CAS: 913376-83-7; Amg-458

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5-(7-methoxyquinolin-4-yloxy)pyridin-2-amine 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid

合成工艺路线路线简述

  • 913376-56-4 + 913375-96-9 = 913376-83-7
    反应条件:1.1 Reagents: Diisopropylethylamine,O-(7-Azabenzotriazol-1-Yl)-N,N,N′,N′-Tetramethyluronium Hexafluorophosphate Solvents: Dimethylformamide; 15 Min,40 °C1.2 18 H,60 °C
    标题:Discovery Of A Potent,Selective,And Orally Bioavailable C-Met Inhibitor: 1-(2-Hydroxy-2-Methylpropyl)-N-(5-(7-Methoxyquinolin-4-Yloxy)Pyridin-2-Yl)-5-Methyl-3-Oxo-2-Phenyl-2,3-Dihydro-1H-Pyrazole-4-Carboxamide (Amg 458)
    作者:Liu,Longbin; Siegmund,Aaron; Xi,Ning; Kaplan-Lefko,Paula; Rex,Karen; Et Al
    参考文献:Journal Of Medicinal Chemistry 日期:2008 卷标:51(13) 页码:3688-3691]

    913376-56-4 + 913375-96-9 = 913376-83-7
    反应条件:1.1 Reagents: Triethylamine,O-(7-Azabenzotriazol-1-Yl)-N,N,N′,N′-Tetramethyluronium Hexafluorophosphate Solvents: Dimethylformamide; 24 H,Rt
    标题:Structure-Based Design Of Novel Class Ii C-Met Inhibitors: 2. Sar And Kinase Selectivity Profiles Of The Pyrazolone Series
    作者:Liu,Longbin; Norman,Mark H.; Lee,Matthew; Xi,Ning; Siegmund,Aaron; Et Al
    参考文献:Journal Of Medicinal Chemistry 日期:2012 卷标:55(5) 页码:1868-1897]

    = 913376-83-7 [标题:Reaction Conditions
    标题:Strategies For Chemical Synthesis Of Pyrazolone Derivatives And Their Bio-Significance
    作者:Dhawan,Sanjeev; Narang,Rakesh; Khatik,Gopal L.; Chopra,Harish Kumar; Nayak,Surendra Kumar
    参考文献:Journal Of Chemical And Pharmaceutical Research 日期:2016 卷标:8(5) 页码:969-981]

    = 913376-83-7 [标题:Reaction Conditions
    标题:Chemical Reactivity Of Methoxy 4-O-Aryl Quinolines: Identification Of Glutathione Displacement Products In Vitro And In Vivo
    作者:Teffera,Yohannes; Colletti,Adria E.; Harmange,Jean Christophe; Hollis,L. Steven; Albrecht,Brian K.; Et Al
    参考文献:Chemical Research In Toxicology 日期:2008 卷标:21(11) 页码:2216-2222
📜5-(7-Methoxyquinolin-4-Yloxy)Pyridin-2-Amine,1-(2-Hydroxy-2-Methylpropyl)-5-Methyl-3-Oxo-2-Phenyl-2,3-Dihydro-1H-Pyrazole-4-Carboxylic Acid置于n,N-二异丙基乙胺,Methanaminium,N-[(Dimethylamino)(3H-1,2,3-Triazolo[4,5-B]Pyridin-3-Yloxy)Methylene]-N-Methyl-,Hexafluorophosphate(1-)体系中,用 N,N-二甲基甲酰胺 作为反应溶剂,化学反应 18.25H,以22%的收率获得产物1-(2-羟基-2-甲基丙基)-N-(5-((7-甲氧基喹啉-4-基)氧基)吡啶-2-基)-5-甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-羧酰胺
参考文献:Discovery Of A Potent,Selective,And Orally Bioavailable C-Met Inhibitor: 1-(2-Hydroxy-2-Methylpropyl)-N-(5-(7-Methoxyquinolin-4-Yloxy)Pyridin-2-yl)-5-Methyl-3-Oxo-2-Phenyl-2,3-Dihydro-1H-Pyrazole-4-Carboxamide (Amg 458)
标题:Discovery Of A Potent,Selective,And Orally Bioavailable C-Met Inhibitor: 1-(2-Hydroxy-2-Methylpropyl)-N-(5-(7-Methoxyquinolin-4-Yloxy)Pyridin-2-yl)-5-Methyl-3-Oxo-2-Phenyl-2,3-Dihydro-1H-Pyrazole-4-Carboxamide (Amg 458)
摘要:Deregulation Of The Receptor Tyrosine Kinase C-Met Has Been Implicated In Human Cancers. Pyrazolones With N-1 Bearing A Pendent Hydroxyalkyl Side Chain Showed Selective Inhibition Of C-Met Over Vegfr2. However,Studies Revealed The Generation Of Active,Nonselective Metabolites. Blocking This Metabolic Hot Spot Led To The Discovery Of 17 (Amg 458). When Dosed Orally,17 Significantly Inhibited Tumor Growth In The Nih3T3/fpr-Met And U-87 Mg Xenograft Models With No Adverse Effect On Body Weight.
DOI:10.1021/jm800401T

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主要参考文献


1: Li B, Torossian A, Sun Y, Du R, Dicker AP, Lu B. Higher Levels of c-Met Expression and Phosphorylation Identify Cell Lines With Increased Sensitivity to AMG-458, a Novel Selective c-Met Inhibitor With Radiosensitizing Effects. Int J Radiat Oncol Biol Phys. 2012 Nov 15;84(4):e525-31. doi: 10.1016/j.ijrobp.2012.06.025. Epub 2012 Jul 24. Epub 2012 Feb 24. Epub 2011 Jun 22. Epub 2010 Mar 4. Epub 2008 Jun 14.

合成参考文献


参考文献:10.1124/mol.119.115964
摘要:Lee TD, Lee OW, Brimacombe KR, Chen L, Guha R, Lusvarghi S, Tebase BG, Klumpp-Thomas C, Robey RW, Ambudkar SV, Shen M, Gottesman MM, Hall MD. A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. Molecular Pharmacology. 2019 Nov;96(5):629–40. doi: 10.1124/mol.119.115964.
参考文献:10.1134/s1068162024606529
摘要:Mattikopp AA, Alegaon SG, Gharge S, Ranade SD, Kavalapure RS. Cytotoxic Potential of Newly Synthesized 4-Aminoquinoline Hybrids on MDA-MB-231 Cells: Insights from Pharmacophore Modeling and Molecular Dynamics Simulation. Russ J Bioorg Chem. 2025 Jul 28;51(4):1624–44. doi: 10.1134/s1068162024606529.
参考文献:10.1021/jm201331s
摘要:Liu L, Norman MH, Lee M, Xi N, Siegmund A, Boezio AA, Booker S, Choquette D, D'Angelo ND, Germain J, Yang K, Yang Y, Zhang Y, Bellon SF, Whittington DA, Harmange JC, Dominguez C, Kim TS, Dussault I. Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series. J Med Chem. 2012 Mar 08;55(5):1868–97. doi: 10.1021/jm201331s.
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