tert-butyl (S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate

• 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: tert-butyl (S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate
• 英文别名: tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1, 4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate；tert-butyl N-[(2S)-1-[[(3S,4S)-5-acetyl-7-cyano-1-[(2-methoxynaphthalen-1-yl)methyl]-4-methyl-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate
• 化学式: C₃₄H₃₉N₅O₆
• 分子量: 613.714
• InChiKey: VTBVMFKSOWDHHO-LPBFERMMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  45
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  132
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl (S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate 在 盐酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.0h， 以80%的产率得到(S)-N-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)-methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]-diazepin-3-yl)-2-(methylamino)propanamide hydrochloride
  参考文献：
  名称：

  2-OXO-2,3,4,5-TETRAHYDRO-1 H-BENZO[B]DIAZEPINES AND THEIR USE IN THE TREATMENT OF CANCER

  摘要：

  本文披露了化合物I式或其药用盐，其中W、Y、Z、R1、R2、R3、R4和R5如本文所述，并且使用所述化合物治疗癌症的方法。

  公开号：

  US20150225449A1
• 作为产物：
  描述：

  3-氟-4-硝基苯腈 在 吡啶 、 盐酸 、 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 caesium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.5h， 生成 tert-butyl (S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate
  参考文献：
  名称：

  Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain

  摘要：

  The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the proapoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNF alpha, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNF alpha in vitro.

  DOI：

  10.1021/jm400732v

文献信息

• 2-OXO-2,3,4,5-TETRAHYDRO-1 H-BENZO[B]DIAZEPINES AND THEIR USE IN THE TREATMENT OF CANCER
  申请人：HOFFMANN-LA ROCHE INC.

  公开号：US20150225449A1

  公开（公告）日：2015-08-13

  Disclosed are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W, Y, Z, R1, R2, R3, R4 and R5 are described herein, and methods of using said compounds in the treatment of cancer.

  本文披露了化合物I式或其药用盐，其中W、Y、Z、R1、R2、R3、R4和R5如本文所述，并且使用所述化合物治疗癌症的方法。
• 2-oxo-2,3,4,5-tetrahydro-1 H-benzo[B]diazepines and their use in the treatment of cancer
  申请人：Hoffmann-La Roche Inc.

  公开号：US09422331B2

  公开（公告）日：2016-08-23

  Disclosed are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein W, Y, Z, R1, R2, R3, R4 and R5 are described herein, and methods of using said compounds in the treatment of cancer.

  本发明涉及Formula I化合物或其药学上可接受的盐，其中W、Y、Z、R1、R2、R3、R4和R5如本文所述，并且本发明涉及使用所述化合物治疗癌症的方法。
• US9422331B2
  申请人：——

  公开号：US9422331B2

  公开（公告）日：2016-08-23
• Optimization of Benzodiazepinones as Selective Inhibitors of the X-Linked Inhibitor of Apoptosis Protein (XIAP) Second Baculovirus IAP Repeat (BIR2) Domain
  作者：Robert F. Kester、Andrew F. Donnell、Yan Lou、Stacy W. Remiszewski、Louis J. Lombardo、Shaoqing Chen、Nam T. Le、Jennifer Lo、John A. Moliterni、Xiaochun Han、J. Heather Hogg、Weiling Liang、Christophe Michoud、Kenneth C. Rupert、Steven Mischke、Kang Le、Martin Weisel、Cheryl A. Janson、Christine M. Lukacs、Adrian J. Fretland、Kyoungja Hong、Ann Polonskaia、Lin Gao、Shirley Li、Dave S. Solis、Doug Aguilar、Christine Tardell、Mark Dvorozniak、Shahid Tannu、Edmund C. Lee、Andy D. Schutt、Barry Goggin

  DOI：10.1021/jm400732v

  日期：2013.10.24

  The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the proapoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNF alpha, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNF alpha in vitro.