tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-propan-2-yl)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 methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-propan-2-yl)carbamate
• 英文别名: tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2',3',4,5,5',6'-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4'-pyran]-3-ylamino)propan-2-yl)carbamate；tert-butyl N-methyl-N-[(2S)-1-oxo-1-[[(3S)-4-oxospiro[3,5-dihydro-1,5-benzoxazepine-2,4'-oxane]-3-yl]amino]propan-2-yl]carbamate
• 化学式: C₂₂H₃₁N₃O₆
• 分子量: 433.505
• InChiKey: PPLFECGYZPSLGC-WMLDXEAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-propan-2-yl)carbamate 在 N-溴代丁二酰亚胺(NBS) 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 以98%的产率得到tert-butyl (S)-1-((S)-8-bromo-4-oxo-2',3',4,5,5'6'-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4'-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate
  参考文献：
  名称：

  [EN] SUBSTITUTED HETERO-AZEPINONES
  [FR] HÉTÉRO-AZÉPINONES SUBSTITUÉES

  摘要：

  提供了符合式（1）的化合物，其中W、X、Y、Z、R1、R2、R3、R4、R5和R6如本文所述。这些化合物对于治疗增殖性疾病，包括癌症，是有用的。

  公开号：

  WO2014023708A1
• 作为产物：
  描述：

  ethyl 2-(dibenzylamino)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetate 在 20% palladium hydroxide-activated charcoal 、 氢气 、 双(三甲基硅烷基)氨基钾 、 氯化铵 、 1-羟基苯并三唑 、 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 、 三乙胺 、 potassium hydroxide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0~65.0 ℃ 、101.33 kPa 条件下， 反应 57.0h， 生成 tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-propan-2-yl)carbamate
  参考文献：
  名称：

  Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain

  摘要：

  XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.

  DOI：

  10.1021/jm400731m

文献信息

• SUBSTITUTED HETERO-AZEPINONES
  申请人：Hoffman-La Roche Inc.

  公开号：US20150361059A1

  公开（公告）日：2015-12-17

  There are provided compounds of the formula wherein: V, W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are described herein. The compounds are useful for the treatment of proliferative diseases, including cancer.

  提供的化合物的公式如下： 其中：V、W、X、Y、Z、R1、R2、R3、R4、R5和R6如本文所述。这些化合物对于治疗增殖性疾病，包括癌症，是有用的。
• Substituted hetero-azepinones
  申请人：Hoffman-La Roche Inc.

  公开号：US09394263B2

  公开（公告）日：2016-07-19

  There are provided compounds of the formula wherein: V, W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are described herein. The compounds are useful for the treatment of proliferative diseases, including cancer.

  提供了以下公式的化合物： 其中：V、W、X、Y、Z、R1、R2、R3、R4、R5和R6的描述已在此处给出。这些化合物可用于治疗增殖性疾病，包括癌症。
• US9394263B2
  申请人：——

  公开号：US9394263B2

  公开（公告）日：2016-07-19
• [EN] SUBSTITUTED HETERO-AZEPINONES<br/>[FR] HÉTÉRO-AZÉPINONES SUBSTITUÉES
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014023708A1

  公开（公告）日：2014-02-13

  There are provided compounds of the formula (1) wherein W, X, Y, Z, R1, R2, R3, R4, R5 and R6 are described herein. These compounds are useful for the treatment of proliferative diseases, including cancer.

  提供了符合式（1）的化合物，其中W、X、Y、Z、R1、R2、R3、R4、R5和R6如本文所述。这些化合物对于治疗增殖性疾病，包括癌症，是有用的。
• Benzazepinones and Benzoxazepinones as Antagonists of Inhibitor of Apoptosis Proteins (IAPs) Selective for the Second Baculovirus IAP Repeat (BIR2) Domain
  作者：Andrew F. Donnell、Christophe Michoud、Kenneth C. Rupert、Xiaochun Han、Douglas Aguilar、Karl B. Frank、Adrian J. Fretland、Lin Gao、Barry Goggin、J. Heather Hogg、Kyoungja Hong、Cheryl A. Janson、Robert F. Kester、Norman Kong、Kang Le、Shirley Li、Weiling Liang、Louis J. Lombardo、Yan Lou、Christine M. Lukacs、Steven Mischke、John A. Moliterni、Ann Polonskaia、Andrew D. Schutt、Dave S. Solis、Anthony Specian、Robert T. Taylor、Martin Weisel、Stacy W. Remiszewski

  DOI：10.1021/jm400731m

  日期：2013.10.24

  XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.