3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo-[3,2-c]-quinoline-2-carboxylic acid | 1398508-18-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo-[3,2-c]-quinoline-2-carboxylic acid
• CAS: 1398508-18-3
• 化学式: C₂₂H₂₂N₂O₅
• 分子量: 394.427
• InChiKey: HXMOWUAWYSKXFO-UHFFFAOYSA-N

物化性质

• 沸点：
  692.1±55.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.81
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  90.53
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride 、 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo-[3,2-c]-quinoline-2-carboxylic acid 在 1-羟基苯并三唑 、 1,2-二氯乙烷 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以76%的产率得到N-[1-(2-hydroxyacetyl)piperidin-4-yl]-3-methoxy-1-methyl-4-oxo-5-phenacyl-6,7,8,9-tetrahydropyrrolo[3,2-c]quinoline-2-carboxamide
  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
• 作为产物：
  描述：

  3-carboethoxy-4-hydroxy-5,6,7,8-tetrahydro-2(1H)-quinolone 在 10% Pd/C 、 氢气 、 sodium hydride 、 三乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基乙酰胺 、 mineral oil 为溶剂， 反应 72.5h， 生成 3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5,6,7,8,9-hexahydro-1H-pyrrolo-[3,2-c]-quinoline-2-carboxylic acid
  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