(4S*,4a'S*,10a'R*)-2-amino-8'-methoxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano-[3,2-b]chromen]-5(1H)-one

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4S*,4a'S*,10a'R*)-2-amino-8'-methoxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano-[3,2-b]chromen]-5(1H)-one
• 英文别名: (4S*,4a'S*,10a'R*)-2-amino-8'-methoxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano[3,2-b]chromen]-5(1H)-one；(4aS,10S,10aR)-2'-amino-8-methoxy-3',4a-dimethylspiro[2,3,4,10a-tetrahydropyrano[3,2-b]chromene-10,5'-imidazole]-4'-one
• 化学式: C₁₇H₂₁N₃O₄
• 分子量: 331.371
• InChiKey: IPOZQTDZNXANPL-JQFCIGGWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  86.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4S*,4a'S*,10a'R*)-2-amino-8'-methoxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano-[3,2-b]chromen]-5(1H)-one 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以86%的产率得到(4S*,4a'S*,10a'R*)-2-amino-8'-hydroxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano-[3,2-b]chromen]-5(1H)-one
  参考文献：
  名称：

  8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

  摘要：

  A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF A beta(1-40) at 60 mg/kg (PO).

  DOI：

  10.1021/jm5015132
• 作为产物：
  描述：

  5-羟基-2-戊酮 在 四氢吡咯 、 劳森试剂 、 咪唑 、 叔丁基过氧化氢 、 dirhodium tetraacetate 、 ammonium hydroxide 、 2-naphthalenesulphonyl azide 、 四丁基氟化铵 、 sodium methylate 、 potassium carbonate 、 sodium hydrogensulfite 、 二乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 94.0h， 生成 (4S*,4a'S*,10a'R*)-2-amino-8'-methoxy-1,4a'-dimethyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano-[3,2-b]chromen]-5(1H)-one
  参考文献：
  名称：

  8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

  摘要：

  A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF A beta(1-40) at 60 mg/kg (PO).

  DOI：

  10.1021/jm5015132

文献信息

• COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES
  申请人：Hunt Kevin W.

  公开号：US20120083501A1

  公开（公告）日：2012-04-05

  The invention provides novel tricyclic compounds of Formula I′ that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.

  本发明提供了一种新型三环化合物I'，其抑制β-分泌酶对APP的裂解，并可用作治疗神经退行性疾病的治疗剂。
• [EN] COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS DE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2012040641A3

  公开（公告）日：2012-06-07
• 8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors
  作者：Allen A. Thomas、Kevin W. Hunt、Brad Newhouse、Ryan J. Watts、Xingrong Liu、Guy Vigers、Darin Smith、Susan P. Rhodes、Karin D. Brown、Jennifer N. Otten、Michael Burkard、April A. Cox、Mary K. Geck Do、Darrin Dutcher、Sumeet Rana、Robert K. DeLisle、Kelly Regal、Albion D. Wright、Robert Groneberg、Jiangpeng Liao、Kimberly Scearce-Levie、Michael Siu、Hans E. Purkey、Joseph P. Lyssikatos

  DOI：10.1021/jm5015132

  日期：2014.12.11

  A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF A beta(1-40) at 60 mg/kg (PO).