6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one | 1229583-76-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one
• 英文别名: 5-bromo-3-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2-one
• CAS: 1229583-76-9
• 化学式: C₁₃H₈BrN₅O
• 分子量: 330.143
• InChiKey: SQZXFMCDIDWEGL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  73.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one 、 3,4,5-三甲氧基苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 乙腈 为溶剂， 反应 0.17h， 以19%的产率得到1-(1H-indol-5-yl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo-[4,5-b]pyrazin-2(3H)-one
  参考文献：
  名称：

  [EN] MIXED LINEAGE KINASE INHIBITORS FOR HIV/AIDS THERAPIES
  [FR] INHIBITEURS DE KINASE DE LIGNAGE MIXTE POUR DES THÉRAPIES POUR LE VIH/SIDA

  摘要：

  揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用有效量的混合谱系激酶抑制剂和抗逆转录病毒药物。此外，还揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用配制成含有表面活性剂的结晶纳米粒子的抗逆转录病毒药物，以及MLK抑制剂。进一步揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用包含抗逆转录病毒和MLK抑制剂的组合物，该组合物配制成含有表面活性剂的结晶纳米粒子。还揭示了包含抗逆转录病毒药物、MLK抑制剂和表面活性剂的组合物，其中该组合物是结晶纳米粒子。还揭示了包含MLK抑制剂与其他药物在纳米粒形式中的组合物，以及其使用方法。

  公开号：

  WO2014085795A1
• 作为产物：
  描述：

  6-bromo-N²-(1H-indol-5-yl)pyrazine-2,3-diamine 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以41%的产率得到6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one
  参考文献：
  名称：

  Discovery, Synthesis, and Characterization of an Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3

  摘要：

  Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here UR/VIC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNF alpha release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple Icinase pathways, including MLK3 and LRRK2 (IC50 = 11 n/M). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.

  DOI：

  10.1021/jm401094t

文献信息

• [EN] MIXED LINEAGE KINASE INHIBITORS FOR HIV/AIDS THERAPIES<br/>[FR] INHIBITEURS DE KINASE DE LIGNAGE MIXTE POUR DES THÉRAPIES POUR LE VIH/SIDA
  申请人：UNIV ROCHESTER

  公开号：WO2014085795A1

  公开（公告）日：2014-06-05

  Disclosed are methods for treating an individual infected with a retrovirus that comprise administering to the individual effective amounts of a mixed lineage kinase inhibitor and antiretroviral drug. In further aspects, disclosed are methods for treating an individual infected with a retrovirus that comprises administering an antiretroviral drug formulated into a crystalline nanoparticle comprising a surfactant, and a MLK inhibitor. Still further disclosed are methods for treating an individual infected with a retrovirus that comprises administering a composition comprising both an antiretroviral and MLK inhibitor formulated into a crystalline nanoparticle, which comprises a surfactant. Still further disclosed are compositions that comprise an antiretroviral drug, a MLK inhibitor, and a surfactant, wherein the composition is a crystalline nanoparticle. Compostions comprising MLK inhibitors with other drugs in nanoparticulate form, and methods of there use, are also disclosed.

  揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用有效量的混合谱系激酶抑制剂和抗逆转录病毒药物。此外，还揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用配制成含有表面活性剂的结晶纳米粒子的抗逆转录病毒药物，以及MLK抑制剂。进一步揭示了治疗感染逆转录病毒的个体的方法，包括向个体施用包含抗逆转录病毒和MLK抑制剂的组合物，该组合物配制成含有表面活性剂的结晶纳米粒子。还揭示了包含抗逆转录病毒药物、MLK抑制剂和表面活性剂的组合物，其中该组合物是结晶纳米粒子。还揭示了包含MLK抑制剂与其他药物在纳米粒形式中的组合物，以及其使用方法。
• MLK INHIBITORS AND METHODS OF USE
  申请人：Gelbard Harris A.

  公开号：US20120053175A1

  公开（公告）日：2012-03-01

  Provided are compounds having an inhibitory effect on Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.

  本文提供了对混合谱系激酶具有抑制作用的化合物。还提供了药物组合物、化合物制备方法、合成中间体和使用这些化合物的方法，这些方法可以独立地或与其他治疗剂联合使用，用于治疗受混合谱系激酶抑制影响的疾病和状况。同时，还提供了通过抑制混合谱系激酶来治疗神经精神障碍的方法。
• Substituted pyrrolo[2,3-B]pyridines as MLK inhibitors
  申请人：Gelbard Harris A.

  公开号：US08877772B2

  公开（公告）日：2014-11-04

  Provided are compounds having an inhibitory effect on Mixed Lineage Kinases, having a structural Formula, Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.

  提供了一些化合物，具有对混合谱系激酶的抑制作用，具有结构式。还提供了药物组合物、制备这些化合物的方法、合成中间体以及使用这些化合物的方法，独立地或与其他治疗剂联合使用，用于治疗受混合谱系激酶抑制影响的疾病和病况。还提供了治疗神经精神障碍的方法，其中包括抑制混合谱系激酶。
• BICYCLIC HETEROARYL KINASE INHIBITORS AND METHODS OF USE
  申请人：Gelbard Harris A.

  公开号：US20130203755A1

  公开（公告）日：2013-08-08

  Provided are compounds having an inhibitory effect on kinases including Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders that comprise the inhibition of Mixed Lineage Kinases.

  提供了一些具有抑制激酶活性的化合物，包括混合谱系激酶。还提供了制药组合物、制备这些化合物的方法、合成中间体以及使用这些化合物的方法，可单独使用或与其他治疗药物结合，用于治疗受混合谱系激酶抑制影响的疾病和病况。还提供了抑制混合谱系激酶的方法，用于治疗神经精神障碍。
• Bicyclic heteroaryl kinase inhibitors and methods of use
  申请人：Gelbard Harris A.

  公开号：US08846909B2

  公开（公告）日：2014-09-30

  Provided are compounds having an inhibitory effect on kinases including Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders that comprise the inhibition of Mixed Lineage Kinases.

  提供了一些具有抑制激酶活性的化合物，包括混合谱系激酶。同时还提供了药物组合物、制备该化合物的方法、合成中间体以及使用该化合物的方法，可以独立使用或与其他治疗药物联合使用，用于治疗受混合谱系激酶抑制影响的疾病和病况。同时还提供了抑制混合谱系激酶的方法，用于治疗神经精神障碍。