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A kind of tetrazolium substituted quinolinone derivative and its preparation method and application

A technology of tetrazolium and quinolinone, applied in the field of organic compound preparation, can solve problems such as low activity in vivo, toxic and side effects, failure to pass FDA certification, etc., so as to prevent or prevent diabetic complications, treat diabetic complications, improve The effect of in vivo availability

Active Publication Date: 2022-07-26
YANCHENG LIMIN CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Carboxylic acid aldose reductase inhibitors exhibit excellent in vitro AKR1B1 inhibitory activity and selectivity, and have good drug prospects, but the structure of such inhibitors contains carboxyl groups, and their dissociation constants (pKa) are often low , in an ionized state under normal physiological pH conditions, it is difficult to penetrate the biofilm to reach the lesion tissue, the biological activity in the body is low, and it has potential risks such as poor membrane permeability, unstable metabolism, and toxic and side effects
Epalrestat (Epalrestat) is a typical carboxylic acid inhibitor. This inhibitor is currently the only AKR1B1 inhibitor drug on the market for the treatment of diabetic complications. It is mainly used to improve peripheral nerve diseases complicated by diabetes, but its activity in vivo is low. The dosage is large and has not passed FDA certification

Method used

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  • A kind of tetrazolium substituted quinolinone derivative and its preparation method and application
  • A kind of tetrazolium substituted quinolinone derivative and its preparation method and application
  • A kind of tetrazolium substituted quinolinone derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In this example, R 1 is tetrazolium; R 2 and R 3 for the hydrogen atom. i.e. compound 1 1-Benzyl-3-(1H-tetrazol-5-yl)quinolin-4(1H)-one.

[0033] see figure 2 , the preparation method of above-mentioned 1-benzyl-3-(1H-tetrazol-5-yl) quinoline-4(1H)-one is as follows:

[0034] Step 1. add 20mmol aniline (compound Ia in the four-necked flask) ) and 30mmol of dimethyl methoxymethylene maleate, the reaction mixture was carried out Neat reaction at 110 ° C, TLC (thin layer chromatography) was monitored until aniline disappeared, after the reaction system was cooled, ether was added dropwise to the system to precipitate Generated, after stirring for 20min, filtered to obtain a solid crude product, the crude product was purified by beating with n-heptane (5vol. (solvent volume, 5 times the volume of the crude product weight (5mL / g crude product weight))) to obtain a white solid compound Ib (ie 2-[(phenylamino)methylene]-1,3-dimethyl ester (4.02 g, yield 85.5%): melt...

Embodiment 2

[0041] In this example, R 1 For tetrazolium, R 2 is a hydrogen atom, R 3 is a fluorine atom. i.e. compound 2 1-(4-Fluorobenzyl)-3-(1H-tetrazol-5-yl)quinolin-4(1H)-one.

[0042] The preparation method of the above-mentioned 1-(4-fluorobenzyl)-3-(1H-tetrazol-5-yl)quinoline-4(1H)-one is the same as that in Example 1, except that 4-fluorobenzyl bromide is used instead of Benzyl bromide in Example 1. The compound 2,1-(4-fluorobenzyl)-3-(1H-tetrazol-5-yl)quinolin-4(1H)-one was finally obtained (melting point: 217-219°C; 1 H NMR (400MHz, [D 6 ]DMSO): δ / ppm=14.19(s, 1H), 8.50(s, 1H), 8.39(dd, J=8.0, 1.6Hz, 1H), 7.46(dd, J=8.2, 1.6Hz, 1H), 7.45-7.52(m, 4H), 7.26-7.18(m, 2H), 5.47(s, 2H); 13 C NMR (100MHz, [D 6 [M+Na] + ).

Embodiment 3

[0044] In this example, R 1 For tetrazolium, R 2 is a hydrogen atom, R 3 for the chlorine atom. i.e. compound 3 1-(4-Chlorobenzyl)-3-(1H-tetrazol-5-yl)quinolin-4(1H)-one.

[0045] The preparation method of above-mentioned 1-(4-chlorobenzyl)-3-(1H-tetrazol-5-yl)quinoline-4(1H)-one is the same as that in Example 1, except that 4-chlorobenzyl bromide is used instead of Benzyl bromide in Example 1. The compound 3,1-(4-chlorobenzyl)-3-(1H-tetrazol-5-yl)quinolin-4(1H)-one was finally obtained (melting point: 215-217°C; 1 H NMR (400MHz, [D 6 ]DMSO): δ / ppm=14.17(s, 1H), 8.47(s, 1H), 8.41(dd, J=7.8, 1.6Hz, 1H), 7.44(dd, J=8.0, 1.6Hz, 1H), 7.51-7.54(m, 4H), 7.31-7.25(m, 2H), 5.44(s, 2H); 13C NMR (100MHz, [D 6 ]DMSO)δ / ppm=177.1,168.4,151.4,141.7,139.2,137.9,131.7,130.8,129.5,127.4,125.2,123.4,115.6,109.4,58.7.MS m / z:360.1[M+Na] + ).

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Abstract

A tetrazole-substituted quinolinone derivative and a preparation method and application thereof belong to the technical field of organic compound preparation. Its structure is the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: wherein, R 1 is tetrazolium; R 2 is a hydrogen atom or a halogen atom; R 3 is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group. The product of the invention is a high-efficiency aldose reductase inhibitor with excellent membrane permeability, which can improve the availability of the inhibitor in vivo, thereby achieving the effect of treating diabetic complications.

Description

technical field [0001] The present invention relates to the technical field of preparation of organic compounds, in particular to a tetrazole-substituted quinolinone derivative and a preparation method and application thereof. Background technique [0002] Diabetic Complications (DCC) is a chronic complication transformed from diabetes, and it is the biggest threat faced by diabetic patients. Almost all the harm of diabetes comes from the various diabetes complications caused by it. DCC has a high morbidity and mortality rate, and the number of deaths due to diabetes complications or its induced factors is 5 million every year, second only to cancer and cardiovascular and cerebrovascular diseases. Abnormally enhanced glucose polyol metabolic pathway caused by altered AKR1B1 activity under persistent hyperglycemia ( figure 1 ) is an important pathogenesis of diabetic complications. Taking AKR1B1 as a drug target, AKR1B1 inhibitors are designed and synthesized to inhibit the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/4709A61P3/10
CPCC07D401/04A61P3/10
Inventor 韩忠飞郝鑫祁刚朱俊凯
Owner YANCHENG LIMIN CHEM
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