tert-butyl ((3R,4S,5S)-5-(3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)carbamate | 1204343-90-7

• 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: tert-butyl ((3R,4S,5S)-5-(3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)carbamate
• 英文别名: {(3r,4s,5s)-5-[3-Fluoro-4-nitro-5-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-benzyl]-4-hydroxy-tetrahydro-thiopyran-3-yl}-carbamic acid tert-butyl ester；tert-butyl N-[(3R,4S,5S)-5-[[3-fluoro-5-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-4-nitrophenyl]methyl]-4-hydroxythian-3-yl]carbamate
• CAS: 1204343-90-7
• 化学式: C₂₀H₂₃F₇N₂O₆S
• 分子量: 552.467
• InChiKey: RTLBVUDAAMSDBY-GMXABZIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  139
• 氢给体数：
  2
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  tert-butyl ((3R,4S,5S)-5-(3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)carbamate 在 盐酸 、 potassium peroxymonosulfate 、 palladium 10% on activated carbon 、 氨 、 氢气 、 sodium acetate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 72.25h， 生成 (3S,4S,5R)-3-(4-amino-3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzyl)-4-hydroxy-5-((3-(2-hydroxypropan-2-yl)benzyl)amino)tetrahydro-2H-thiopyran 1,1-dioxide
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y
• 作为产物：
  描述：

  3,5-二氟-4-硝基苯腈 在 lithium aluminium tetrahydride 、 氯化亚砜 、 palladium diacetate 、 三溴化磷 、 双(三甲基硅烷基)氨基钾 、 二异丁基氢化铝 、 potassium carbonate 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 正庚烷 、 甲基叔丁基醚 、 丙酮 为溶剂， 反应 74.0h， 生成 tert-butyl ((3R,4S,5S)-5-(3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)carbamate
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y

文献信息

• Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: Structure based design and in vivo reduction of amyloid β-peptides
  作者：Heinrich Rueeger、Rainer Lueoend、Rainer Machauer、Siem Jacob Veenstra、Laura Helen Jacobson、Matthias Staufenbiel、Sandrine Desrayaud、Jean-Michel Rondeau、Henrik Möbitz、Ulf Neumann

  DOI：10.1016/j.bmcl.2013.07.071

  日期：2013.10

  hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2′ subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.

  我们实验室中以前基于结构的优化导致鉴定出一种新型的，高亲和力的环砜羟乙基胺衍生抑制剂，例如1，可在向转基因APP51 / 16小鼠口服后降低CNS衍生的Aβ。在这里，我们报告了在BACE1的S3和S2'子位中的SAR对环状亚砜羟乙基胺抑制剂的开发，在此工作中采用的合成方法以及优化的化合物（例如11d）的体内数据。
• Cyclic sulfones with aminobenzyl substitution useful as BACE inhibitors
  申请人：Briard Emmanuelle

  公开号：US20100056490A1

  公开（公告）日：2010-03-04

  The invention relates to novel heterocyclic compounds of the formula in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

  本发明涉及新的杂环化合物，其化学式如下： 其中所有变量的定义如规范中所述，可以是自由形式或盐形式，涉及其制备、用作药物以及包含它们的药物。
• CYCLIC SULFONES WITH AMINOBENZYL SUBSTITUTION USEFUL AS BACE INHIBITORS
  申请人：Novartis AG

  公开号：EP2303857A1

  公开（公告）日：2011-04-06
• US8093406B2
  申请人：——

  公开号：US8093406B2

  公开（公告）日：2012-01-10
• [EN] CYCLIC SULFONES WITH AMINOBENZYL SUBSTITUTION USEFUL AS BACE INHIBITORS<br/>[FR] SULFONES CYCLIQUES AVEC SUBSTITUTION PAR AMINOBENZYLE UTILES EN TANT QU'INHIBITEURS DE BACE
  申请人：NOVARTIS AG

  公开号：WO2010003976A1

  公开（公告）日：2010-01-14

  The invention relates to novel heterocyclic compounds of the formula (I); in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.