4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor and application thereof

A technology of halogenated alkyl and alkyl, which is applied in the field of new FLT3 kinase inhibitor compounds, and can solve the problems that there are no selective FLT3 inhibitors on the market.

Active Publication Date: 2019-07-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] So far, the selective FLT3 inhibitor AC220 developed by Daiichi Sankyo has entered phase III clinical research, and no selective FLT3 inhibitor has yet been launched

Method used

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  • 4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor and application thereof
  • 4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor and application thereof
  • 4-(saturated aliphatic ring-pyrimidine/pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] 1-Methyl-4-(4-nitrobenzyl)piperazine (I-a)

[0109]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 (70.3 mmol) in 20 mL of dichloromethane was heated to reflux for 1 h after the addition, and the starting 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 ...

Embodiment 2

[0111] 4-((4-Methylpiperazin-1-yl)methyl)aniline (I-b)

[0112] 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

[0114] N-(4-((4-methylpiperazin-1-yl)methyl)phenyl-4-nitro-1H-pyrazole-3-carboxamide (I-c)

[0115] 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 ).

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Abstract

The invention relates to 4-(saturated aliphatic ring-pyrimidine / pyridine substituted)amino-1H-3-pyrazol carboxamide FMS-like tyrosine kinase 3 (FLT3) inhibitor, an application thereof, or pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug of the FLT3 inhibitor, a preparation method of the pharmaceutically acceptable salt, solvate, isomer, ester, acid, metaboliteor prodrug of the FLT3 inhibitor, a pharmaceutical composition comprising the compound, and a medical uses of the compounds and medical composition.

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] Cell signal transduction plays a key role in regulating cell growth, proliferation, differentiation, apoptosis and other processes. The imbalance of cell proliferation and apoptosis leads to the occurrence of major diseases such as cancer, and the essence of cell carcinogenesis is the disorder of cell signal transduction. When the cell signal transduction pathway that regulates the normal physiological activities of cells is changed under the action of carcinogens, the normal biological effects of regulating cell growth, division and dif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/517A61K31/5377A61P35/00A61P35/02A61P3/10A61P37/00
CPCC07D403/12
Inventor 王越卢帅支燕乐尧超陆涛李保泉陈璞洲鲍吉银
Owner CHINA PHARM UNIV
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