3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxylicacid | 918643-04-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxylicacid
• 英文别名: 3-Methyl-2-oxo-1-phenylpyrrolidine-3-carboxylic acid
• CAS: 918643-04-6
• 化学式: C₁₂H₁₃NO₃
• 分子量: 219.24
• InChiKey: UEMWXYBZHJIITB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxylicacid 、 4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluoroaniline 在 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 为溶剂， 以48%的产率得到N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Novel Class II c-Met Inhibitors: 1. Identification of Pyrazolone-Based Derivatives

  摘要：

  Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

  DOI：

  10.1021/jm201330u
• 作为产物：
  描述：

  methyl 3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxylate 在 水 、 potassium hydroxide 作用下， 以 甲醇 为溶剂， 以0.084 g的产率得到3-methyl-2-oxo-1-phenylpyrrolidine-3-carboxylicacid
  参考文献：
  名称：

  Structure-Based Design of Novel Class II c-Met Inhibitors: 1. Identification of Pyrazolone-Based Derivatives

  摘要：

  Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

  DOI：

  10.1021/jm201330u

文献信息

• Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy
  作者：Hao Hu、Fei Chen、Yuhong Dong、Yajing Liu、Ping Gong

  DOI：10.1016/j.bioorg.2020.103970

  日期：2020.8

  acquired resistance in clinical trials of c-Met inhibitors, based on the synergistic effects between c-Met and HDAC, novel c-Met and HDAC dual inhibitors were designed and synthesized. We introduced 2-pyrrolidinone to form the 5-atoms linker for c-Met inhibitor and hydroxamic acid as a zinc binding motif for HDAC inhibitor. The highly active dual inhibitor 15f showed excellent and balanced activity against

  由于c-Met抑制剂的临床试验疗效低下且获得性耐药，基于c-Met与HDAC的协同作用，设计并合成了新型的c-Met和HDAC双重抑制剂。我们引入了2-吡咯烷酮以形成c-Met抑制剂的5原子接头，而异羟肟酸作为HDAC抑制剂的锌结合基序。高活性双重抑制剂15f对c-Met（IC 50  = 12.50 nM）和HDAC1（IC 50  = 26.97 nM）均显示出优异且平衡的活性。在那些经过测试的肿瘤细胞系中，15f与伏立诺他（SAHA）和卡波替尼（XL184）相比，具有更高的有效抗增殖活性。但是，通过与SAHA和Foretinib的等摩尔混合物进行比较，我们没有观察到这些化合物显示出明显的协同抗增殖作用。然而，发现化合物15f诱导细胞凋亡并导致细胞周期停滞在G2 / M期。这项概念验证研究为发现多靶点抗肿瘤药物提供了有效的策略。
• Inhibitors of VEGF receptor and HGF receptor signaling
  申请人：Saavedra Mario Oscar

  公开号：US20070004675A1

  公开（公告）日：2007-01-04

  The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions

  该发明涉及抑制VEGF受体信号和HGF受体信号。该发明提供了抑制VEGF受体信号和HGF受体信号的化合物和方法。该发明还提供了治疗细胞增殖性疾病和病况的组合物和方法。
• Fused heterocycles as inhibitors of VEGF receptor and HGF receptor signaling
  申请人：Methylgene Inc.

  公开号：US08093264B2

  公开（公告）日：2012-01-10

  The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds of general formula (A) wherein A1 is sulfur, A3 is CH, A2 is CH, D is heterocycle, Z is oxygen, SO0-2 or NR, Ar is phenyl and G is not a ring, and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

  本发明涉及抑制VEGF受体信号和HGF受体信号的方法。本发明提供了通式（A）的化合物，其中A1为硫，A3为CH，A2为CH，D为杂环，Z为氧，SO0-2或NR，Ar为苯基，G不是环，并提供了抑制VEGF受体信号和HGF受体信号的方法。本发明还提供了用于治疗细胞增殖性疾病和病症的组合物和方法。
• INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
  申请人：Saavedra Oscar Mario

  公开号：US20120083482A1

  公开（公告）日：2012-04-05

  The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds of general formula (A) wherein A 1 is sulfur, A 3 is CH, A 2 is CH, D is heterocycle, Z is oxygen, SO 0-2 or NR, Ar is phenyl and G is not a ring, and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

  本发明涉及抑制VEGF受体信号和HGF受体信号的技术。本发明提供了通式（A）的化合物，其中A1为硫，A3为CH，A2为CH，D为杂环，Z为氧，SO0-2或NR，Ar为苯基，G不是环，并提供了抑制VEGF受体信号和HGF受体信号的方法。本发明还提供了治疗细胞增殖性疾病和病情的组合物和方法。
• US8093264B2
  申请人：——

  公开号：US8093264B2

  公开（公告）日：2012-01-10