(2S)-2-amino-4-methyl-N-(3-methyl-4-oxo-5H-2,3-benzodiazepin-5-yl)pentanamide | 400820-02-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-2-amino-4-methyl-N-(3-methyl-4-oxo-5H-2,3-benzodiazepin-5-yl)pentanamide
• CAS: 400820-02-2
• 化学式: C₁₆H₂₂N₄O₂
• 分子量: 302.376
• InChiKey: QQYIPYUJQRZMGE-LSLKUGRBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  87.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2S)-2-amino-4-methyl-N-(3-methyl-4-oxo-5H-2,3-benzodiazepin-5-yl)pentanamide 、 环己基乙酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 (2S)-2-[(2-cyclohexylacetyl)amino]-4-methyl-N-(3-methyl-4-oxo-5H-2,3-benzodiazepin-5-yl)pentanamide
  参考文献：
  名称：

  Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer’s disease

  摘要：

  We report on the design of benzodiazepin ones as peptidomimetics at the carboxy terminus of hydroxyamides. structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to AP reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.04.082
• 作为产物：
  描述：

  2-(2-甲酰基苯基)乙酸 在 palladium on activated charcoal 2,4,6-三异丙基苯磺酰叠氮化物 、 氢气 、 氯甲酸乙酯 、 双(三甲基硅烷基)氨基钾 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， -78.0~140.0 ℃ 、101.33 kPa 条件下， 反应 7.67h， 生成 (2S)-2-amino-4-methyl-N-(3-methyl-4-oxo-5H-2,3-benzodiazepin-5-yl)pentanamide
  参考文献：
  名称：

  Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer’s disease

  摘要：

  We report on the design of benzodiazepin ones as peptidomimetics at the carboxy terminus of hydroxyamides. structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to AP reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.04.082

文献信息

• Benzodiazepinone beta -amyloid inhibitors: arylacetamidoalanyl derivatives
  申请人：——

  公开号：US20020022621A1

  公开（公告）日：2002-02-21

  There is provided a series of arylacetamidoalanyl derivatives of benzodiazepinones of Formula I 1 wherein R 1 through R 7 and n are defined herein, which are inhibitors of &bgr;-amyloid peptide (&bgr;-AP) production and are useful in the treatment of Alzheimer's Disease and other conditions characterized by aberrant extract cellular deposition of amyloid.

  提供了一系列苯二氮平酮的芳基乙酰胺基丙氨酸衍生物，其化学式为I1，其中R1至R7和n的定义如本文所述，这些衍生物是β-淀粉样肽（β-AP）生产的抑制剂，可用于治疗阿尔茨海默病和其他因淀粉样物质在细胞中异常沉积而引起的疾病。
• US6432944B1
  申请人：——

  公开号：US6432944B1

  公开（公告）日：2002-08-13
• Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): A γ-secretase inhibitor with Aβ lowering activity in a transgenic mouse model of Alzheimer’s disease
  作者：C.V.C. Prasad、Ming Zheng、Shikha Vig、Carl Bergstrom、David W. Smith、Qi Gao、Suresh Yeola、Craig T. Polson、Jason A. Corsa、Valerie L. Guss、Alice Loo、Jian Wang、Bogdan G. Sleczka、Charles Dangler、Barbara J. Robertson、Joseph P. Hendrick、Susan B. Roberts、Donna M. Barten

  DOI：10.1016/j.bmcl.2007.04.082

  日期：2007.7

  We report on the design of benzodiazepin ones as peptidomimetics at the carboxy terminus of hydroxyamides. structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to AP reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses. (C) 2007 Elsevier Ltd. All rights reserved.