axitinib | 1639138-00-3

• 分子结构分类: 有机化合物 - 苯类化合物
• 英文名称: axitinib
• 英文别名: 2-((1-Acetyl-3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide (Axitinib Impurity)；2-(1-acetyl-3-iodoindazol-6-yl)sulfanyl-N-methylbenzamide
• CAS: 1639138-00-3
• 化学式: C₁₇H₁₄IN₃O₂S
• 分子量: 451.288
• InChiKey: DHUHBTLTOGAYQU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.81
• 重原子数：
  24.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  63.99
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-乙烯基吡啶 、 axitinib 以 N-甲基吡咯烷酮 为溶剂， 生成 阿西替尼杂质J
  参考文献：
  名称：

  Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib

  摘要：

  The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

  DOI：

  10.1021/op400088k
• 作为产物：
  描述：

  2-巯基-N-甲基苯甲酰胺 在 tris-(dibenzylideneacetone)dipalladium(0) 、 碘 、 palladium diacetate 、 碳酸氢钠 、 N,N-二异丙基乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 potassium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 水 为溶剂， 反应 9.0h， 生成 axitinib
  参考文献：
  名称：

  Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib

  摘要：

  The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

  DOI：

  10.1021/op400088k

文献信息

• Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib
  作者：Linda Heintze、Dorian Schmidt、Theo Rodat、Lydia Witt、Julia Ewert、Malte Kriegs、Rainer Herges、Christian Peifer

  DOI：10.3390/ijms21238961

  日期：——

  In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

  在这项研究中，我们旨在将光药理学的概念应用于已批准的血管内皮生长因子受体（VEGFR）-2激酶抑制剂阿西替尼。在先前的研究中，我们发现阿西替尼的苯乙烯类双键的光异构化在水溶液中是单向的，因为存在竞争性不可逆的[2+2]-环加成反应。因此，我们接着通过将偶氮苯和二氮环骨架作为光响应元素，对阿西替尼进行了偶氮化改造。在概念上，二氮环（桥联偶氮苯）相对于标准偶氮苯表现出更有利的光切换特性，因为热力学稳定的Z异构体通常是生物不活性的，而从生物活性的E异构体到Z异构体的反向异构化是热力学的。在这里，我们报道了将硫-二氮环和碳-二氮环连接到阿西替尼药效团的发展，这些二氮环可以在VEGFR-2活性中实现可逆切换。对于最佳的硫-二氮环，我们在VEGFR-2激酶测定中验证了Z异构体是生物不活性的（IC50 >> 10,000 nM），而经过蓝光（405 nm）照射后可以观察到显著的VEGFR-2抑制作用，导致IC50值为214 nM。总的来说，我们成功地开发了可逆光切换激酶抑制剂，其在照射后在生物活性上表现出40倍以上的差异。此外，我们展示了二氮环光开关相对于标准偶氮苯的潜在优势。