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Quinoline substituted chalcone compound as well as preparation method and application thereof

A technology of chalcones and compounds, which is applied in the field of medicinal chemistry, can solve the problems of difficult synthesis, poor water solubility, and large toxic and side effects, and achieve the effects of low toxicity, stable metabolic properties, and excellent anti-tumor activity

Active Publication Date: 2019-03-15
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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  • Quinoline substituted chalcone compound as well as preparation method and application thereof
  • Quinoline substituted chalcone compound as well as preparation method and application thereof
  • Quinoline substituted chalcone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] (E)-3-(1H-indol-5-yl)propyl-1-(2-methylquinolin-4-yl)-2-enyl-1-one

[0041] (a) Mix indole-2,3-dione (10g, 68mmol) and 85% KOH aqueous solution at 50°C and stir for 1h, then add 50mL of acetone dropwise, continue stirring for 15h, spin off the acetone, and adjust the pH to 3. Suction filtration and drying to obtain 11 g of 2-methylquinoline-4-carboxylic acid (white solid, 86.7%); 2-methylquinoline-4-carboxylic acid (500 mg, 2.7 mml) was dissolved in dichloromethane, Add dimethylhydroxylamine hydrochloride (310mg, 3.2mmol), triethylamine (440μL, 3.2mmol), EDCI (1g, 5.4mmol), catalytic amount of DMAP, stir at room temperature for 2h, dilute with water, extract with dichloromethane (50mL ×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 510 mg of N-methoxy-N,2-dimethylquinoline-4-carboxamide, with a yield of 83.1%; (b ) Dissolve N-methoxy-N,2-dimethylquinoline-4-carboxamide (500m...

Embodiment 2

[0044]

[0045] (E)-3-(1H-indol-4-yl)propyl-1-(2-methylquinolin-4-yl)-2-enyl-1-one

[0046] According to the operation of Example 1 (c), 63 mg of yellow solid was obtained, and the yield was 50%; 1 H NMR (300MHz, CDCl 3 )δ9.11(s,1H),8.11(dd,J=8.2,4.6Hz,2H),7.97(d,J=16.1Hz,1H),7.78-7.66(m,1H),7.53(d,J =7.1Hz,1H),7.48(d,J=3.4Hz,1H),7.44(m,2H),7.38(s,1H),7.35-7.27(m,1H),7.19(t,J=7.8Hz ,1H),6.74(s,1H),2.81(s,3H); 13 C NMR (75MHz, CDCl 3 )δ194.85,158.04,147.94,146.93,145.16,135.97,129.53,128.51, 126.78,126.33,125.77,125.64,124.84,122.58,121.44,119.69,114.10,100.73, 76.99,76.56,76.14,24.83;ESI-MS m / z:312.1calcd for C 21 h 16 N 2 O[M+H] + 313.1.

Embodiment 3

[0048]

[0049] (E)-3-(3-Hydroxy-4-methoxyphenyl)-1-(2-methylquinolin-4-yl)propyl-2-enyl-1-one

[0050] According to the operation of Example 1(c), 120 mg of a yellow solid was obtained with a yield of 70.5%; 1 H NMR (300 MHz, DMSO) δ9.26 (s, 1H), 8.03 (d, J = 9.0Hz, 2H), 7.76 (t, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.57 ( t,J=7.9Hz,1H),7.50(d,J=16.0Hz,1H),7.33–7.22(m,2H),7.20 (d,J=6.3Hz,1H),6.97(d,J=8.4 Hz,1H),3.83(s,3H),2.74(s,3H); 13 C NMR(75 MHz,DMSO)δ193.80,158.59,150.87,147.82,147.55,146.77,144.27,129.66, 128.80,126.94,126.61,124.96,123.60,122.60,122.37,120.42,114.68,111.91, 55.65,40.34,40.06, 39.79, 39.51, 39.23, 38.95, 38.68, 24.81; ESI-MS m / z: 319.1 calcd for C 21 h 17 NO 3 [M+H] + 320.1.

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Abstract

The invention discloses a novel quinoline substituted chalcone compound as well as pharmaceutically acceptable salts and a preparation method thereof. The invention further discloses a pharmaceuticalcomposition which comprises a therapeutically effective amount of the novel quinoline substituted chalcone compound and / or the pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. The invention further discloses a tubulin inhibitor which comprises the novel quinoline substituted chalcone compound and / or the pharmaceutically acceptable salts. The invention further disclosesapplication of the novel quinoline substituted chalcone compound and / or the pharmaceutically acceptable salts in preparing drugs for treating but not limited to colon cancer, leukemia, liver cancer, breast cancer and other diseases. The compound in the application shows excellent anti-tumor activity, and has more stable metabolic properties and better druggability prospect.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of quinoline-substituted chalcone compounds with antitumor activity. The invention also discloses the pharmaceutical composition containing the compound and the application of the compound in the preparation of medicines for treating tumors and other diseases or diseases by inhibiting tubulin activity. 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 vinbl...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D215/14C07D215/38C07D215/227C07D401/04C07D215/48C07F9/60C07D215/18A61K31/675A61K31/4704A61K31/47A61K31/5377A61K31/4709A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D215/14C07D215/18C07D215/227C07D215/38C07D215/48C07D401/04C07D401/06C07F9/60
Inventor 徐进宜李文龙徐盛涛徐飞杰帅雯孙翃昊朱哲英姚鸿
Owner CHINA PHARM UNIV
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