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Nitrogen substitutive 3-oxygen substitutive-6-tetrahydroquinoxaline substitutive structure compound and preparation method and medical application thereof

A kind of technology of tetrahydroquinoxaline and compound, applied in the field of medicine, can solve problems such as poor water solubility, limited clinical application and the like

Active Publication Date: 2016-11-23
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its poor water solubility and its tendency to undergo isomerization of double bonds to form inactive trans isomers limit its clinical application.

Method used

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  • Nitrogen substitutive 3-oxygen substitutive-6-tetrahydroquinoxaline substitutive structure compound and preparation method and medical application thereof
  • Nitrogen substitutive 3-oxygen substitutive-6-tetrahydroquinoxaline substitutive structure compound and preparation method and medical application thereof
  • Nitrogen substitutive 3-oxygen substitutive-6-tetrahydroquinoxaline substitutive structure compound and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of 1-(4-methoxybenzyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (5a)

[0048]

[0049] (1) Preparation of 3-nitro-4-aminobenzoic acid methyl ester (2a)

[0050] Put 3-nitro-4-aminobenzoic acid (that is, compound 1, 4.50g, 24.7mmol) and anhydrous methanol (80mL) into a 250mL three-necked bottle in turn, and when the temperature dropped to 0°C, drop Slowly add thionyl chloride (5.38mL, 74.1mmol, 3equiv) dropwise into the liquid funnel, after the dropwise addition, continue to stir at 0°C for 30 minutes, then raise the temperature to 50°C for 4h, a large amount of yellow solid is produced, suction filter, and the filtrate The methanol in the mixture was evaporated to dryness, 30 mL of water and 30 mL of ethyl acetate were added, the layers were separated, the organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain a yellow solid, which was combined with the previous filter cake and ...

Embodiment 2

[0058] Preparation of 1-(3,4-dimethoxybenzyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (5b)

[0059]

[0060] Except that 3,4-dimethoxybenzyl chloride was used instead of 4-methoxybenzyl chloride in step (4), other steps and purification methods were the same as in Example 1 to obtain 29 mg of white solid with a yield of 56.1%. Melting point: 155.9-157.5°C. 1 H NMR (300MHz, CDCl 3 )δ9.05(s,1H),7.65(dd,J=8.5,1.8Hz,1H),7.50(d,J=1.8Hz,1H),6.82(s,2H),6.79-6.74(m,2H ),4.43(s,2H),3.92(s,2H),3.87(s,6H),3.83(s,3H). 13 C NMR (75MHz, CDCl 3 )δ166.8, 165.8, 149.5, 148.7, 138.9, 127.6, 126.6, 125.2, 120.0, 119.9, 116.8, 111.4, 110.9, 110.5, 56.0, 53.2, 52.0, 51.6. HRMS (ESI): calcd for C 19 h 21 N 2 o 5 [M+H] + 357.14450, found 357.14450.

Embodiment 3

[0062] Preparation of 1-(2,3,4-trimethoxybenzyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (5c)

[0063]

[0064] Except that 3,4,5-trimethoxybenzyl chloride was used instead of 4-methoxybenzyl chloride in step (4), other steps and purification methods were the same as in Example 1 to obtain 38 mg of white solid with a yield of 67.8% . Melting point: 188.9-191.0°C. 1 H NMR (300MHz, CDCl 3 )δ8.02(brs,1H),7.67(dd,J=8.5,1.9Hz,1H),7.43(d,J=1.9Hz,1H),6.78(d,J=8.6Hz,1H),6.47( s,2H),4.42(s,2H),3.93(s,2H),3.88(s,3H),3.84(s,3H),3.81(s,6H). 13 C NMR (75MHz, CDCl 3 )δ166.7, 165.7, 153.8, 138.8, 137.5, 131.0, 126.7, 125.1, 120.2, 116.8, 111.0, 104.3, 60.9, 56.2, 53.8, 52.0, 51.8. HRMS (ESI): calcd for C 20 h 23 N 2 o 6 [M+H] + 387.15506,found 387.15512.

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Abstract

Disclosed are nitrogen substitutive 3-oxygen substitutive-6-tetrahydroquinoxaline substitutive structure compound and preparation method and medical application thereof. The general structure of the compound is as shown in the formula (I). The compound has tubulin polymerization inhibition activities, and is good in tumor disease resistance and proliferative disease apart from tumors.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a nitrogen-substituted 3-oxo-6-substituted tetrahydroquinoxaline structure compound, a preparation method and a medical application thereof. Background technique [0002] Microtubules are tubular polymers formed by the polymerization of α and β tubulin heterodimers. They have many functions in cells, especially participating in the process of cell mitosis in the form of spindles. Tumor cells have the ability to proliferate rapidly. If the formation of their spindles is inhibited, mitosis will be blocked, and the growth of tumor cells will stagnate at G 2 / M phase, inhibit cell proliferation. [0003] Microtubules exist in two forms, cytoplasmic microtubules and spindle microtubules, and participate in cell movement, organelle positioning, intracellular material transport, and mitotic processes of eukaryotic cells. When cells enter division, their cytoplasmic microtubules dep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/44A61P35/00A61P35/02A61K31/498A61K31/5377
CPCC07D241/44
Inventor 齐建国王建红张亚宏冬海洋黄静张树峰牛林强
Owner HENAN UNIVERSITY
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