2′-amino-7-(5-chloropyridin-3-yl)-1′,3,3-trimethyl-3,4-dihydro-1′H,2H-spiro[naphthalene-1,4′-pyrimidin]-6′(5′H)-one | 1338093-21-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: 2′-amino-7-(5-chloropyridin-3-yl)-1′,3,3-trimethyl-3,4-dihydro-1′H,2H-spiro[naphthalene-1,4′-pyrimidin]-6′(5′H)-one
• 英文别名: 2'-amino-6-(5-chloropyridin-3-yl)-2,2,3'-trimethylspiro[1,3-dihydronaphthalene-4,6'-5H-pyrimidine]-4'-one
• CAS: 1338093-21-2
• 化学式: C₂₁H₂₃ClN₄O
• 分子量: 382.893
• InChiKey: DYJMRYUXJYQJSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  7-bromo-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one 在 盐酸 、 titanium(IV) tetraethanolate 、 正丁基锂 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 sodium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 二异丙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.5h， 生成 2′-amino-7-(5-chloropyridin-3-yl)-1′,3,3-trimethyl-3,4-dihydro-1′H,2H-spiro[naphthalene-1,4′-pyrimidin]-6′(5′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

文献信息

• COMPOUNDS FOR TREATING NEURODEGENERATIVE DISEASES
  申请人：Clark Christopher T.

  公开号：US20120065195A1

  公开（公告）日：2012-03-15

  The invention provides novel spirotetrahydronaphthalene compounds of Formula α 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的螺四氢萘酚化合物，其化学式为α，可以抑制β-分泌酶对APP的切割，并且可用作治疗神经退行性疾病的治疗剂。