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Compound containing conjugated allenamide structure, preparation method, pharmaceutical composition and use thereof

A compound, selected technology, applied in the direction of drug combination, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of compound biological activity, uncertainty in the application prospect of pharmacological properties, etc.

Active Publication Date: 2020-03-10
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the properties of compounds containing conjugated allenamide structural fragments are uncertain in terms of biological activity, pharmaceutical properties, and application prospects for treating diseases.

Method used

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  • Compound containing conjugated allenamide structure, preparation method, pharmaceutical composition and use thereof
  • Compound containing conjugated allenamide structure, preparation method, pharmaceutical composition and use thereof
  • Compound containing conjugated allenamide structure, preparation method, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0180] Example 1 Synthesis of N-[2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-ind Indol-3-yl)pyrimidin-2-yl)amino)phenyl]-2,3-butenamide (1)

[0181]

[0182] Step 1: Synthesis of 3-(2-chloropyrimidin-4-yl)-1H-indole (GB011)

[0183] CH 3MgCl (3M in tetrahydrofuran, 14 mL, 42 mmol) was added dropwise to a solution of indole (5 g, 42 mmol) in 1,2-dichloroethane (250 mL). The resulting solution was stirred for 15 minutes, then 2,4-dichloropyrimidine (9.48 g, 64 mmoL) was added in one portion. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The reaction was quenched by the addition of methanol (25 mL) and the resulting mixture was concentrated in vacuo and the residue was adsorbed onto silica gel and purified using a normal phase silica gel column to afford GB011 (3 g) as a yellowish solid. 1 H NMR (DMSO-d 6 ,400MHz): 7.18-7.27(m,2H),7.46-7.53(m,1H), 7.90(d,1H,J=5.36Hz), 8.38-8.44(m,1H), 8.48...

Embodiment 2

[0198] Example 2 Synthesis of (S)-N-[2-(tetrahydrofuran-3-yl)oxyl-4-methoxyl-5-((4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-yl)amino)phenyl]-2,3-butenamide (2)

[0199]

[0200] Step 1: Synthesis of (S)-N-(2-methoxy-4-(tetrahydrofuran-3-yl)oxy-5-nitro)phenyl-4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-ylamine (GB056)

[0201] Potassium tert-butoxide (0.366g, 3.81mmol) was added into N,N-dimethylformamide (10mL) and stirred at 0°C, and 0.167g (1.9mmol) of (S)-(+)-3-hydroxy Tetrahydrofuran, reacted for 1 hour. Add GB17 (0.500 g, 1.27 mmol) and react at room temperature for 3 hours. Add 100 mL of water to the resulting suspension, adjust the pH to 7-8, stir, filter with suction, dry the filter cake, and purify through a silica gel column to obtain 0.15 g of the target product GB056.1 H NMR (DMSO-d 6 ,400MHz):8.77(s,1H),8.28-8.40(m,3H),8.18(s,1H),7.51(d,1H,J=7.95Hz),7.20-7.28(m,2H),7.07- 7.13(m,1H),6.93(s,1H),5.34-5.41(m,1H),4.00(s,3H),3.93-3.98(m,1H),3.76-3.92(m,2H),3.87( s,3H),...

Embodiment 3

[0206] Example 3 Synthesis of N-[2-(4-methylpiperazinyl)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2- Base) amino) phenyl] -2,3-butenamide (3)

[0207]

[0208] Step 1: Synthesis of N-(4-(4-methylpiperazinyl)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) Pyrimidin-2-ylamine (GB066)

[0209] Add GB017 (0.1g, 0.254mmol) to 5mL N-ylpyrrolidone and stir at room temperature, add nitrogen methyl piperazine (0.025g, 0.254mmol), then add diisopropylethylamine (0.1mL), and heat up to Reaction at 140°C. React for 2.5 hours and cool down to room temperature. Add 100mL of water to the above reaction solution, filter with suction, dry the filter cake, and purify through a silica gel column to obtain 0.1g of the target product GB066. 1 H NMR (CDCl 3 ,400MHz):9.66(s,1H),8.40(d,1H,J=5.25Hz),8.29(s,1H),8.14-8.20 (m,1H),7.57(s,1H),7.39-7.44( m,1H),7.28-7.36(m,2H),7.20(d,1H,J=5.29Hz),6.63(s,1H), 4.00(s,3H),3.95(s,3H),3.10-3.19 (m,4H), 2.62-2.72(m,4H), 2.40(s,3H). ESI-MS...

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Abstract

The invention relates to a compound containing a conjugated allene amide structure and a preparation method, a medicine composition and application thereof, in particular to a compound containing a conjugated allene amide structure shown in a formula (I), and a preparation method, a medicine composition and application thereof in preparation of an EGFR (epidermal growth factor receptor) inhibitoror a medicine for preventing and / or treating EGFR-related diseases, especially cancers. (The formula (I) is shown in the description.).

Description

technical field [0001] The present invention relates to a compound containing a conjugated allenamide structure, a preparation method thereof, a pharmaceutical composition and an application thereof, in particular to a compound containing a conjugated allenamide structure represented by the following general formula (I), a preparation method thereof, and a drug Composition and use in preparation of epidermal growth factor receptor (EGFR) inhibitor, or medicine for preventing and / or treating EGFR-related diseases, especially cancer. Background technique [0002] The chemical structures of carbonyl-conjugated alkenes and carbonyl-conjugated alkynes can form covalent bonds with amino acid residues such as cysteine ​​and lysine in proteins, and are widely used in the design and development of irreversible small molecule drugs. Small-molecule drugs containing carbonyl-conjugated olefins are widely used clinically. For example, the following seven drugs approved for marketing all ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D405/14C07D403/14C07D471/04C07D401/14C07D401/04C07D487/04C07D495/04C07D413/14A61K31/506A61K31/5377A61K31/517A61K31/519A61P37/00A61P29/00A61P9/10A61P35/00
CPCC07D401/04C07D401/14C07D403/04C07D403/14C07D405/14C07D413/14C07D471/04C07D487/04C07D495/04
Inventor 赵玉军郭德祥严子琴
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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