(E)-3-(1-(2-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)-1,2,4-oxadiazol-5(4H)-one | 1207546-38-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: (E)-3-(1-(2-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)-1,2,4-oxadiazol-5(4H)-one
• 英文别名: (E)-2-fluoro-8-(2-propylbenzimidazol-1-yl)methyl-11-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine；3-[(1E)-1-[2-fluoro-8-[(2-propylbenzimidazol-1-yl)methyl]-6H-benzo[c][1]benzoxepin-11-ylidene]ethyl]-4H-1,2,4-oxadiazol-5-one
• CAS: 1207546-38-0
• 化学式: C₂₉H₂₅FN₄O₃
• 分子量: 496.541
• InChiKey: UCPPHTQISPRTFW-WPWMEQJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  77.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-氟苯酚 在 2,6-二甲基吡啶 、 甲醇 、 锂硼氢 、 三氟化硼乙醚 、 1,3-双(二苯基膦)丙烷 、 羟胺 、 sodium methylate 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 三乙胺 、 三氟乙酸酐 、 lithium bromide 、 lithium diisopropyl amide 、 甲基磺酸酐 作用下， 以 四氢呋喃 、 乙醇 、 正庚烷 、 二氯甲烷 、 乙基苯 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 62.5h， 生成 (E)-3-(1-(2-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)-1,2,4-oxadiazol-5(4H)-one
  参考文献：
  名称：

  Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

  摘要：

  We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

  DOI：

  10.1016/j.bmc.2019.115122

文献信息

• TRICYCLIC COMPOUND
  申请人：Yanagisawa Arata

  公开号：US20110201640A1

  公开（公告）日：2011-08-18

  Provided is a tricyclic compound having a PPAR γ agonist activity, which is represented by the general formula (I) wherein Z represents a single bond or the like, Y represents a hydrogen atom, lower alkyl optionally having substituent(s) or the like, X represents a hydrogen atom or the like, A represents aryl or the like, B and C are the same or different and each represents an aromatic carbocycle or the like, R 4 -R 9 are the same or different and each represents hydrogen or the like, V represents a single bond or the like, R 10 and R 11 are the same or different and each represents hydrogen or the like, or a pharmaceutically acceptable salt thereof or the like:

  提供了一种三环化合物，具有PPARγ激动剂活性，其通式表示为（I），其中Z代表单键或类似物，Y代表氢原子，可选具有取代基的低碳基或类似物，X代表氢原子或类似物，A代表芳基或类似物，B和C相同或不同，每个代表芳香烃环或类似物，R4-R9相同或不同，每个代表氢原子或类似物，V代表单键或类似物，R10和R11相同或不同，每个代表氢原子或类似物，或其药学上可接受的盐或类似物。
• US8486980B2
  申请人：——

  公开号：US8486980B2

  公开（公告）日：2013-07-16
• Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold
  作者：Keisuke Yamamoto、Tomohiro Tamura、Rina Nakamura、Shintaro Hosoe、Masahiro Matsubara、Keiko Nagata、Hiroshi Kodaira、Takeshi Uemori、Yuichi Takahashi、Michihiko Suzuki、Jun-ichi Saito、Kimihisa Ueno、Satoshi Shuto

  DOI：10.1016/j.bmc.2019.115122

  日期：2019.11

  We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.