(10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-7,7-diyl)dimethanol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-7,7-diyl)dimethanol
• 英文别名: [(6aR,10aS)-10a-(4-chlorophenyl)sulfonyl-1,4-difluoro-7-(hydroxymethyl)-6a,8,9,10-tetrahydro-6H-benzo[c]chromen-7-yl]methanol
• 化学式: C₂₁H₂₁ClF₂O₅S
• 分子量: 458.911
• InChiKey: DCLAUMXJFMZEKA-UWJYYQICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  92.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-7,7-diyl)dimethanol 在 甲基磺酰氯 、 三乙胺 、 sodium hydride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 3.0h， 生成 10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-6,6a,8,9,10,10a-hexahydrospiro[benzo[c]chromene-7,3′-oxetane]
  参考文献：
  名称：

  [EN] SPIROCYCLIC SULFONES AS GAMMA SECRETASE INHIBITORS
  [FR] SULFONES SPIROCYCLIQUES EN TANT QU'INHIBITEURS DE GAMMA SÉCRÉTASE

  摘要：

  公开号：

  WO2014085211A3
• 作为产物：
  描述：

  烯丙基丙二酸二甲酯 在 9-borabicyclo[3.3.1]nonane dimer 、 potassium tert-butylate 、 4-甲基苯磺酸吡啶 、 二异丁基氢化铝 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 28.58h， 生成 (10a-((4-chlorophenyl)sulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene-7,7-diyl)dimethanol
  参考文献：
  名称：

  Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors

  摘要：

  In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent ?-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-? (A beta) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of ?-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.

  DOI：

  10.1021/acs.jmedchem.5b00774

文献信息

• [EN] SPIROCYCLIC SULFONES AS GAMMA SECRETASE INHIBITORS<br/>[FR] SULFONES SPIROCYCLIQUES EN TANT QU'INHIBITEURS DE GAMMA SÉCRÉTASE
  申请人：MERCK SHARP & DOHME

  公开号：WO2014085211A3

  公开（公告）日：2014-10-30
• SPIROCYCLIC SULFONES AS GAMMA SECRETASE INHIBITORS
  申请人：PISSARNITSKI Dmitri

  公开号：US20150307533A1

  公开（公告）日：2015-10-29

  Disclosed herein are compounds of Formula (I), wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the compound of Formula (I) and use of the compound in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.
• US9464103B2
  申请人：——

  公开号：US9464103B2

  公开（公告）日：2016-10-11
• Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors
  作者：Zhiqiang Zhao、Dmitri A. Pissarnitski、Hubert B. Josien、Wen-Lian Wu、Ruo Xu、Hongmei Li、John W. Clader、Duane A. Burnett、Giuseppe Terracina、Lynn Hyde、Julie Lee、Lixin Song、Lili Zhang、Eric M. Parker

  DOI：10.1021/acs.jmedchem.5b00774

  日期：2015.11.25

  In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent ?-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-? (A beta) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of ?-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.