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FGFR4 inhibitor, preparation method, pharmaceutical composition and application thereof

A composition and drug technology, applied in the field of biomedicine, can solve the problems of inability to distinguish tumor cells, reduce adverse reaction rate, side effects, etc., and achieve the effect of improving therapeutic effect and good anti-tumor pharmacological activity

Active Publication Date: 2021-01-29
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often leading to serious side effects. Targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce adverse reaction rate

Method used

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  • FGFR4 inhibitor, preparation method, pharmaceutical composition and application thereof
  • FGFR4 inhibitor, preparation method, pharmaceutical composition and application thereof
  • FGFR4 inhibitor, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 3-(2,6-Dichlorophenyl)-1-(2-(6-methoxyindolin-1-yl)pyridin-4-yl)-1-methylurea

[0046]

[0047] Synthesis of compound 1c:

[0048] Dissolve compound 1a (37.4g, 200.0mmol), 1b (37.2g, 200.0mmol), potassium carbonate (41.4g, 300.0mmol) in acetonitrile (500mL), react at room temperature for 10 hours, monitor the reaction by TLC, and filter after the reaction , the filtrate was concentrated and separated by column chromatography to obtain 58.3 g of off-white (compound 1c), with a yield of 78.3%.

[0049] Synthesis of Compound 1:

[0050] Compound 1c (3.7g, 10.0mmol), compound 1d (1.5g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd 2 (dba) 3 (458mg, 0.5mmol), Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), heated to 100°C and stirred for 6 hours, TLC monitored the reaction, after the reaction was completed, add water to quench the reaction, ethyl acetate (50mL each time) After two extractions, the organic layer was concentrated and separated by column chrom...

Embodiment 2

[0052] 3-(2,6-Dichlorophenyl)-1-(2-(6-fluoroindolin-1-yl)pyridin-4-yl)-1-methylurea

[0053]

[0054] The synthesis of compound 1c was carried out according to Example 1.

[0055] Synthesis of Compound 2:

[0056] Compound 1c (3.7g, 10.0mmol), compound 2a (1.4g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd 2 (dba) 3 (458mg, 0.5mmol), Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), heated to 100°C and stirred for 6 hours, TLC monitored the reaction, after the reaction was completed, add water to quench the reaction, ethyl acetate (50mL each time) After two extractions, the organic layer was concentrated and separated by column chromatography to obtain 2.7 g of a light yellow solid (compound 2), with a yield of 62.8%. ESI(+) m / z=431.1.

Embodiment 3

[0058] 3-(2,6-Dichlorophenyl)-1-(2-(7-fluoroindolin-1-yl)pyridin-4-yl)-1-methylurea

[0059]

[0060] The synthesis of compound 1c was carried out according to Example 1.

[0061] Synthesis of compound 3:

[0062] Compound 1c (3.7g, 10.0mmol), compound 3a (1.4g, 10.0mmol), cesium carbonate (6.5g, 20.0mmol), Pd 2 (dba) 3 (458mg, 0.5mmol), Xantphos (578mg, 1.0mmol) were dissolved in DMF (50mL), heated to 100°C and stirred for 6 hours, TLC monitored the reaction, after the reaction was completed, add water to quench the reaction, ethyl acetate (50mL each time) After two extractions, the organic layer was concentrated and separated by column chromatography to obtain 2.0 g of a light yellow solid (compound 3), with a yield of 46.5%. ESI(+) m / z=431.1.

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Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to an FGFR4 inhibitor, a preparation method, a pharmaceutical composition and application thereof. The FGFR4 inhibitor is a compound with a structure shown in a formula I or pharmaceutically acceptable salt thereof, wherein the structure shown in the formula I is shown in the specification; R1 representsa substituted or unsubstituted phenyl group or an aromatic heterocyclic group, R2 represents H, F, Cl, Br, MeO, CN and CONH2, and n is 1 or 2. The FGFR4 inhibitor provided by the invention has good capability of inhibiting the activity of FGFR4, and is beneficial to improving the treatment level of cancer and effectively reducing the adverse reaction rate.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to an FGFR4 inhibitor, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] Cancer is one of the major diseases that threaten human health. At present, the main treatment methods for cancer include drug therapy, surgery therapy and radiation therapy, among which drug therapy is one of the most commonly used treatment methods. Traditional cytotoxic drugs cannot distinguish between tumor cells and normal cells, often causing serious side effects, while targeted drugs use tumor cells as specific targets, can accurately act on tumors, and can effectively improve the treatment level of cancer. Reduce the rate of adverse reactions. [0003] FGFR (Fibroblast Growth Factors Receptor, fibroblast growth factor) belongs to receptor protein tyrosine kinases, and this family mainly includes FGFR1, FGFR2, FGFR3, and FGFR4. F...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14A61P35/00A61P35/02A61K31/4439A61K31/444A61K31/4709
CPCA61P35/00A61P35/02C07D401/04C07D401/14
Inventor 王永广常俊美贾冰洁苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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