N-cyclopropyl-4-(6-(2-hydroxyphenoxy)-8-((tetrahydro-2H-pyran-4-yl)methylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide | 1263424-19-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-cyclopropyl-4-(6-(2-hydroxyphenoxy)-8-((tetrahydro-2H-pyran-4-yl)methylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide
• 英文别名: N-cyclopropyl-4-[6-(2-hydroxyphenoxy)-8-(oxan-4-ylmethylamino)imidazo[1,2-b]pyridazin-3-yl]benzamide
• CAS: 1263424-19-6
• 化学式: C₂₈H₂₉N₅O₄
• 分子量: 499.569
• InChiKey: UWDDQSLWJFYWBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  三光气 、 N-cyclopropyl-4-(6-(2-hydroxyphenoxy)-8-((tetrahydro-2H-pyran-4-yl)methylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide 、 [(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] 2-(2-hydroxyethyldisulfanyl)ethyl carbonate 在 4-二甲氨基吡啶 作用下， 以 N,N-二甲基甲酰胺 、 N,N-二甲基甲酰胺-d7 为溶剂， 反应 13.0h， 以20 mg的产率得到
  参考文献：
  名称：

  [EN] NANOPARTICLES FOR CHEMOTHERAPY, TARGETED THERAPY, PHOTODYNAMIC THERAPY, IMMUNOTHERAPY, AND ANY COMBINATION THEREOF
  [FR] NANOPARTICULES POUR CHIMIOTHÉRAPIE, THÉRAPIE CIBLÉE, THÉRAPIE PHOTODYNAMIQUE, IMMUNOTHÉRAPIE ET N'IMPORTE QUELLE COMBINAISON DE CES DERNIÈRES

  摘要：

  含有脂质基团连接到药物衍生物的前药，例如通过含有二硫键的连接剂连接到抗癌药物衍生物的前药被描述。还描述了涂有含有前药的脂质层的纳米粒子，包含这些纳米粒子的配方，以及在治疗疾病的方法中使用这些纳米粒子，例如癌症，单独或与额外的药物化合物、靶向剂和/或免疫疗法剂联合使用，例如靶向CTLA-4、PD-1/PD-L1、IDO、LAG-3、CCR-7或其他途径的免疫抑制抑制剂，或者靶向这些途径的多种免疫抑制抑制剂的组合。可选地，纳米粒子可以包含光敏剂或其衍生物，并可用于涉及光动力疗法的方法。由所披露的纳米粒子和/或纳米粒子配方提供的多种疗法模式的组合导致协同治疗效果。

  公开号：

  WO2017201528A1
• 作为产物：
  描述：

  4-氨甲基四氢吡喃 在 4-二甲氨基吡啶 、 N-碘代丁二酰亚胺 、 [1,1'-二(二叔丁基膦)二茂铁]合二氯钯(II) 、 sodium hydride 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 25.17h， 生成 N-cyclopropyl-4-(6-(2-hydroxyphenoxy)-8-((tetrahydro-2H-pyran-4-yl)methylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide
  参考文献：
  名称：

  Discovery of Imidazo[1,2-b]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity

  摘要：

  Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.

  DOI：

  10.1021/jm501599u

文献信息

• Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof
  申请人：The University of Chicago

  公开号：US11246877B2

  公开（公告）日：2022-02-15

  Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and/or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1/PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and/or nanoparticle formulations.

