2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one | 1311265-24-3

• 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: 2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one
• 英文别名: 2'-amino-1',2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'(1'H)-one；2'-amino-2,2,3'-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3H-chromene-4,5'-imidazole]-4'-one
• CAS: 1311265-24-3
• 化学式: C₂₀H₂₈BN₃O₄
• 分子量: 385.271
• InChiKey: GSFWXGGXFCTMIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.53
• 重原子数：
  28
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 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：

  2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one 在 双氧水 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 0.75h， 生成 2′-amino-6-hydroxy-1′,2,2-trimethylspiro[chroman-4,4′-imidazol]-5′(1′H)-one
  参考文献：
  名称：

  Spirocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid β in a Higher Species

  摘要：

  A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (A beta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. A beta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A beta in vivo, despite efflux. Starting with spirocycle la, we explore structure activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A beta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A beta in rodents and in monkey.

  DOI：

  10.1021/jm4002154
• 作为产物：
  描述：

  6-溴-2,2-二甲基-4-二氢色原酮 在 四(三苯基膦)钯 劳森试剂 、 叔丁基过氧化氢 、 ammonium hydroxide 、 sodium hydride 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 90.0h， 生成 2′-amino-1′,2,2-trimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one
  参考文献：
  名称：

  [EN] S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
  [FR] SPIRO[CHROMANE-4,4'-IMIDAZOL]ONES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE

  摘要：

  这项发明提供了Formula I和Formula II的新型螺环色苷化合物，可以抑制APP的β-分泌酶裂解，并可用作治疗神经退行性疾病的治疗剂。

  公开号：

  WO2011072064A1

文献信息

• [EN] S PIRO [CHROMAN - 4, 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS<br/>[FR] SPIRO[CHROMANE-4,4'-IMIDAZOL]ONES EN TANT QU'INHIBITEURS DE BÊTA-SÉCRÉTASE
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2011072064A1

  公开（公告）日：2011-06-16

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

  这项发明提供了Formula I和Formula II的新型螺环色苷化合物，可以抑制APP的β-分泌酶裂解，并可用作治疗神经退行性疾病的治疗剂。
• Spirocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid β in a Higher Species
  作者：Kevin W. Hunt、Adam W. Cook、Ryan J. Watts、Christopher T. Clark、Guy Vigers、Darin Smith、Andrew T. Metcalf、Indrani W. Gunawardana、Michael Burkard、April A. Cox、Mary K. Geck Do、Darrin Dutcher、Allen A. Thomas、Sumeet Rana、Nicholas C. Kallan、Robert K. DeLisle、James P. Rizzi、Kelly Regal、Douglas Sammond、Robert Groneberg、Michael Siu、Hans Purkey、Joseph P. Lyssikatos、Allison Marlow、Xingrong Liu、Tony P. Tang

  DOI：10.1021/jm4002154

  日期：2013.4.25

  A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (A beta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. A beta is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF A beta in vivo, despite efflux. Starting with spirocycle la, we explore structure activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF A beta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF A beta in rodents and in monkey.