ethyl 6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-{[(trifluoromethyl) sulfonyl]oxy}-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate | 1268476-79-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: ethyl 6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-{[(trifluoromethyl) sulfonyl]oxy}-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
• 英文别名: Ethyl 6-ethyl-1-methyl-4-oxo-5-phenacyl-3-(trifluoromethylsulfonyloxy)pyrrolo[3,2-c]pyridine-2-carboxylate；ethyl 6-ethyl-1-methyl-4-oxo-5-phenacyl-3-(trifluoromethylsulfonyloxy)pyrrolo[3,2-c]pyridine-2-carboxylate
• CAS: 1268476-79-4
• 化学式: C₂₂H₂₁F₃N₂O₇S
• 分子量: 514.479
• InChiKey: JREYKLPUFVLVMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  120
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  ethyl 6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-{[(trifluoromethyl) sulfonyl]oxy}-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 在 四(三苯基膦)钯 、 palladium 10% on activated carbon 氢气 作用下， 以 甲醇 、 水 为溶剂， 反应 5.0h， 生成 ethyl 3,6-diethyl-5-(2-hydroxy-2-phenylethyl)-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
  参考文献：
  名称：

  FUSED HETEROCYCLIC RING DERIVATIVE AND USE THEREOF

  摘要：

  公开号：

  EP2471791B1
• 作为产物：
  描述：

  3-氧代戊酸甲酯 在 吡啶 、 乙酸铵 、 三氟甲磺酸酐 、 sodium ethanolate 、 potassium carbonate 、 三乙胺 、 三氯氧磷 作用下， 以 甲醇 、 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 157.5h， 生成 ethyl 6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-{[(trifluoromethyl) sulfonyl]oxy}-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate
  参考文献：
  名称：

  Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility

  摘要：

  We recently reported the discovery of the novel pyrrolo[3,2-c] quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C-max value 3.63 mu g/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.07.034

文献信息

• US8927718B2
  申请人：——

  公开号：US8927718B2

  公开（公告）日：2015-01-06
• FUSED HETEROCYCLIC RING DERIVATIVE AND USE THEREOF
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP2471791B1

  公开（公告）日：2014-11-12
• Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility
  作者：Tomohiro Ohashi、Yuya Oguro、Toshio Tanaka、Zenyu Shiokawa、Yuta Tanaka、Sachio Shibata、Yoshihiko Sato、Hiroko Yamakawa、Harumi Hattori、Yukiko Yamamoto、Shigeru Kondo、Maki Miyamoto、Mitsuhiro Nishihara、Yoshimasa Ishimura、Hideaki Tojo、Atsuo Baba、Satoshi Sasaki

  DOI：10.1016/j.bmc.2012.07.034

  日期：2012.9

  We recently reported the discovery of the novel pyrrolo[3,2-c] quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C-max value 3.63 mu g/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors. (C) 2012 Elsevier Ltd. All rights reserved.