(R)-tert-butyl3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate | 845543-89-7

• 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: (R)-tert-butyl3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
• 英文别名: (R)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate；tert-butyl (3R)-3-[(4S,5S)-4-[(3,5-difluorophenyl)methyl]-2-oxo-1,3-oxazolidin-5-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 845543-89-7
• 化学式: C₂₄H₂₆F₂N₂O₄
• 分子量: 444.478
• InChiKey: WWXZCUBHNHZPSN-HBMCJLEFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 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：

  (R)-tert-butyl3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 在 三氟乙酸 、 水 、 sodium carbonate 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 3.0h， 以100%的产率得到(4S,5R)-4-(3,5-difluorobenzyl)-5-((R)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one
  参考文献：
  名称：

  Substituted Tetrahydroisoquinolines as Beta-secretase Inhibitors

  摘要：

  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。

  公开号：

  US20080153868A1
• 作为产物：
  描述：

  (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one 在 过氧化氢,锂盐(1:1) 、 三氟甲磺酸二丁硼 、 叠氮磷酸二苯酯 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 生成 (R)-tert-butyl3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
  参考文献：
  名称：

  Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2011.06.116

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。
• [EN] CYCLIC AMINE BASE-1 INHIBITORS HAVING A HETEROCYCLIC SUBSTITUENT<br/>[FR] INHIBITEURS D'AMINES CYCLIQUES BACE-1 RENFERMANT UN SUBSTITUANT HETEROCYCLIQUE
  申请人：SCHERING CORP

  公开号：WO2005014540A1

  公开（公告）日：2005-02-17

  Disclosed are novel compounds of the formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is formula (I) X is -0-, -C(R14)2- or -N(R)-; Z is -C(R14)2- or -N(R)-; t is 0, 1, 2 or 3; each R and R2 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; each R14 is H, alkyl, alkenyl, alkynyl, halo, -CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, -OR35, -N(R24)(R25) or -SR35; R41 is alkyl, cycloalkyl, -S02(alkyl), -C(O)-alkyl, -C(O)-cycloalkyl or -alkyl-NH-C(O)CH3; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula (I). Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.

  揭示了具有以下结构的新化合物（I）或其药学上可接受的盐或溶剂，其中R1为结构（I），X为-0-，-C(R14)2-或-N(R)-；Z为-C(R14)2-或-N(R)-；t为0、1、2或3；每个R和R2独立地为H、烷基、环烷基、环烷基烷基、芳基、杂环芳基、杂环烷基、芳基烷基、杂环芳基烷基、杂环烷基烷基、烯基或炔基；每个R14为H、烷基、烯基、炔基、卤素、-CN、卤代烷基、环烷基、环烷基烷基、芳基、杂环芳基、芳基烷基、杂环芳基烷基、杂环烷基烷基、-OR35、-N(R24)(R25)或-SR35；R41为烷基、环烷基、-S02(烷基)、-C(O)-烷基、-C(O)-环烷基或-烷基-NH-C(O)CH3；其余变量如规范中所定义。还揭示了包括化合物的药物组合物（I）的制剂以及使用化合物（I）治疗认知或神经退行性疾病的方法。还揭示了包括化合物（I）的药物组合物和治疗方法，其与治疗认知或神经退行性疾病有用的其他药剂结合使用。
• CYCLIC AMINE BACE-1 INHIBITORS HAVING A HETEROCYCLIC SUBSTITUENT
  申请人：Cumming Jared N.

