Pyridine substituted chalcone type compound or medicinal salt thereof and preparation method and application thereof

A technology for chalcones and compounds, which is applied in the field of pyridine-substituted chalcones or their pharmaceutically acceptable salts and their preparations, which can solve the problems of large toxic and side effects, poor water solubility, and difficult synthesis.

Active Publication Date: 2019-03-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have the disadvantages of large toxic and side effects, difficult synthesis, poor water solubility, and easy drug resistance.

Method used

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  • Pyridine substituted chalcone type compound or medicinal salt thereof and preparation method and application thereof
  • Pyridine substituted chalcone type compound or medicinal salt thereof and preparation method and application thereof
  • Pyridine substituted chalcone type compound or medicinal salt thereof and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104]

[0105] (E)-1-(2,6-dimethoxypyridin-4-yl)-3-(4-methoxyphenyl)-2-methylpropane-2-en-1-one

[0106] (a) Dissolve 2,6-dichloroisonicotinic acid (10g, 52mmol) in anhydrous THF, under nitrogen protection, drop into 2M ethylmagnesium bromide (80ml, 160mmol) under ice-bath conditions, react at room temperature for 2h, then add water Dilute, extract with dichloromethane (50mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate and column chromatography (PE / EA 4:1) to give 1-(2,6-dichloropyridine -4-yl)propan-1-one 9g, yield 85%;

[0107] (b) Dissolve 1-(2,6-lutidine-4-yl)propan-1-one (6g, 29.4mmol) in toluene, add DBU (12.43ml, 88.2mmol), 2-bromoethanol ( 10.42ml, 147mmol), react overnight at 80°C. Spin dry toluene, dilute with water, extract with dichloromethane (20mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate and column chromatography (PE / EA 40:1) to give...

Embodiment 2

[0112]

[0113] (E)-3-(3,4-dimethoxyphenyl)-1-(2,6-dimethoxypyridin-4-yl)-2-methylpropane-2-en-1-one

[0114] According to the operation of Example 1(d), 100 mg of a yellow solid was obtained with a yield of 72%;

[0115] 1 H NMR (300MHz, CDCl 3 )δ7.21(s, 1H), 7.14-7.03(m, 3H), 6.45(s, 2H), 3.93(s, 6H), 3.88(s, 6H), 2.11(s, 3H); 13 C NMR (75MHz, CDCl 3 )δ196.33, 165.45, 150.34, 149.26, 149.11, 138.82, 136.39, 129.75, 124.08, 112.72, 111.80, 101.84, 55.98, 55.89, 53.80, 16.41; ESI-MS m / z: 343.1 C for calc 19 h 22 NO 5 [M+H] + 344.1.

Embodiment 3

[0117]

[0118] (E)-1-(2,6-dimethoxypyridin-4-yl)-2-methyl-3-(3,4,5-trimethoxyphenyl)-propane-2-ene-1 -ketone

[0119] According to the operation of Example 1(d), 82 mg of yellow solid was obtained, and the yield was 70%;

[0120] 1 H NMR (300MHz, CDCl 3)δ7.20(s, 1H), 6.64(s, 2H), 6.47(s, 2H), 3.97(s, 6H), 3.89(s, 3H), 3.88(s, 6H), 2.25(s, 3H ); 13 C NMR (75MHz, CDCl 3 )δ196.33, 165.44, 153.30, 149.27, 139.51, 138.49, 136.07, 130.20, 107.70, 101.85, 60.83, 56.20, 53.79, 16.33; ESI-MS m / z: 373.1 calcd for C 20 h 24 NO 6 [M+H] + 374.1.

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Abstract

The invention discloses a pyridine substituted chalcone type compound with a structure as shown in a general formula I or a medicinal salt thereof, and also discloses a preparation method and application of the compound or the medicinal salt thereof. The compound or the medicinal salt thereof disclosed by the invention has small toxic or side effects and strong water solubility, is not easy to generate drug resistance, can effectively inhibit the aggregation of tubulin, has stronger anti-tumor activity in vitro and in vivo, can ensure more stable metabolism and has good pharmacological prospects. The invention also discloses combined application of the pyridine substituted chalcone type compound or the medicinal salt thereof and a TACC3 inhibitor for effectively inhibiting the activity oftumor cells resistant to tubulin.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a pyridine-substituted chalcone compound or a pharmaceutically acceptable salt thereof and a preparation method and use thereof. Background technique [0002] Microtubules are the main components of the cytoskeleton and play an important role in maintaining cell shape, cell division, signal transduction, etc. Therefore, tubulin is a very promising target for new chemotherapy drugs. Tubulin inhibitors can prevent the excessive proliferation of tumor cells and are an important class of anti-tumor drugs. At present, clinically used microtubule inhibitors mainly include drugs that inhibit tubulin depolymerization represented by paclitaxel and drugs that inhibit tubulin aggregation represented by vinblastines. However, these drugs have the disadvantages of large toxic and side effects, difficult synthesis, poor water solubility, and easy drug resistance. Contents of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/69C07D401/06C07D213/64C07D213/61C07D405/14A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D213/61C07D213/64C07D213/69C07D401/06C07D405/14
Inventor 徐进宜徐飞杰徐盛涛
Owner CHINA PHARM UNIV
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