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Compound containing conjugated allene amide structure and preparation method, medicine composition and application thereof

A technology for compounds and alkyl groups, which is applied in the fields of compounds containing conjugated allenamide structures, their preparation, pharmaceutical compositions and uses, and can solve problems such as uncertainties in the biological activity and pharmaceutical properties of compounds

Active Publication Date: 2018-05-25
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • 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 allene amide structure and preparation method, medicine composition and application thereof
  • Compound containing conjugated allene amide structure and preparation method, medicine composition and application thereof
  • Compound containing conjugated allene amide structure and preparation method, medicine composition and application 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-indyl) (Dole-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] Under 0℃ and nitrogen protection, the CH 3 MgCl (3M, tetrahydrofuran solution, 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, and then 2,4-dichloropyrimidine (9.48 g, 64 mmoL) was added all at once. The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours. The reaction was quenched by adding methanol (25 mL), and then the resulting mixture was concentrated in vacuo, the residue was adsorbed on silica gel, and purified by a normal phase silica gel column to obtain GB011 (3 g) as a yellow-like 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=...

Embodiment 2

[0198] Example 2 Synthesis of (S)-N-[2-(tetrahydrofuran-3-yl)oxy-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl) (Pyrimidine-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] Add potassium tert-butoxide (0.366g, 3.81mmol) to N,N-dimethylformamide (10mL) and stir at 0℃, add 0.167g (1.9mmol) of (S)-(+)-3-hydroxyl Tetrahydrofuran, react for 1 hour. Add GB17 (0.500g, 1.27mmol) and react at room temperature for 3 hours. Add 100 mL of water to the obtained suspension, adjust the pH to 7-8, stir, filter with suction, dry the filter cake, and purify by silica gel column to obtain 0.15 g of the target 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 = 7.95 Hz), 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), 3.76-3.84 (m, 1H)...

Embodiment 3

[0206] Example 3 Synthesis of N-[2-(4-methylpiperazinyl)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine-2- (Yl)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) Pyrimidine-2-ylamine (GB066)

[0209] Add GB017 (0.1g, 0.254mmol) into 5mL N-pyrrolidone and stir at room temperature, add nitrogen methyl piperazine (0.025g, 0.254mmol), then add diisopropylethylamine (0.1mL), and heat to 140°C reaction. React for 2.5 hours and cool to room temperature. 100 mL of water was added to the above reaction solution, filtered with suction, the filter cake was dried, and purified by a silica gel column to obtain 0.1 g of the target 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 = 5.29 Hz), 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). E...

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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 use thereof, and specifically relates to a class of compounds containing a conjugated allenamide structure represented by the following general formula (I), a preparation method thereof, and a medicine The composition and the use in the preparation of epithelial growth factor receptor (EGFR) inhibitors, or the prevention and / or treatment of 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 non-reversible small molecule drugs. Small molecule drugs containing carbonyl conjugated olefins have a wide range of clinical applications. For example, the following sev...

Claims

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Application Information

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Patent Type & Authority Applications(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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