2-甲基-2-丙基[(2R,3S)-7-氟-2-甲基-4-氧代-2,3,4,5-四氢-1,5-苯并氧氮杂卓-3-基]氨基甲酸酯 | 889459-37-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 中文名称: 2-甲基-2-丙基[(2R,3S)-7-氟-2-甲基-4-氧代-2,3,4,5-四氢-1,5-苯并氧氮杂卓-3-基]氨基甲酸酯
• 英文名称: tert-butyl N-[(2R,3S)-7-fluoro-2-methyl-4-oxo-3,5-dihydro-2H-1,5-benzoxazepin-3-yl]carbamate
• 英文别名: ((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester；tert-Butyl ((2R,3S)-7-fluoro-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate
• CAS: 889459-37-4
• 化学式: C₁₅H₁₉FN₂O₄
• 分子量: 310.325
• InChiKey: JZFUCZIHNFLBSM-PELKAZGASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-甲基-2-丙基[(2R,3S)-7-氟-2-甲基-4-氧代-2,3,4,5-四氢-1,5-苯并氧氮杂卓-3-基]氨基甲酸酯 在 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 palladium 10% on activated carbon 、 氢气 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 141.25h， 生成 (S)-tert-butyl 4-acetamido-5-(2-((2-((2R,3S)-7-fluoro-3-((S)-2-hydroxy-2-methyl-3-oxo-3-(2,2,3,3,3-pentafluoropropylamino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5-(2H)-yl)ethoxy)carbonylamino)ethylamino)-5-oxopentanoate
  参考文献：
  名称：

  [EN] TARGETED NOTCH PATHWAY INHIBITORS
  [FR] INHIBITEURS DE LA VOIE DE NOTCH CIBLÉE

  摘要：

  本发明涉及式(I)的新型共轭物：S - L - A (I)或其盐，其中A为γ-分泌酶抑制剂，L为连接子，S为肽酶特异性底物，以及它们的制备方法、包含它们的药物组合物及其作为药物，特别是用于治疗肾脏疾病和肾脏组织损伤的用途。

  公开号：

  WO2016198366A1

文献信息

• Malonamide derivatives
  申请人：Flohr Alexander

  公开号：US20060122168A1

  公开（公告）日：2006-06-08

  The invention relates to compounds of the formula I wherein R, R 1 , R 2 , R 3 , X, and n are defined in the specification. The invention also provides pharmaceutically suitable acid addition salts thereof and all forms of optically pure enantiomers, recemates or diastereomers and diastereomeric mixtures thereof. Compounds of the invention are useful for the treatment of Alzheimer's disease.

  本发明涉及具有以下结构的化合物，其中R、R1、R2、R3、X和n在规范中有定义。本发明还提供了这些化合物的药用合适的酸盐以及所有形式的光学纯对映体、复旋体或二对映体和它们的对映异构体混合物。本发明的化合物对治疗阿尔茨海默病有用。
• Targeted notch pathway inhibitors
  申请人：Hoffmann-La Roche Inc.

  公开号：US10632127B2

  公开（公告）日：2020-04-28

  The instant invention relates to novel conjugates of the compound of formula (I): S—L—A  (I) or salts thereof, wherein A is a γ-secretase inhibitor, L is a linker and S is a peptidase-specific substrate, as well as processes for their manufacture, pharmaceutical compositions comprising them, and their use as medicaments.

  本发明涉及式（I）化合物的新型共轭物： S-L-A (I) 或其盐，其中 A 是 γ-分泌酶抑制剂，L 是连接体，S 是肽酶特异性底物，以及它们的制造工艺、包含它们的药物组合物和它们作为药物的用途。
• Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases
  作者：Lucienne Juillerat-Jeanneret、Alexander Flohr、Manfred Schneider、Isabelle Walter、Jean-Christophe Wyss、Rajesh Kumar、Dela Golshayan、Johannes D. Aebi

  DOI：10.1021/acs.jmedchem.5b00912

  日期：2015.10.22

  Notch is a membrane inserted protein activated by the membrane-inserted gamma-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the gamma-secretase inhibitor-based prodrugs 13a and 15a as substrates for gamma-glutamyltranspeptidase (gamma-CT) and/or gamma-glutamylcy-dotransferase (gamma-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-gamma-Glu-gamma-secretase inhibitor prodrug 13a (gamma-GT-targeting and gamma-GCT-targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notchl could be selectively down-regulated upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a.
• MALONAMIDE DERIVATIVES AS INHIBITORS OF GAMMA-SECRETASE FOR THE TREATMENT OF ALZHEIMER'S DISEASE
  申请人：F.HOFFMANN-LA ROCHE AG

  公开号：EP1828151A2

  公开（公告）日：2007-09-05
• TARGETED NOTCH PATHWAY INHIBITORS
  申请人：F. Hoffmann-La Roche AG

  公开号：EP3307721B1

  公开（公告）日：2020-06-17