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Heterocycle type derivative and preparing method and pharmaceutical application thereof

A technology of heterocyclic groups and compounds, which is applied in the fields of heterocyclic derivatives and their preparation and their application in medicine, and can solve the problems of insufficient research and disclosure of anti-tumor tumors such as liver cancer

Active Publication Date: 2018-07-10
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] A series of patents on FGFR inhibitors have been published, but there are few patent disclosures for FGFR4 selective inhibition. For FGFR4 selective inhibitors, they have the advantage of less toxicity compared to FGFR inhibitors (Brown, AP et al (2005 ), Toxocol.Pathol., 449-455), but at this stage, the research on FGFR4 inhibitors against liver cancer and other tumors is far from enough, and it is still necessary to study and develop new FGFR4 inhibitors

Method used

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  • Heterocycle type derivative and preparing method and pharmaceutical application thereof
  • Heterocycle type derivative and preparing method and pharmaceutical application thereof
  • Heterocycle type derivative and preparing method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] N-(4-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3-(dimethylamino)propyl)-2-oxo-1 , 2-dihydro-1,6-naphthyridin-7-yl)amino)tetrahydrofuran-3-yl)acrylamide

[0183]

[0184] first step

[0185] 6-Chloro-4-((3-(dimethylamino)propyl)amino)nicotinic acid ethyl ester

[0186] 4,6-Dichloronicotinic acid ethyl ester 1a (30.1g, 136.99mmol) and N 1 , N 1 Dimethylpropane-1,3-diamine 1b (18.95 mL, 150.46 mmol) was dissolved in 300 mL tetrahydrofuran, and reacted at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 6-chloro-4-((3-(dimethylamino)propyl)amino)nicotinic acid Ethyl ester 1c (22.84 g, white solid), yield: 58.5%.

[0187] MS m / z(ESI): 286.0[M+1]

[0188] second step

[0189] (6-Chloro-4-((3-(dimethylamino)propyl)amino)pyridin-3-yl)methanol

[0190] Dissolve ethyl 6-chloro-4-((3-(dimethylamino)propyl)amino)nicotinate 1c (16.5g, 57.7...

Embodiment 2

[0218] N-(2-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3-(dimethylamino)propyl)-2-oxo-1 , 2-dihydro-1,6-naphthyridin-7-yl)amino-3-fluorophenyl)acrylamide

[0219]

[0220]

[0221] first step

[0222] 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3-(dimethylamino)propyl)-7-((2-fluoro-6-nitrobenzene Base)amino)-1,6-naphthyridin-2(1H)-one

[0223] Under argon protection, 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3-(dimethylamino)propyl)-1,6 -Naphthyridin-2(1H)-one 1h (200mg, 0.425mmol), 2-fluoro-6-nitroaniline 2a (94mg, 0.467mmol), 4,5-bisdiphenylphosphine-9,9-bis Methyl xanthene (49 mg, 0.085 mmol), tris(dibenzylideneacetone) dipalladium (39 mg, 0.0425 mmol) and cesium carbonate (415 mg, 1.270 mmol) were dissolved in 10 mL of toluene, heated to 120 ° C for 4 hours . The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (developing solvent: system C) to obtain 3-(2,6-dichloro-3,5-di...

Embodiment 3

[0243] N-(2-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3-(dimethylamino)propyl)-2-oxo-1 , 2-dihydro-1,6-naphthyridin-7-yl)amino-5-morpholinylphenyl)acrylamide

[0244]

[0245]

[0246] first step

[0247] N-(4-Bromo-2-nitrophenyl)acetamide

[0248] 4-Bromo-2-nitroaniline 3a (30.3g, 138mmol) was dissolved in 240mL of acetic acid, acetic anhydride (22.44g, 220.2mmol) was added, and heated to 95°C for 7.5 hours. The reaction solution was cooled to room temperature and poured into 600mL of ice water. After the ice melted, it was extracted with dichloromethane (90mL×3). The solid was dissolved in 600mL of dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was decompressed. Concentration gave N-(4-bromo-2-nitrophenyl)acetamide 3b (35.4 g, orange solid), yield: 99.1%.

[0249] MS m / z(ESI): 258.8[M+1]

[0250] second step

[0251] N-(4-morpholino-2-nitrophenyl)acetamide

[0252] Under argon protection, N-(4-br...

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Abstract

The invention relates to a novel heterocycle type derivative, a preparing method thereof, a medicine composition containing the derivative and application of the heterocycle type derivative as therapeutic agent, particularly an FGFR4 inhibitor. The preferable compound has a good inhibiting effect on FGFR4.

Description

field of invention [0001] The present invention relates to a novel heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an FGFR4 inhibitor. Background of the invention [0002] The fibroblast growth factor receptor (FGFR) family is composed of four members (FGFR1, FGFR2, FGFR3, and FGFR4), which belong to the receptor tyrosine kinase family of kinases, and FGF binding leads to FGFR dimerization, followed by receptor tyrosine kinases. Autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to rejuvenate and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival. Thus, the FGF / FGFR signaling pathway has pleiotropic effects in many biological processes critical to tumor cell proliferation, migration, invasion, angiogenesis, and ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4375A61K31/5377A61K31/496A61K31/444A61P35/00
CPCC07D471/04Y02P20/55
Inventor 陈磊关东亮白骅凌龙赵松锋
Owner ZHEJIANG HISUN PHARMA CO LTD