  公开号：US20090312341A1

  公开（公告）日：2009-12-17

  Disclosed are novel compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is X is —O—, —C(R 14 ) 2 — or —N(R)—; Z is —C(R 14 ) 2 — or —N(R)—; t is 0, 1, 2 or 3; each R and R 2 is independently H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, alkenyl or alkynyl; each R 14 is H, alkyl, alkenyl, alkynyl, halo, —CN, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, —OR 35 , —N(R 24 ) (R 25 ) or —SR 35 ; R 41 is alkyl, cycloalkyl, —SO 2 (alkyl), —C(O)-alkyl, —C(O)-cycloalkyl or -alkyl-NH—C(O)CH 3 ; and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I and methods of treating cognitive or neurodegenerative diseases with compounds of formula I. Also disclosed are pharmaceutical compositions and methods of treatment comprising compounds of formula I in combination with other agents useful in treating cognitive or neurodegenerative diseases.

  本发明涉及公式I的新化合物或其药学上可接受的盐或溶剂，其中R1为X为—O—，—C（R14）2—或—N（R）—；Z为—C（R14）2—或—N（R）—；t为0、1、2或3；每个R和R2独立地为H，烷基，环烷基，环烷基烷基，芳基，杂芳基，杂环烷基，芳基烷基，杂芳基烷基，杂环烷基烷基，烯基或炔基；每个R14为H，烷基，烯基，炔基，卤素，—CN，卤代烷基，环烷基，环烷基烷基，芳基，杂芳基，杂环烷基，芳基烷基，杂芳基烷基，杂环烷基烷基，—OR35，—N（R24）（R25）或—SR35；R41为烷基，环烷基，—SO2（烷基），—C（O）-烷基，—C（O）-环烷基或-烷基-NH-C（O）CH3；其余变量如规范中所定义。本发明还涉及包含公式I化合物的制药组合物以及使用公式I化合物治疗认知或神经退行性疾病的方法。本发明还涉及包含公式I化合物的制药组合物和治疗方法，其中该组合物与其他对治疗认知或神经退行性疾病有用的药物一起使用。
• Substituted tetrahydroisoquinolines as β-secretase inhibitors
  申请人：Bristol-Myers Squibb Company

  公开号：US07902218B2

  公开（公告）日：2011-03-08

  There is provided a series of tetrahydroisoquinoline diaminopropane compounds of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R, R8 and R9 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.

  提供了一系列四氢异喹啉二氨基丙烷化合物，其化学式为（I）或其立体异构体；或其药学上可接受的盐，其中R，R8和R9如本文中所定义，其药物组成物和使用方法。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，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，如阿尔茨海默病和其他受抗淀粉样蛋白活性影响的疾病的化合物。
• CYCLIC AMINE BACE-1 INHIBITORS HAVING A BENZAMIDE SUBSTITUENT
  申请人：Cumming Jared N.

  公开号：US20100152138A1

  公开（公告）日：2010-06-17

  Disclosed are compounds of the formula or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is R is —C(O)—N(R 27 )(R 28 ) or and the remaining variables are as defined in the specification. Also disclosed are pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of treating cognitive or neurodegenerative diseases such as Alzheimer's disease. Also disclosed are pharmaceutical compositions and methods of treating cognitive or neurodegenerative diseases comprising the compounds of formula I in combination with a β-secretase inhibitor other than those of formula I, an HMG-CoA reductase inhibitor, a gamma-secretase inhibitor, a non-steroidal anti-inflammatory agent, an N-methyl-D-aspartate receptor antagonist, a cholinesterase inhibitor or an anti-amyloid antibody.

  本发明揭示了式I的化合物，或其药学上可接受的盐或溶剂，其中R1是R是—C（O）—N（R27）（R28）或，其余变量如规范中所定义。本发明还揭示了包括式I化合物的药物组成物。本发明还揭示了治疗认知或神经退行性疾病，如阿尔茨海默病的方法。本发明还揭示了包括式I化合物的药物组成物和治疗认知或神经退行性疾病的方法，其中该组成物与β-分泌酶抑制剂（非式I的）、HMG-CoA还原酶抑制剂、γ-分泌酶抑制剂、非甾体抗炎药、N-甲基-D-天门冬氨酸受体拮抗剂、胆碱酯酶抑制剂或抗淀粉样蛋白抗体结合使用。