(5S,8S,10aR)-methyl 5-(tert-butoxycarbonylamino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate | 1071993-12-8

• 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: (5S,8S,10aR)-methyl 5-(tert-butoxycarbonylamino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
• 英文别名: methyl (5S,8S,10aR)-3-(3-methylbutanoyl)-5-[(2-methylpropan-2-yl)oxycarbonylamino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
• CAS: 1071993-12-8
• 化学式: C₂₁H₃₅N₃O₆
• 分子量: 425.525
• InChiKey: RFRWFEXHZOYKIQ-PMPSAXMXSA-N

物化性质

• 沸点：
  593.9±50.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (5S,8S,10aR)-methyl 5-(tert-butoxycarbonylamino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate 以82的产率得到(5S,8S,10aR)-5-((tert-Butoxycarbonyl)amino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  参考文献：
  名称：

  J. Med. Chem. 2011, 54, 2714-2726

  摘要：

  DOI：
• 作为产物：
  描述：

  (2S)-5-烯丙基-1,2-吡咯烷二羧酸 1-叔丁酯 2-甲酯 在 盐酸 、 palladium on activated charcoal 、 氢气 、 三乙酰氧基硼氢化钠 、 1-羟基苯并三唑 、 臭氧 、 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 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 异丙醇 、 乙腈 为溶剂， 生成 (5S,8S,10aR)-methyl 5-(tert-butoxycarbonylamino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
  参考文献：
  名称：

  Debio-1143. Inhibitor of apoptosis protein (IAP) antagonist, Cancer therapy

  摘要：

  Inhibitors of apoptosis proteins (IAPs) block caspases, modulate nuclear factor NF-kappa B signaling pathways and are involved in resistance to cancer therapies. Debio-1143, a mimetic of an endogenous IAP inhibitor (second mitochondria-derived activator of caspases [SMAC]), may help to overcome treatment resistance and has demonstrated antitumor activity in various cancer cell lines and xenograft models, alone or in combination with chemotherapy, radiotherapy or immunotherapies. So far, about 150 cancer patients have been enrolled in 5 registered early-phase clinical trials testing Debio-1143. Tolerability was acceptable even when the drug was used in combination therapies. In monotherapy, pharmacokinetics was linear, but varied considerably among patients in combination settings. High tumor penetration and on-target activity were consistently shown in patient surrogate tissues and tumor biopsies. Tumor responses to second-(or higher) line monotherapy in patients with various advanced cancers were rather weak, but currently followed approaches as an adjunct to existing cancer therapies look[GRAPHICS]encouraging. Still, to identify ideal target populations and concomitant regimens remains challenging.

  DOI：

  10.1358/dof.2017.042.12.2702829

文献信息

• DIAZO BICYCLIC SMAC MIMETICS AND THE USES THEREOF
  申请人：Wang Shaomeng

  公开号：US20100273812A1

  公开（公告）日：2010-10-28

  The invention relates to diazo bicyclic mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.

  该发明涉及一种Smac的重氮双环模拟物，其作为细胞凋亡抑制蛋白抑制剂。该发明还涉及利用这些模拟物诱导细胞凋亡死亡以及使细胞对凋亡诱导剂敏感的用途。
• A Potent and Orally Active Antagonist (SM-406/AT-406) of Multiple Inhibitor of Apoptosis Proteins (IAPs) in Clinical Development for Cancer Treatment
  作者：Qian Cai、Haiying Sun、Yuefeng Peng、Jianfeng Lu、Zaneta Nikolovska-Coleska、Donna McEachern、Liu Liu、Su Qiu、Chao-Yie Yang、Rebecca Miller、Han Yi、Tao Zhang、Duxin Sun、Sanmao Kang、Ming Guo、Lance Leopold、Dajun Yang、Shaomeng Wang

  DOI：10.1021/jm101505d

  日期：2011.4.28

  We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, and cIAP2 proteins with K(i) of 66.4, 1.9, and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein, and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates, and dogs, is highly effective in induction of apoptosis in xenograft tumors, and is capable of complete inhibition of tumor growth. Compound 2 is currently in phase I clinical trials for the treatment of human cancer.
• J. Med. Chem. 2011, 54, 2714-2726
  作者：

  DOI：——

  日期：——
• HETEROARYL-SUBSTITUTED BICYCLIC SMAC MIMETICS AND THE USES THEREOF
  申请人：Wang Shaomeng

  公开号：US20110046189A1

  公开（公告）日：2011-02-24

  The invention relates to heteroaryl-substituted bicyclic mimetics of Smac which function as inhibitors of Inhibitor of Apoptosis Proteins. The invention also relates to the use of these mimetics for inducing apoptotic cell death and for sensitizing cells to inducers of apoptosis.
• US8278293B2
  申请人：——

  公开号：US8278293B2

  公开（公告）日：2012-10-02