2′-amino-6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one | 1430416-54-8

• 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-6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one
• 英文别名: 2'-amino-6-bromo-2,2-dimethyl-3'-(2,2,2-trifluoroethyl)spiro[3H-chromene-4,5'-imidazole]-4'-one
• CAS: 1430416-54-8
• 化学式: C₁₅H₁₅BrF₃N₃O₂
• 分子量: 406.202
• InChiKey: FYJCAYHXHANXRG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2′-amino-6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one 、 3-氯苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 水 、 甲苯 为溶剂， 反应 16.0h， 以85%的产率得到2′-amino-6-(3-chlorophenyl)-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[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 劳森试剂 、 叔丁基过氧化氢 、 ammonium hydroxide 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 224.0h， 生成 2′-amino-6-bromo-2,2-dimethyl-1′-(2,2,2-trifluoroethyl)spiro[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