WMS-2539 | 1257844-26-0

• 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: WMS-2539
• 英文别名: (2S,4S)-2-[(4S)-2,2-diphenyl-1,3-dioxolan-4-yl]-4-fluoropiperidine；4-fluorodexoxadrol；G922A8S2QV
• CAS: 1257844-26-0
• 化学式: C₂₀H₂₂FNO₂
• 分子量: 327.399
• InChiKey: OLGOYYOHTNZCEO-GBESFXJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  30.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  benzyl (2S,4S)-2-[(4S)-2,2-diphenyl-1,3-dioxolan-4-yl]-4-fluoropiperidine-1-carboxylate 在 10% palladium on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 反应 4.0h， 生成 WMS-2539
  参考文献：
  名称：

  Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

  摘要：

  A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from D-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K-i = 28 nM), a fluorine atom ((S,S,S)-6, WMS-2539, K-i = 7 nM) and two fluorine atoms ((S,S)-7, K-i = 48 nM) in position 4 represent the most potent NMDA antagonists with high selectivity against sigma(1) and sigma(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.09.047

文献信息

• EP2908827A1
  申请人：——

  公开号：EP2908827A1

  公开（公告）日：2015-08-26
• VITAMIN D ANALOGUES FOR THE TREATMENT OF A NEUROLOGICAL DISORDER
  申请人：CELUS PHARMACEUTICALS, INC.

  公开号：US20150246061A1

  公开（公告）日：2015-09-03

  Disclosed herein are methods that use a vitamin D analogue to treat a neurological disorder. Additionally, pharmaceutical compositions comprising a vitamin D analogue and a neurotherapeutic agent are disclosed, and methods of using the same. The pharmaceutical compositions and methods of the invention are useful for the treatment of a neurological disorder, for example, Alzheimer's disease, multiple sclerosis, Parkinson's disease, epilepsy, neuropathic pain, or other conditions that affect the central or peripheral nervous system of a subject.
• [EN] VITAMIN D ANALOGUES FOR THE TREATMENT OF A NEUROLOGICAL DISORDER<br/>[FR] UTILISATION D'ANALOGUES DE LA VITAMINE D POUR LE TRAITEMENT D'UNE AFFECTION NEUROLOGIQUE
  申请人：CELUS PHARMACEUTICALS INC

  公开号：WO2014063105A1

  公开（公告）日：2014-04-24

  Disclosed herein are methods that use a vitamin D analogue to treat a neurological disorder. Additionally, pharmaceutical compositions comprising a vitamin D analogue and a neurotherapeutic agent are disclosed, and methods of using the same. The pharmaceutical compositions and methods of the invention are useful for the treatment of a neurological disorder, for example, Alzheimer's disease, multiple sclerosis, Parkinson's disease, epilepsy, neuropathic pain, or other conditions that affect the central or peripheral nervous system of a subject.
• Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists
  作者：Ashutosh Banerjee、Dirk Schepmann、Jens Köhler、Ernst-Ulrich Würthwein、Bernhard Wünsch

  DOI：10.1016/j.bmc.2010.09.047

  日期：2010.11.15

  A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from D-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K-i = 28 nM), a fluorine atom ((S,S,S)-6, WMS-2539, K-i = 7 nM) and two fluorine atoms ((S,S)-7, K-i = 48 nM) in position 4 represent the most potent NMDA antagonists with high selectivity against sigma(1) and sigma(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity. (C) 2010 Elsevier Ltd. All rights reserved.