7,8-二氟-4-羟基喹啉 | 1142193-11-0

• 物质功能分类: 医药中间体 - 杂环化合物 - 喹啉类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: 7,8-二氟-4-羟基喹啉
• 英文名称: 7,8-difluoroquinolin-4-ol
• 英文别名: 7,8-Difluoro-4-hydroxyquinoline；7,8-difluoro-1H-quinolin-4-one
• CAS: 1142193-11-0
• 化学式: C₉H₅F₂NO
• 分子量: 181.142
• InChiKey: FCMOETXRLDHWLW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• WGK Germany：
  3

反应信息

• 作为产物：
  描述：

  7,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 在 二苯醚 作用下， 生成 7,8-二氟-4-羟基喹啉
  参考文献：
  名称：

  Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant

  摘要：

  Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.12.056

文献信息

• PYRROLIDINE AND PIPERIDINE COMPOUNDS
  申请人：Yuhan Corporation

  公开号：EP4055014A1

  公开（公告）日：2022-09-14
• Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant
  作者：Izzat T. Raheem、Michael J. Breslin、Joseph Bruno、Tamara D. Cabalu、Andrew Cooke、Christopher D. Cox、Donghui Cui、Susan Garson、Anthony L. Gotter、Steven V. Fox、C. Meacham Harrell、Scott D. Kuduk、Wei Lemaire、Thomayant Prueksaritanont、John J. Renger、Craig Stump、Pamela L. Tannenbaum、Peter D. Williams、Christopher J. Winrow、Paul J. Coleman

  DOI：10.1016/j.bmcl.2014.12.056

  日期：2015.2

  Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class. (C) 2014 Elsevier Ltd. All rights reserved.