tert-butyl ((3RS,5SR)-5-(3,5-difluoro-4-nitrobenzyl)-4-oxotetrahydro-2H-thiopyran-3-yl)carbamate

• 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 ((3RS,5SR)-5-(3,5-difluoro-4-nitrobenzyl)-4-oxotetrahydro-2H-thiopyran-3-yl)carbamate
• 英文别名: [(3R*,5S*)-5-(3,5-difluoro-4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester；[(3R*,5S*)-5-(3,5-Difluoro 4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester；tert-butyl N-[(3R,5S)-5-[(3,5-difluoro-4-nitrophenyl)methyl]-4-oxothian-3-yl]carbamate
• 化学式: C₁₇H₂₀F₂N₂O₅S
• 分子量: 402.419
• InChiKey: GCJKBRXBLUNIFL-MFKMUULPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl ((3RS,5SR)-5-(3,5-difluoro-4-nitrobenzyl)-4-oxotetrahydro-2H-thiopyran-3-yl)carbamate 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 、 乙醇 、 正庚烷 为溶剂， 反应 3.0h， 生成 ((3R,4S,5S)-5-(3,5-difluoro-4-nitrobenzyl)-4-hydroxy-1,1-dioxidotetrahydro-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
• 作为产物：
  描述：

  3,5-二氟-4-硝基苯腈 在 氯化亚砜 、 palladium diacetate 、 三溴化磷 、 二异丁基氢化铝 、 potassium carbonate 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 正己烷 、 甲基叔丁基醚 、 丙酮 为溶剂， 反应 47.0h， 生成 tert-butyl ((3RS,5SR)-5-(3,5-difluoro-4-nitrobenzyl)-4-oxotetrahydro-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

• AMINOBENZYL-SUBSTITUTED CYCLIC SULFONES USEFUL AS BACE INHIBITORS
  申请人：Briard Emmanuelle

  公开号：US20090054427A1

  公开（公告）日：2009-02-26

  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.

  这项发明涉及到新型杂环化合物的公式，其中所有变量如规范中定义，以自由形式或盐形式存在，以及它们的制备方法，作为药物的用途，以及包含它们的药物。
• 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。
• [EN] AMINOBENZYL-SUBSTITUTED CYCLIC SULFONES USEFUL AS BACE INHIBITORS<br/>[FR] SULFONES CYCLIQUES SUBSTITUÉES PAR AMINO-BENZYLE, UTILES EN TANT QU'INHIBITEURS DE BACE
  申请人：NOVARTIS AG

  公开号：WO2009024615A1

  公开（公告）日：2009-02-26

  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.
• [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.