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Miazines compound, preparation method and medical application thereof

A technology of pyrimidines and compounds, which can be used in pharmaceutical formulations, organic chemistry, anti-tumor drugs, etc., and can solve off-target problems

Inactive Publication Date: 2015-08-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the covalent binding of irreversible inhibitors to the target protein can usually enhance the drug efficacy and prolong the action time, when its electrophilicity is too strong, it is easy to have non-specific covalent binding with the nucleophilic group of the non-target protein, resulting in off-target Phenomenon

Method used

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  • Miazines compound, preparation method and medical application thereof
  • Miazines compound, preparation method and medical application thereof
  • Miazines compound, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] Preparation of 2-methoxy-4-fluoroaniline (1)

[0056] Add 2-nitro-5-fluoroanisole (1.00g, 5.81mmol) and 5% palladium carbon (0.62g, 0.29mmol) into 35mL THF, stir with hydrogen gas at room temperature for 5h, filter with suction, and spin to dry the solvent , 0.80 g of a light yellow solid was obtained, with a yield of 97%.

[0057] Preparation of 2-methoxy-4-fluoro-5-nitroaniline (2)

[0058] Under ice bath, 1 (1.00g, 5.42mmol) was dissolved in 6.50mL concentrated sulfuric acid in batches, and NaNO was added in batches 3 (0.46g, 5.41mmol), continued to stir for 4 hours, adjusted to neutral with 2% NaOH solution, extracted with dichloromethane, and spin-dried the solvent to obtain 0.64g of an orange-red solid, with a yield of 64%.

[0059] Preparation of 1-methyl-3-(2-chloropyrimidin-4-yl)indole (3)

[0060] Dissolve 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 25 mL of ethylene glycol dimethyl ether, cool in an ice bath, and add AlCl in batches 3 (0.98g...

Embodiment 2

[0072] N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(imidazol-2-yl)acrylamide (LY-2)

[0073]

[0074] Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with imidazole-2-carbaldehyde, the yield was 73%, and mp: 137-139°C. ESI-MS: 591.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.11(s, 6H), 2.28(br, 2H), 2.72(s, 3H), 2.99(br, 2H), 3.88(s, 3H), 3.90(s, 3H), 7.14 (br, 2H), 7.24(br, 2H), 8.06(br, 2H), 8.26(d, 1H, J=6.93Hz), 8.34(m, 1H), 8.59(s, 1H), 9.19(s, 1H), 10.24(br, 1H).

Embodiment 3

[0076] N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(furan-2-yl)acrylamide (LY-3)

[0077]

[0078] Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with furan-2-carbaldehyde, the yield was 81%, and mp: 174-176°C. ESI-MS: 591.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.11(s, 6H), 2.45(m, 2H), 2.72(s, 3H), 2.99(m, 2H), 3.88(s, 3H), 3.91(s, 3H), 6.87 (m, 1H), 7.14(m, 2H), 7.24(m, 2H), 7.46(d, 1H, J=3.54Hz), 7.52(d, 1H, J=7.98Hz), 7.99(s, 1H) , 8.08(s, 1H), 8.21(s, 1H), 8.26(d, 1H, J=8.10Hz), 8.33(d, 1H, J=5.31Hz), 8.60(s, 1H), 9.16(s, 1H), 10.26(s, 1H).

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Abstract

The invention belongs to the medicine field, and concretely relates to a miazines compound having a structure of a formula (1), its pharmaceutically acceptable salt, a preparation method and an application of the compound for preparing an antitumor drug. The pharmacological experiment result shows that the compound has good inhibition effect to an epidermal growth factor acceptor (EGFR) and its mutant, can inhibit propagation of a plurality of tumor cells, and can be taken as an EGFR inhibitor used for preparing the antitumor drug.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a pyrimidine compound, its preparation method and medical application, especially the application in the preparation of antitumor drugs. Background technique [0002] Protein tyrosine kinases are important regulatory factors in cell signal transduction pathways. Among the 518 known protein kinases, 90 belong to protein tyrosine kinases. It can catalyze the transfer of γ-phosphate on ATP to the tyrosine residue of the substrate protein, and promote the transformation of the kinase from an inactive conformation to an activated conformation, thereby activating downstream signaling molecules and further triggering various biological effects of cells. It plays an important role in processes such as proliferation and differentiation (Oncogene, 2000, 19(49): 5548-5557). In normal cells, the catalytic activity of protein tyrosine kinase is strictly regulated, but when its gene is mu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D405/14C07D403/04C07D401/14A61K31/506A61K31/5377A61P35/00
CPCC07D401/14C07D403/04C07D403/14C07D405/14
Inventor 赖宜生杨凤娇马骏罗明昊张姗张奕华
Owner CHINA PHARM UNIV
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