(2R,3'R)-5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide | 1146852-39-2

• 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: (2R,3'R)-5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide
• 英文别名: 5-fluoro-2-methyl-N-[2-methyl-4-[(3R)-3-[(2R)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]benzamide
• CAS: 1146852-39-2
• 化学式: C₂₄H₃₀FN₃O
• 分子量: 395.52
• InChiKey: RTNOWHVTNCEMDM-WIYYLYMNSA-N

物化性质

• 沸点：
  492.0±45.0 °C(predicted)
• 密度：
  1.187±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl-1'-carboxylic acid tert-butyl ester 在 N-甲基吗啉 、 盐酸 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 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 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (2R,3'R)-5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide
  参考文献：
  名称：

  Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

  摘要：

  This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H-3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S, 3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.068

文献信息

• 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。
• US8618159B2
  申请人：——

  公开号：US8618159B2

  公开（公告）日：2013-12-31
• Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide
  作者：Zhongli Gao、William J. Hurst、Etienne Guillot、Raisa Nagorny、Marie-Pierre Pruniaux、James A. Hendrix、Pascal G. George

  DOI：10.1016/j.bmcl.2013.05.068

  日期：2013.7

  This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H-3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S, 3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. (C) 2013 Elsevier Ltd. All rights reserved.