2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one | 1261117-14-9

• 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: 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one
• 英文别名: 2-amino-1-[3-(3,4-difluoroanilino)-2-(4-fluorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-2-methyl-propan-1-one；2-amino-1-[3-(3,4-difluoroanilino)-2-(4-fluorophenyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-2-methylpropan-1-one
• CAS: 1261117-14-9
• 化学式: C₂₂H₂₂F₃N₅O
• 分子量: 429.445
• InChiKey: WGKXETUOZHHSRI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  76.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one 在 二氧化锰 作用下， 反应 2.0h， 生成 8-(3,4-difluorophenylamino)-9-(4-fluorophenyl)-2,2-dimethyl-1,2,5,6-tetrahydrodiimidazo[1,2-a: 2',1'-c]pyrazin-3 (10bH)-one
  参考文献：
  名称：

  COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES

  摘要：

  本发明提供了一类化合物，包括该类化合物的药物组合物和使用该类化合物治疗或预防疟疾的方法。

  公开号：

  US20130281403A1
• 作为产物：
  描述：

  N-(3,4-difluorophenyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyrazin-3-amine 在 palladium on carbon 、 氢气 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-amino-1-(3-(3,4-difluorophenylamino)-2-(4-fluorophenyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-methylpropan-1-one
  参考文献：
  名称：

  Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents

  摘要：

  Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

  DOI：

  10.1021/jm2003359

文献信息

• COMPOUNDS AND COMPOSITIONS USEFUL FOR THE TREATMENT OF PARASITIC DISEASES
  申请人：Chatterjee Arnab K.

  公开号：US20110059934A1

  公开（公告）日：2011-03-10

  The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

  本发明提供了一类化合物，包括该类化合物的药物组合物以及使用该类化合物治疗或预防疟疾的方法。
• Compounds and compositions useful for the treatment of parasitic diseases
  申请人：Chatterjee Arnab K.

  公开号：US08557801B2

  公开（公告）日：2013-10-15

  The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

  本发明提供了一类化合物，包括这些化合物的制药组合物以及使用这些化合物治疗或预防疟疾的方法。
• COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF PARASITIC DISEASES
  申请人：Chatterjee Arnab K.

  公开号：US20130281403A1

  公开（公告）日：2013-10-24

  The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

  本发明提供了一类化合物，包括该类化合物的药物组合物和使用该类化合物治疗或预防疟疾的方法。
• Imidazo[1,2a]pyrazines and compositions comprising them for the treatment of parasitic diseases
  申请人：IRM LLC

  公开号：EP2737927A1

  公开（公告）日：2014-06-04

  The invention provides compounds of formula Ia, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent malaria.

  本发明提供了式 Ia 化合物、包含此类化合物的药物组合物以及使用此类化合物治疗或预防疟疾的方法。
• Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents
  作者：Advait Nagle、Tao Wu、Kelli Kuhen、Kerstin Gagaring、Rachel Borboa、Caroline Francek、Zhong Chen、David Plouffe、Xuena Lin、Christopher Caldwell、Jared Ek、Suzanne Skolnik、Fenghua Liu、Jianling Wang、Jonathan Chang、Chun Li、Bo Liu、Thomas Hollenbeck、Tove Tuntland、John Isbell、Tiffany Chuan、Philip B. Alper、Christoph Fischli、Reto Brun、Suresh B. Lakshminarayana、Matthias Rottmann、Thierry T. Diagana、Elizabeth A. Winzeler、Richard Glynne、David C. Tully、Arnab K. Chatterjee

  DOI：10.1021/jm300041e

  日期：2012.5.10

  On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.