(2S)-2-[(3S)-3-butyl-2-oxopyrrolidin-1-yl]-N-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]propan-2-yl]-4-phenylbutanamide | 1034606-31-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (2S)-2-[(3S)-3-butyl-2-oxopyrrolidin-1-yl]-N-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]propan-2-yl]-4-phenylbutanamide
• CAS: 1034606-31-9
• 化学式: C₃₆H₄₃F₂N₃O₃
• 分子量: 603.753
• InChiKey: GUUJUIXBOCRPLX-ZKZCUZKLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  81.7
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  L-高苯丙氨酸甲酯 在 N-甲基吗啉 、 三乙基硅烷 、 palladium on activated charcoal 、 HATU 、 氢气 、 臭氧 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 生成 (2S)-2-[(3S)-3-butyl-2-oxopyrrolidin-1-yl]-N-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]propan-2-yl]-4-phenylbutanamide
  参考文献：
  名称：

  Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE)

  摘要：

  The synthesis, evaluation, and structure-activity relationships of a class of gamma-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of gamma-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.109

文献信息

• Substituted Tetrahydroisoquinolines as Beta-secretase Inhibitors
  申请人：Thompson Lorin A.

  公开号：US20080153868A1

  公开（公告）日：2008-06-26

  There is provided a series of tetrahydroisoquinoline diaminopropane compounds of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R, R 8 and R 9 are as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.

  提供一系列Formula (I)的四氢异喹啉二氨基丙烷化合物或其立体异构体；或其药学上可接受的盐，其中R，R8和R9如本文所定义，它们的药物组合物和使用方法。这些化合物抑制β-分泌酶对淀粉样前体蛋白（APP）的加工，更具体地说，抑制Aβ肽的产生。本公开涉及用于治疗与β-淀粉样蛋白产生相关的神经系统疾病的化合物，如阿尔茨海默病和其他受抗淀粉样活性影响的疾病。
• Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors
  作者：Lorin A. Thompson、Jianliang Shi、Carl P. Decicco、Andrew J. Tebben、Richard E. Olson、Kenneth M. Boy、Jason M. Guernon、Andrew C. Good、Ann Liauw、Changsheng Zheng、Robert A. Copeland、Andrew P. Combs、George L. Trainor、Daniel M. Camac、Jodi K. Muckelbauer、Kimberley A. Lentz、James E. Grace、Catherine R. Burton、Jeremy H. Toyn、Donna M. Barten、Jovita Marcinkeviciene、Jere E. Meredith、Charles F. Albright、John E. Macor

  DOI：10.1016/j.bmcl.2011.06.116

  日期：2011.11

  The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats. (C) 2011 Elsevier Ltd. All rights reserved.
• US7902218B2
  申请人：——

  公开号：US7902218B2

  公开（公告）日：2011-03-08
• Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE)
  作者：Kenneth M. Boy、Jason M. Guernon、Jianliang Shi、Jeremy H. Toyn、Jere E. Meredith、Donna M. Barten、Catherine R. Burton、Charles F. Albright、Jovita Marcinkeviciene、Andrew C. Good、Andrew J. Tebben、Jodi K. Muckelbauer、Daniel M. Camac、Kimberley A. Lentz、Joanne J. Bronson、Richard E. Olson、John E. Macor、Lorin A. Thompson

  DOI：10.1016/j.bmcl.2011.06.109

  日期：2011.11

  The synthesis, evaluation, and structure-activity relationships of a class of gamma-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of gamma-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented. (C) 2011 Elsevier Ltd. All rights reserved.