Pharmaceutical composition containing FGFR4 inhibitor

A composition and drug technology, applied in the field of drugs, can solve the problems of side effects, weak inhibition of FGFR4 activity, etc.

Active Publication Date: 2019-05-14
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors against FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia Other target-related side effects

Method used

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  • Pharmaceutical composition containing FGFR4 inhibitor
  • Pharmaceutical composition containing FGFR4 inhibitor
  • Pharmaceutical composition containing FGFR4 inhibitor

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0337] Preparation of intermediates

[0338] Intermediate 1: Preparation of 6-amino-4-fluoronicotine nitrile

[0339]

[0340] The first step: the preparation of 4-fluoro-5-iodopyridin-2-amine

[0341]

[0342] 4-fluoropyridin-2-amine (9g, 80mmol), NIS (19.8g, 88mmol), TFA (3.65g, 32mmol) were mixed in MeCN (290mL), and reacted overnight at room temperature. Diluted with ethyl acetate (300 mL), saturated with Na 2 SO 3 The aqueous solution (150 mL×2) was washed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 4-fluoro-5-iodopyridin-2-amine (15.8 g, 83%).

[0343] MS m / z(ESI):238.9[M+H] + .

[0344] The second step: the preparation of 6-amino-4-fluoronicotine nitrile

[0345]

[0346] 4-Fluoro-5-iodopyridin-2-amine (15.8g, 66.4mmol), Zn(CN) 2 (8.2g, 69.8mmol), Zn (0.87g, 13.3mmol) were mixed in DMA (55mL), and Pd was added under nitrogen atmosphere 2 (dba) 3 (2.4g, 2.62mmol) and...

Embodiment 1

[0694] N-(5-cyano-4-(((trans)-2-methoxycyclopentyl)amino)pyridin-2-yl)-7-formyl-6-((3-carbonylmorpholino )methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0695]

[0696] The first step: N-(5-cyano-4-(((trans)-2-methoxycyclopentyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)- Preparation of 6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0697]

[0698] 6-amino-4-(((trans)-2-methoxycyclopentyl)amino)nicotine nitrile (20mg, 0.09mmol), phenyl 7-(dimethoxymethyl)-6-(( 3-Carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (38 mg, 0.09 mmol) was mixed in THF (5 mL), N 2 Under the atmosphere, it was cooled to -78°C, a solution of LiHMDS in THF (0.2 mL, 0.2 mmol) was added dropwise, and the reaction was allowed to rise to room temperature overnight. Add saturated NH 4 Cl aqueous solution (50mL), extracted with ethyl acetate (50mL×2), the organic phase was washed with saturated brine, dried over anhydrous sodium s...

Embodiment 29

[0706] (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1 ,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

[0707]

[0708] The first step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide synthesis

[0709]

[0710](R)-6-amino-4-((1-methoxypropan-2-yl)amino)nicotine nitrile (30mg, 0.14mmol), phenyl 7-(dimethoxymethyl)-6-( (2-Carbonyl-1,3-oxazepan-3-yl)methyl)-3,4-dihydro-1,8-naphthalene-1(2H)-carboxylate (60mg, 0.13 mmol) was dissolved in THF (5mL), N 2 Cool to -78°C under atmosphere, add a solution of LiHMDS in THF (0.3mL, 0.3mmol) dropwise to the reaction solution, and let it rise to room temperature to react overnight. Add saturated NH 4 Cl aqueous solution (50mL), extracted with ethyl acetate (50mL×2), the combined organic phases were washed with saturated brine, dried over anhydrou...

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Abstract

The invention relates to a pharmaceutical composition containing an FGFR4 inhibitor, in particular to the pharmaceutical composition containing the FGFR4 inhibitor with a structure shown in a formula(I). The pharmaceutical composition developed by the invention has strong inhibition effect on FGFR4 kinase activity, and can be widely used for preparing medicaments for treating cancers, especiallyliver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer, pancreatic cancer, esophageal cancer, glioma or rhabdomyosarcoma. (See the instruction for specific formula).

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition containing an FGFR4 inhibitor, a preparation method and application thereof. Background technique [0002] Fibroblast growth factor receptor (FGFR) belongs to receptor tyrosine kinase transmembrane receptors, including four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates multiple functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and various body functions of adults. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor targeted therapy research. [0003] FGFR4 is a member of the FGFR receptor family. By binding to its ligand, fibroblast growth factor 19 (FGF19), it forms dimers on the cell membrane. Phosphorylation of amino acid residues, thereby activating m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/444A61K31/4985A61K31/5383A61K31/675A61K31/5377A61K31/553A61K31/551A61K31/496A61K31/547A61P35/00
Inventor 孙长安高鹏刘磊包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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