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Pharmaceutical composition having pyrimidine compound as active ingredient

A technology of pharmaceutical composition and pyrimidine, which is applied in the field of pharmaceutical composition with pyrimidine compound as the active ingredient, and can solve the problems of FGFR4 inhibitory effect and liver cancer effect not disclosed

Inactive Publication Date: 2016-04-13
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, this document specifically discloses the compound that is an active ingredient of the pharmaceutical composition of the present invention as an example compound, but there is no disclosure about the FGFR4 inhibitory effect and the effect on liver cancer

Method used

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  • Pharmaceutical composition having pyrimidine compound as active ingredient
  • Pharmaceutical composition having pyrimidine compound as active ingredient
  • Pharmaceutical composition having pyrimidine compound as active ingredient

Examples

Experimental program
Comparison scheme
Effect test

manufacture example 1

[0098] Production Example 1 Production of Compound A

[0099] (1) Cool a mixture of methyl 3,5-dimethoxybenzoate (1 g) and acetonitrile (20 mL) with ice, add N-fluoro-N'-(chloromethyl) triethylenediamine bis(tetra Fluoroborate) (4.09 g), stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, anhydrous magnesium sulfate and basic silica gel were added, stirred for 30 minutes, and then filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain methyl 2,6-difluoro-3,5-dimethoxybenzoate (292 mg).

[0100] MS(ESI+):233[(M+H) + ].

[0101] (2) Cool the mixture of methyl 2,6-difluoro-3,5-dimethoxybenzoate (10g) and tetrahydrofuran (57mL) with ice, add lithium borohydride (3.0mol / L tetrahydrofuran solution, 43mL ), stirr...

manufacture example 2

[0110] Production Example 2 Production of Compound B

[0111] (1) Under an argon atmosphere, 2-chloro-5-[(2,6-difluoro-3,5-dimethoxybenzyl )oxy]pyrimidine (800mg), 2-(4-amino-1H-pyrazol-1-yl)ethanol (642mg), 1,1'-binaphthyl-2,2'-diylbis(diphenyl Palladium acetate (113 mg) was added to a mixture of phosphine) (472 mg), cesium carbonate (2.47 g) and dioxane (16 mL), and stirred at 100° C. for 6 hours. Water and chloroform were added to the reaction mixture, and after insoluble matter was filtered off, the filtrate was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy yl]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]ethanol (compound B: 139 mg).

[0112] MS(ESI+):408[(M+H) + ].

[0113] NMR (DMSO-d 6 ):3....

manufacture example 3

[0114] Production Example 3 Production of Compound C

[0115] (1) Under an argon atmosphere, 2-chloro-5-[(2,6-difluoro-3,5-dimethoxybenzyl )oxy]pyrimidine (1.33g), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-amine (913mg), 1,1'-binaphthyl-2,2' -Cesium carbonate (4.11 g) was added to a mixture of diylbis(diphenylphosphine) (785 mg), palladium acetate (189 mg) and dioxane (26.6 mL), and stirred at 100° C. for 4 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N -[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine (1.73 g).

[0116] MS(APCI / ESI+):448[(M+H) + ].

[0117] (2) to 5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[1-(tetrahyd...

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Abstract

To provide a pharmaceutical composition for treating FGFR4-related cancer, FGF19-related cancer, or FGF19 gene amplification positive liver cancer. The inventors perfected the present invention through study of compounds having FGFR4 inhibitory effect, verifying that specific pyrimidine compounds have FGFR4 inhibitory effect, and that pharmaceutical compositions having these compounds as active ingredients have therapeutic effect against FGFR4-related cancer, or in another mode against FGF19-related cancer, or in yet another mode against FGF19 gene amplification positive liver cancer.

Description

technical field [0001] The present invention relates to a pharmaceutical composition for treating FGFR4-related cancers containing a pyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient, and relates to a pharmaceutical composition containing a pyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient and The pharmaceutical composition for treating FGF19-associated cancer relates to a pharmaceutical composition for treating FGF19 gene amplification-positive liver cancer, which contains a pyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient. Background technique [0002] The signaling pathway formed by fibroblast growth factor (FGF) and its receptor fibroblast growth factor receptor (FGFR) is the most important function in the stages of generative progression from early embryogenesis to the formation of various organs One of the signaling pathways. There are 18 genes enco...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61P1/16A61P35/00A61P43/00
CPCA61K31/506A61P1/16A61P35/00A61P43/00
Inventor 二见崇史竹下留美
Owner ASTELLAS PHARMA INC
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