep–wake disorders
  作者：Zhongli Gao、William J. Hurst、Werngard Czechtizky、Dominique Francon、Guy Griebel、Raisa Nagorny、Philippe Pichat、Lothar Schwink、Siegfried Stengelin、James A. Hendrix、Pascal G. George

  DOI：10.1016/j.bmcl.2013.09.006

  日期：2013.11

  Previous studies have shown that compound 1 displayed high affinity towards histamine H-3 receptor (H3R), (human (h-H3R), K-i = 8.6 nM, rhesus monkey (rh-H3R), K-i = 1.2 nM, and rat (r-H3R), K-i = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders. (c) 2013 Elsevier Ltd. All rights reserved.