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Pyrimidine compound, its preparation method and medical application

A technology of pyrimidines and compounds, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve off-target and other problems

Inactive Publication Date: 2017-10-20
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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  • Pyrimidine compound, its preparation method and medical application
  • Pyrimidine compound, its preparation method and medical application
  • Pyrimidine compound, its preparation method and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

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

[0056] 2-nitro-5-fluoroanisole (1.00g, 5.81mmol) and 5% palladium carbon (0.62g, 0.29mmol) were added to 35mLTHF, hydrogen was passed through at room temperature and stirred for 5h, suction filtered, and the solvent was spin-dried. 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 ...

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 medicine, and in particular relates to a pyrimidine compound, a preparation method and medical use thereof, and in particular to the application in the preparation of antitumor drugs. Background technique [0002] Protein tyrosine kinases are important regulators 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 conversion of the kinase from an inactive conformation to an active conformation, thereby activating downstream signaling molecules, and further triggering various biological effects of cells. It plays an important role in the processes of proliferation and differentiation (Oncogene, 2000, 19(49): 5548-5557). In normal cells, the catalytic activity of protein tyrosine kinases is strictly regulated, but when their genes are mutat...

Claims

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Application Information

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Patent Type & Authority Patents(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