  本文描述了含有脂质分子的原药，这些脂质分子通过包含二硫基团的连接体连接到药物衍生物（如抗癌药物衍生物）上。还描述了涂有包含原药的脂质层的纳米颗粒、包含纳米颗粒的制剂，以及纳米颗粒在治疗疾病（如癌症）的方法中的用途，单独使用或与其他药物化合物、靶向制剂和/或免疫疗法制剂（如靶向 CTLA-4、PD-1/PD-L1、IDO、LAG-3、CCR-7 或其他途径的免疫抑制抑制剂，或靶向此类途径组合的多种免疫抑制抑制剂）组合使用。可选地，纳米颗粒可包含光敏剂或其衍生物，并可用于涉及光动力疗法的方法中。所公开的纳米颗粒和/或纳米颗粒制剂提供的多种方式的组合可产生协同治疗效果。
• NANOPARTICLES FOR CHEMOTHERAPY, TARGETED THERAPY, PHOTODYNAMIC THERAPY, IMMUNOTHERAPY, AND ANY COMBINATION THEREOF
  申请人：The University of Chicago

  公开号：US20190269706A1

  公开（公告）日：2019-09-05

  Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and/or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1/PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and/or nanoparticle formulations.
• [EN] NANOPARTICLES FOR CHEMOTHERAPY, TARGETED THERAPY, PHOTODYNAMIC THERAPY, IMMUNOTHERAPY, AND ANY COMBINATION THEREOF<br/>[FR] NANOPARTICULES POUR CHIMIOTHÉRAPIE, THÉRAPIE CIBLÉE, THÉRAPIE PHOTODYNAMIQUE, IMMUNOTHÉRAPIE ET N'IMPORTE QUELLE COMBINAISON DE CES DERNIÈRES
  申请人：UNIV CHICAGO

  公开号：WO2017201528A1

  公开（公告）日：2017-11-23

  Prodrugs containing lipid moieties attached to drug derivatives, such as anti-cancer drug derivatives, via linkers comprising disulfide groups are described. Also described are nanoparticles coated with a lipid layer containing the prodrugs, formulations comprising the nanoparticles, and the use of the nanoparticles in methods of treating diseases, such as cancer, alone or in combination with additional drug compounds, targeting agents, and/or immunotherapy agents, such as immunosuppression inhibitors that target the CTLA-4, PD-1/PD-L1, IDO, LAG-3, CCR-7 or other pathways, or multiple immunosuppression inhibitors targeting a combination of such pathways. Optionally, the nanoparticles can comprise a photosensitizer or a derivative thereof and can be used in methods involving photodynamic therapy. Synergistic therapeutic effects result from combinations of multiple modalities provided by the disclosed nanoparticles and/or nanoparticle formulations.

  含有脂质基团连接到药物衍生物的前药，例如通过含有二硫键的连接剂连接到抗癌药物衍生物的前药被描述。还描述了涂有含有前药的脂质层的纳米粒子，包含这些纳米粒子的配方，以及在治疗疾病的方法中使用这些纳米粒子，例如癌症，单独或与额外的药物化合物、靶向剂和/或免疫疗法剂联合使用，例如靶向CTLA-4、PD-1/PD-L1、IDO、LAG-3、CCR-7或其他途径的免疫抑制抑制剂，或者靶向这些途径的多种免疫抑制抑制剂的组合。可选地，纳米粒子可以包含光敏剂或其衍生物，并可用于涉及光动力疗法的方法。由所披露的纳米粒子和/或纳米粒子配方提供的多种疗法模式的组合导致协同治疗效果。
• Discovery of Imidazo[1,2-<i>b</i>]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity
  作者：Ken-ichi Kusakabe、Nobuyuki Ide、Yataro Daigo、Takeshi Itoh、Takahiko Yamamoto、Hiroshi Hashizume、Kohei Nozu、Hiroshi Yoshida、Genta Tadano、Sachie Tagashira、Kenichi Higashino、Yousuke Okano、Yuji Sato、Makiko Inoue、Motofumi Iguchi、Takayuki Kanazawa、Yukichi Ishioka、Keiji Dohi、Yasuto Kido、Shingo Sakamoto、Shigeru Ando、Masahiro Maeda、Masayo Higaki、Yoshiyasu Baba、Yusuke Nakamura

  DOI：10.1021/jm501599u

  日期：2015.2.26

  Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.