Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

4-(aromatic heterocycle substituted) amino-1h-3-pyrazole carboxamide flt3 inhibitors and uses thereof

A formamide and pyrazole technology, applied in the field of novel FLT3 kinase inhibitor compounds, can solve the problems of difficult FLT3 effective dose, limited therapeutic effect, weak inhibitor selectivity, etc., and achieve strong inhibitory activity, strong antitumor activity, Excellent selectivity and inhibitory activity

Active Publication Date: 2020-04-17
CHINA PHARM UNIV
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] So far, FLT3 small-molecule inhibitors have been explored in the treatment of AML patients. Although some small-molecule FLT3 inhibitors are currently in the clinical research stage, the therapeutic effect is still very limited.
This is because the structure of various tyrosine kinase receptors has a high degree of homology, resulting in poor selectivity of inhibitors, so within the range of drug tolerance, it is difficult to achieve an effective dose to inhibit FLT3 in AML patients

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
  • 4-(aromatic heterocycle substituted) amino-1h-3-pyrazole carboxamide flt3 inhibitors and uses thereof
  • 4-(aromatic heterocycle substituted) amino-1h-3-pyrazole carboxamide flt3 inhibitors and uses thereof
  • 4-(aromatic heterocycle substituted) amino-1h-3-pyrazole carboxamide flt3 inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] 1-Methyl-4-(4-nitrobenzyl)piperazine (I-a)

[0123] Add 10 g (46.3 mmol) of p-nitrobenzyl bromide and 100 mL of dichloromethane into a 500 mL single-necked bottle, and slowly add 4.7 g (47.0 mmol) of N-methylpiperazine (47.0 mmol) and three A mixture of 7.1 g (70.3 mmol) of ethylamine and 20 mL of dichloromethane was added and heated to reflux for 1 h. The raw material disappeared as detected by TLC (ethyl acetate:petroleum ether=1:2). Add 150 mL of chloroform and 100 mL of saturated sodium bicarbonate solution into the reaction liquid, and vigorously stir at room temperature for 30 min. The reaction solution was extracted with chloroform (100 mL×3), and the combined organic layers were washed once with water and saturated sodium chloride (100 mL×1). Dry over anhydrous magnesium sulfate, filter, and distill off the solvent under reduced pressure to obtain 8.5 g of a light yellow solid with a yield of 78.1%. The product does not need further purification and is directly...

Embodiment 2

[0125] 4-((4-Methylpiperazin-1-yl)methyl)aniline (I-b)

[0126] Add I-a crude product 8.5g (36.2mmol), FeO(OH) / C catalyst 2.0g and 95% ethanol 100mL in 500mL single-necked bottle, heat to reflux, slowly add dropwise the mixed solution of hydrazine hydrate 25mL and 95% ethanol 20mL, TLC The disappearance of the starting material was detected (methanol:chloroform=1:15). After hot suction filtration, the filter cake was washed twice with hot ethanol (30 mL×2), and the solvent was evaporated under reduced pressure to obtain a white solid, which was dried in vacuo to obtain (I-b) 6.7 g, yield 90.3%. The product was directly put into the next reaction without further purification. 1 H NMR (300MHz, DMSO) δ8.1(d, J=8.5Hz, 2H, ArH), 7.5(d, J=8.5Hz, 2H, ArH), 4.0(s, 2H, -NH 2 ), 3.5(s, 2H, -CH 2 -), 2.3-2.5 (br, 8H, -CH 2 -×4), 2.1(s, 3H, -CH 3 )

Embodiment 3

[0128] N-(4-((4-methylpiperazin-1-yl)methyl)phenyl-4-nitro-1H-pyrazole-3-carboxamide (I-c)

[0129] In a 250mL round bottom flask, add 7.5g (36.6mmol) of I-a' crude product, 6.3g (40.1mmol) of 4-nitro-1H-pyrazole-3-carboxylic acid, 8.4g (44.0mmol) of EDC·HCl, HOBt 6.0g (44.4mmol) and anhydrous DMF100mL, stirred at room temperature for 24h. The disappearance of the starting material was detected by TLC (methanol:chloroform=1:10). The reaction solution was poured into 200 mL of ice water, a large amount of light yellow solid was precipitated, left to stand, and filtered to obtain a yellow solid, the obtained crude product was recrystallized with a mixed solvent of ethyl acetate and methanol to obtain (I-e) 11.1 g, yield 88.2%. MS[M+H] + 345.3. 1 H NMR (300MHz, DMSO) δ14.2 (s, 1H, -NH-, Pyrazole), 10.6 (s, 1H, -NHCO-), 8.8 (s, 1H, ArH), 7.6 (d, J=8.7Hz , 2H, ArH), 7.3 (d, J=8.7Hz, 2H, ArH), 3.4 (s, 2H, -CH 2 -), 2.3-2.4 (br, 8H, -CH 2 -×4), 2.2(s, 3H, -CH 3 ).

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 novel 4-(aromatic heterocyclic substituted)amino-1H-3-pyrazolecarboxamide compound or pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites or pro-drugs thereof and a preparation method thereof. The invention provides medical compositions comprising the compounds and medical application thereof.

Description

technical field [0001] The present invention relates to a novel FLT3 kinase inhibitor compound, pharmaceutical compositions comprising the same, and the use of these compounds and compositions to reduce or inhibit FLT3 kinase and / or mutant FLT3 kinase activity in cells or subjects and in affected Uses and methods for preventing or treating cell proliferative disorders and / or FLT3-related disorders in a subject. Background technique [0002] Protein kinases are enzymatic components of signal transduction pathways that catalyze the transfer of the terminal phosphate of ATP to the hydroxyl groups of tyrosine, serine and / or threonine residues of proteins. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been shown to play an important role in the development of many diseases, including diabetes, angiogenesis, psoriasis , restenosis, eye disease, schizophrenia, rheumatoid arthritis, ather...

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): C07D403/12A61K31/5377A61K31/506A61P35/00
CPCC07D403/12
Inventor 卢帅王越支燕乐尧超陆涛李保泉陈璞洲鲍吉银
Owner CHINA PHARM UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com