6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide | 1186231-83-3

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
• 英文别名: TAK-221；TAK-441；6-ethyl-N-[1-(2-hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-phenacyl-3-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxamide
• CAS: 1186231-83-3
• 化学式: C₂₈H₃₁F₃N₄O₆
• 分子量: 576.573
• InChiKey: ZADWXQMNNVICKB-UHFFFAOYSA-N

物化性质

• 沸点：
  761.6±60.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  9

制备方法与用途

TAK-441（化合物11d）是一种高效的口服刺猬（Hh）信号抑制剂，其IC50值为4.4 nM。该化合物在实体瘤中表现出较强的抗肿瘤活性。

反应信息

• 作为反应物：
  描述：

  6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide 在 sodium tetrahydroborate 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 5.0h， 以51%的产率得到6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-5-(2-hydroxy-2-phenylethyl)-1-methyl-4-oxo-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
  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：

  methyl (2Z)-3-aminopent-2-enoate 在 sodium ethanolate 、 potassium carbonate 、 1-羟基苯并三唑 、 caesium carbonate 、 1,2-二氯乙烷 、 三乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 100.0h， 生成 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-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

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。
• COCRYSTAL
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US20200048245A1

  公开（公告）日：2020-02-13

  Improving the solubility of an organic compound. A cocrystal of (1) 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide and (2) L-malic acid or L-tartaric acid.

  提高有机化合物的溶解度。一种由(1) 6-乙基-N-[1-(羟乙酰基)哌啶-4-基]-1-甲基-4-氧代-5-(2-氧代-2-苯基乙基)-3-(2,2,2-三氟乙氧基)-4,5-二氢-1H-吡咯并[3,2-c]吡啶-2-羧酰胺和(2) L-苹果酸或L-酒石酸的共晶体。
• Cocrystal
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US10906898B2

  公开（公告）日：2021-02-02

  Improving the solubility of an organic compound. A cocrystal of (1) 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide and (2) L-malic acid or L-tartaric acid.

  提高有机化合物的溶解度。(1) 6-乙基-N-[1-(羟基乙酰基)哌啶-4-基]-1-甲基-4-氧代-5-(2-氧代-2-苯基乙基)-3-(2,2,2-三氟乙氧基)-4,5-二氢-1H-吡咯并[3,2-c]吡啶-2-甲酰胺和 (2) L-苹果酸或 L-酒石酸的共晶体。
• Antibodies specific to Sonic Hedgehog and method of use thereof
  申请人：The Regents of the University of California

  公开号：US11479601B2

  公开（公告）日：2022-10-25

  Antibodies that specifically bind to a Sonic Hedgehog (Shh) polypeptide, or an antigen binding fragment thereof, are provided. Also provided are methods of treating an individual for cancer using the Shh polypeptide antibodies. Methods of analyzing a tissue sample for cell-surface expression of a full-length Shh polypeptide are also provided.

  本研究提供了能与音速刺猬（Shh）多肽或其抗原结合片段特异性结合的抗体。还提供了使用 Shh 多肽抗体治疗癌症的方法。还提供了分析组织样本细胞表面表达全长 Shh 多肽的方法。
• COMPOUNDS FOR USE IN REGULATING FOLLICLE MATURATION
  申请人：Aarhus Universitet

  公开号：EP3727354A2

  公开（公告）日：2020-10-28