Quinolinone derivatives as inhibitors of c-fms kinase

A solvate and compound technology, applied in the field of quinolinone derivatives as c-fms kinase inhibitors, can solve problems such as oncogene transcription

Inactive Publication Date: 2006-11-22
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Receptor binding results in the initiation of multiple intracellular tyrosine kinase-dependent phosphorylation processes that ultimately lead to the transcription of oncogenes

Method used

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  • Quinolinone derivatives as inhibitors of c-fms kinase
  • Quinolinone derivatives as inhibitors of c-fms kinase
  • Quinolinone derivatives as inhibitors of c-fms kinase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0225] Example 1: General method for the synthesis of quinolones and naphthyridones by cyclocondensation

[0226] To a mixture of substituted acetic acid (1 mmol) and aminoketone (1 mmol) was added POCl 3 (3ml). The resulting mixture was heated at 70°C for 12 hours under a nitrogen atmosphere. Remove POCl 3 , and the residue was dried under vacuum for 1 h. Then, the residue was dissolved in HOAc (98% acid, 2% water) (2ml) and NH 4 Ac (77mg, 1mmol) was heated at 90°C for 3 hours. The reaction mixture was cooled to room temperature and HOAc was removed. The resulting residue was purified on silica gel using an appropriate solvent system.

Embodiment 2

[0227] Example 2: General method for the synthesis of quinolones and naphthyridones by cyclocondensation

[0228] To a mixture of 2-substituted acetic acid (1.5 mmol) and aminoketone (1 mmol), DIEA (0.7 ml, 4 mmol) in THF (10 ml) was added PyBrop (730 mg, 1.5 mmol). The resulting mixture was stirred overnight at room temperature. If LC / MS and / or TLC of the reaction mixture shows complete formation of the expected fully cyclized product, the solvent is removed and the product is isolated by silica gel chromatography using an appropriate solvent system. If the cyclization reaction was found to be incomplete, toluene (10ml) and piperidine (1ml) were added to the reaction mixture and the resulting mixture was heated at 70°C until complete formation of the expected quinolone was observed by LC / MS. The solvent is then removed and the product isolated by conventional means.

Embodiment 3

[0229] Example 3: 3-(3-Methyl-isoxazol-5-yl)-4-phenyl-1H-[1,5]naphthyridine-2-one

[0230]

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Abstract

The invention is directed to compounds of Formulae I and II: (I) (II) wherein R<1>, R<2>, R<3>, R<5>, R<6>, Y<1>, Y<2>, Y<3>, Y<4> and X are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase.

Description

[0001] References to related applications [0002] This application is a non-provisional application of provisional USSN 60 / 488,811 filed July 22,2003. field of invention [0003] The present invention relates to novel compounds which act as inhibitors of protein tyrosine kinases. More specifically, the present invention relates to novel quinolinone derivatives that function as c-fms kinase inhibitors. Background of the invention [0004] Protein kinases are enzymes that are key components of signal transduction pathways by catalyzing the transfer of the terminal phosphate of ATP to the hydroxyl groups of tyrosine, serine and threonine residues in proteins. Thus, protein kinase inhibitors and substrates are important tools for evaluating the physiological consequences of protein kinase activation. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been shown to play an important...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4704A61K31/4375A61K31/4709A61P35/00C07D215/22C07D215/227C07D401/04C07D409/04C07D413/04C07D413/14C07D417/04C07D471/04
CPCA61P3/10A61P9/00A61P9/10A61P13/12A61P17/06A61P19/02A61P25/28A61P29/00A61P35/00A61P43/00C07D215/227C07D401/04C07D409/04C07D413/04C07D413/14C07D417/04C07D471/04Y02P20/582
Inventor M·J·沃尔M·R·普莱耶R·J·佩奇S·米加拉刘健C·R·伊利格W·张陈锦生D·阿斯加里
Owner JANSSEN PHARMA NV
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