1-Quinolin-3-ylspiro[indole-3,4'-piperidine]-2-one | 1086282-09-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-Quinolin-3-ylspiro[indole-3,4'-piperidine]-2-one
• CAS: 1086282-09-8
• 化学式: C₂₁H₁₉N₃O
• 分子量: 329.401
• InChiKey: JPNCTGNJNZPPCW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  45.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-苄基-2-(氯甲基)-1H-咪唑 、 1-Quinolin-3-ylspiro[indole-3,4'-piperidine]-2-one 在 三乙胺 作用下， 以 DCM 为溶剂， 反应 2.0h， 生成 1'-[(1-benzyl-1H-imidazol-2-yl)methyl]-1-quinolin-3-ylspiro[indole-3,4'-piperidin]-2(1H)-one
  参考文献：
  名称：

  WO2008/144266

  摘要：

  公开号：
• 作为产物：
  描述：

  1’-BOC-1,2-二氢-2-氧代-螺[3H-吲哚-3,4’-哌啶] 在 盐酸 、 copper(l) iodide 、 potassium carbonate 、 N,N'-二甲基乙二胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 生成 1-Quinolin-3-ylspiro[indole-3,4'-piperidine]-2-one
  参考文献：
  名称：

  1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia

  摘要：

  The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.

  DOI：

  10.1021/jm201542d

文献信息

• SPIROINDALONES
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2160187B1

  公开（公告）日：2013-05-22
• US8309544B2
  申请人：——

  公开号：US8309544B2

  公开（公告）日：2012-11-13
• [EN] SPIROINDALONES<br/>[FR] SPIROINDALONES
  申请人：MERCK & CO INC

  公开号：WO2008144266A1

  公开（公告）日：2008-11-27

  [EN] The present invention relates to spiroindalone compounds useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
  [FR] La présente invention concerne des composés de spiroindalone qui s'utilisent en tant qu'inhibiteurs de prolylhydroxylase HIF pour traiter l'anémie et des troubles similaires.
• 1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia
  作者：Petr Vachal、Shouwu Miao、Joan M. Pierce、Deodial Guiadeen、Vincent J. Colandrea、Matthew J. Wyvratt、Scott P. Salowe、Lisa M. Sonatore、James A. Milligan、Richard Hajdu、Anantha Gollapudi、Carol A. Keohane、Russell B. Lingham、Suzanne M. Mandala、Julie A. DeMartino、Xinchun Tong、Michael Wolff、Dietrich Steinhuebel、Gerard R. Kieczykowski、Fred J. Fleitz、Kevin Chapman、John Athanasopoulos、Gregory Adam、Can D. Akyuz、Dhirendra K. Jena、Jeffrey W. Lusen、Juncai Meng、Benjamin D. Stein、Lei Xia、Edward C. Sherer、Jeffrey J. Hale

  DOI：10.1021/jm201542d

  日期：2012.4.12

  The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
• WO2008/144266
  申请人：——

  公开号：——

  公开（公告）日：——