Unlock instant, AI-driven research and patent intelligence for your innovation.

Fused heterocycle derivative and application thereof

A compound, heteroaryl technology

Active Publication Date: 2013-07-03
HAINAN SIMCERE PHARMA CO LTD
View PDF18 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a class of fused heterocyclic naphthyridine derivatives has not been reported for the treatment of tyrosine kinase and / or serine-threonine kinase inhibitors

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Fused heterocycle derivative and application thereof
  • Fused heterocycle derivative and application thereof
  • Fused heterocycle derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] Embodiment 1: the preparation of compound 1

[0196]

[0197] Preparation of (Z)-ethyl-3-hydroxy-2-phenylacrylate

[0198] Place 28g of ethyl phenylacetate and 230mL of ethyl formate in a 1L three-necked flask in an ice bath. Weigh 20g of NaH and slowly add it into the three-necked bottle, a large amount of gas will come out, and the adding time is about 30 minutes. After the addition, stir at room temperature for 5 hours to stop the reaction, add the reaction solution to an appropriate amount of water, adjust the pH to be acidic, extract the organic layer with an appropriate amount of ethyl acetate, combine, dry, and spin off the organic solvent to obtain 32 g of an oily product.

[0199] Preparation of (Z)-ethyl-3-((2-chloropyridin-4-yl)amino)-2-phenylacrylate

[0200] Add ethyl-3-hydroxy-2-phenylacrylate (19g, 1eq), 2-chloro-4-aminopyridine (12.7g, 1eq), ethanol (300mL), concentrated hydrochloric acid (0.5mL) into the reaction flask, Mix well and heat up to 85°...

Embodiment 2

[0206] Embodiment 2: the preparation of compound 2

[0207]

[0208] 3-Chloro-4-(2-fluoro-4-((4-oxo-3-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)amino)phenoxy)-2 - Preparation of amidopyridines

[0209] Add 5-chloro-3-phenyl-1,6-naphthyridin-4(1H)-one (150mg, 1eq), 4-(4-amino-2-fluorophenoxy)-3- Chloro-2-amidopyridine (162mg, 1eq), concentrated hydrochloric acid (3 drops), and isopropanol (130mL) were mixed, stirred electromagnetically, heated to 50°C and reacted for 3 hours, filtered off insoluble matter, and the filter cake was washed with isopropanol After vacuum drying, 3-chloro-4-(2-fluoro-4-((4-oxo-3-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)amino)benzene Oxy)-2-amidopyridine (68 mg). 5-((4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)amino)-3-phenyl-1,6-naphthyridine-4(1H)- Preparation of ketones

[0210] 3-chloro-4-(2-fluoro-4-((4-oxo-3-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)amino)phenoxy )-2-amidopyridine (65mg, 1eq), acetonitrile (35mL), ethyl acetate (...

Embodiment 3

[0212] Embodiment 3: the preparation of compound 3

[0213]

[0214] Preparation of 4-(4-amino-2-fluorophenoxy)-3-iodo-2-pyridinamide

[0215] Add 3-iodo-4-chloro-2-pyridinamide (281mg, 1.0eq), 2-fluoro-4-aminophenol (127mg, 1.0eq), potassium tert-butoxide (145.6mg, 1.3eq ), anhydrous DMF (25mL), heated to 90 ° C for 4 hours, the plate reaction was complete, the reaction was stopped, the solvent was recovered under reduced pressure, and the crude residue was obtained by silica gel column chromatography to obtain 4-(4-amino-2-fluorobenzene) - 3-iodo-2-pyridineamide (300 mg).

[0216] 4-(2-fluoro-4-((4-oxo-3-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)amino)phenoxy)-3-iodo-2 - Preparation of amidopyridines

[0217] To a 100mL round bottom flask was added 4-(4-amino-2-fluorophenoxy)-3-iodo-2-pyridineamide (580mg, 1.0eq), 5-chloro-3-(4-fluorophenyl )-1,6-naphthyridin-4(1H)-one (426mg, 1eq), isopropanol 100mL, concentrated hydrochloric acid 0.1mL, heated to 50°C for 6 hours, st...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a fused heterocycle derivative and application thereof. The fused heterocycle derivative has a structure shown in a formula (I). The compound with the structure shown in the formula (I), which is disclosed by the invention, has a good inhibiting effect on activities of various kinase and has median inhibitory concentration of less than 10<-7> mol / L in general for kinase such as c-Met, KDR (vascular endothelial growth factor receptor) and c-kit. Meanwhile, the compound with the structure in the formula (I), which is prepared in the embodiment of the invention, has an inhibiting effect on various cancer cells. Moreover, the invention further relates to an intermediate of the compound and a preparation method of the intermediate. The formula (I) is figured above.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of condensed heterocyclic derivatives with the structure of formula (I) and their application in the preparation of tyrosine kinase inhibitors or serine-threonine kinase inhibitors. The present invention also relates to the intermediates of the compounds and the preparation methods of the intermediates. Background technique [0002] As an integrated regulatory mechanism of cells, signal transduction transmits various extracellular signals to the inside of cells, so that cells respond and realize processes such as proliferation, differentiation, and apoptosis. Protein kinases (PKs) play an important role in this process. PKs can be divided into tyrosine kinases (PTKs) and serine / threonine kinases (STKs), PTKs can phosphorylate tyrosine residues on proteins, and STKs can phosphorylate serine / threonine residues on proteins They play an important role in the signal transduction m...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D471/04C07D519/00A61K31/517A61K31/444A61K31/4375A61K31/4709A61K31/519A61K31/5377A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D471/04
Inventor 黄伟丛欣叶军赵兴俄王佳
Owner HAINAN SIMCERE PHARMA CO LTD