3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde | 1204343-94-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: 3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde
• 英文别名: 3,3-Dimethyl-1,3-dihydroisobenzofuran-5-carbaldehyde；3,3-dimethyl-1H-2-benzofuran-5-carbaldehyde
• CAS: 1204343-94-1
• 化学式: C₁₁H₁₂O₂
• 分子量: 176.215
• InChiKey: AFCUNSBUPXWWBE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde 、 (3R,4S,5S)-3-amino-5-(4-amino-3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide 在 sodium acetate 、 sodium cyanoborohydride 、 盐酸 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 18.25h， 生成 (3S,4S,5R)-3-(4-amino-3-fluoro-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)benzyl)-5-(((3,3-dimethyl1,3-dihydroisobenzofuran-5-yl)methyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride
  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：

  6-bromo-1,1-dimethyl-1,3-dihydro-2-benzofuran 、 ethyl acetate n-hexane 反应 0.02h， 生成 3,3-dimethyl-1,3-dihydro-isobenzofuran-5-carbaldehyde
  参考文献：
  名称：

  Cyclic sulfones with aminobenzyl substitution useful as BACE inhibitors

  摘要：

  本发明涉及新的杂环化合物，其化学式为，在该式中所有变量的定义如规范中所述，以自由形式或盐形式存在，涉及其制备、用作药物和包含它们的药物。

  公开号：

  US08093406B2

文献信息

• 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.
• 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
  作者：Heinrich Rueeger、Rainer Lueoend、Olivier Rogel、Jean-Michel Rondeau、Henrik Möbitz、Rainer Machauer、Laura Jacobson、Matthias Staufenbiel、Sandrine Desrayaud、Ulf Neumann

  DOI：10.1021/jm300069y

  日期：2012.4.12

  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.
• 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。