6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide hydrochloride | 1186231-70-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide hydrochloride
• 英文别名: 6-ethyl-3-methoxy-1-methyl-4-oxo-5-phenacyl-N-piperidin-4-ylpyrrolo[3,2-c]pyridine-2-carboxamide;hydrochloride
• CAS: 1186231-70-8
• 化学式: C₂₅H₃₀N₄O₄*ClH
• 分子量: 486.999
• InChiKey: SMZZABJQGPOVOJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  92.7
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide hydrochloride 、 乙酰氧基乙酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 15.0h， 生成 2-(4-(6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamido)piperidin-1-yl)-2-oxoethyl acetate
  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：

  6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo-[3,2-c]-pyridine-2-carboxylic acid 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 2.0h， 以97.2 mg的产率得到6-ethyl-3-methoxy-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide hydrochloride
  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

• FUSED HETEROCYCLIC DERIVATIVE AND USE THEREOF
  申请人：FUJII Nobuhiro

  公开号：US20090227561A1

  公开（公告）日：2009-09-10

  The present invention provides a compound having a superior Smo inhibitory activity and lower toxicity, which is sufficiently satisfactory as a pharmaceutical product. The present invention provides a compound represented by the formula wherein ring A is 5- to 7-membered ring optionally having substituent(s), where substituents are optionally bonded to each other to form a ring; X is O, S or NR 1 (R 1 is a hydrogen atom or a hydrocarbon group optionally having substituent(s)); R 2 is carbamoyl optionally having substituent(s); and R 3 is hydroxy optionally having substituent(s), or a salt thereof.

  本发明提供了一种具有优异的Smo抑制活性和较低毒性的化合物，该化合物作为药物产品是完全令人满意的。本发明提供了一种由下式表示的化合物： 其中，环A是5-至7-成员环，可选择地具有取代基，其中取代基可选择地与彼此结合形成环；X是O、S或NR1（R1是氢原子或具有取代基的碳氢基团）；R2是氨基甲酰，可选择地具有取代基；R3是羟基，可选择地具有取代基，或其盐。
• Fused heterocyclic derivative and use thereof
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US08217176B2

  公开（公告）日：2012-07-10

  The present invention provides a compound having a superior Smo inhibitory activity and lower toxicity, which is sufficiently satisfactory as a pharmaceutical product. The present invention provides a compound represented by the formula wherein ring A is 5- to 7-membered ring optionally having substituent(s), where substituents are optionally bonded to each other to form a ring; X is O, S or NR1 (R1 is a hydrogen atom or a hydrocarbon group optionally having substituent(s)); R2 is carbamoyl optionally having substituent(s); and R3 is hydroxy optionally having substituent(s), or a salt thereof.

  本发明提供了一种化合物，具有优越的Smo抑制活性和较低的毒性，足以作为药物产品。本发明提供的化合物由以下式子表示：其中环A是5-至7-成员环，可选地具有取代基，其中取代基可选择结合在一起形成环；X是O、S或NR1（R1是氢原子或具有取代基的碳氢基团）；R2是氨基甲酰基，可选地具有取代基；R3是羟基，可选地具有取代基，或其盐。
• US8217176B2
  申请人：——

  公开号：US8217176B2

  公开（公告）日：2012-07-10
• US8399449B2
  申请人：——

  公开号：US8399449B2

  公开（公告）日：2013-03-19
• 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.