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Acetazolamide derivative, preparation method thereof and application thereof in preparation of medicine for treating coronary heart disease

A technology of acetazolamide and its derivatives, which is applied in the field of preparation of drugs for the treatment of coronary heart disease, can solve the problems of reduced efficacy of myocardial hypoxia, poor therapeutic effect, etc., and achieve reduced heart hypoxic area, improved efficacy, The effect of improving cell vitality

Active Publication Date: 2020-11-20
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Technical problem: In order to solve the problems of the existing non-steroidal anti-inflammatory drugs in the treatment of myocardial hypoxia under hypoxic conditions, such as reduced drug efficacy and poor therapeutic effect, the present invention provides a carbonic anhydrase inhibitor acetazolamide through linking A class of acetazolamide derivatives obtained by linking aspirin with non-steroidal anti-inflammatory drugs represented by carboxylic acid groups, this class of acetazolamide derivatives overcomes the traditional non-steroidal anti-inflammatory Drug resistance under the condition of myocardial hypoxia injury, the drug effect is significantly improved in the hypoxic microenvironment, and the invention also discloses its preparation method and its application in the preparation of drugs for the treatment of coronary heart disease

Method used

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  • Acetazolamide derivative, preparation method thereof and application thereof in preparation of medicine for treating coronary heart disease
  • Acetazolamide derivative, preparation method thereof and application thereof in preparation of medicine for treating coronary heart disease
  • Acetazolamide derivative, preparation method thereof and application thereof in preparation of medicine for treating coronary heart disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1. Preparation of 5-amino-1,3,4-thiadiazole-2-sulfonamide (compound 1)

[0046]

[0047] 1

[0048] Weigh 5.0 g of acetazolamide into a flask, add 30 mL of absolute ethanol, stir at room temperature, add 5 mL of concentrated hydrochloric acid, heat the oil bath to reflux at 85 °C, and monitor the reaction by thin-layer chromatography after all the solids are dissolved. After the reaction is complete, spin dry, and adjust the pH to alkaline with a small amount of saturated sodium bicarbonate solution. It was extracted three times with ethyl acetate, and the solvent was spin-dried to obtain 3.5 g of white solid with a yield of 86.4%.

[0049] 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.06 (s, 2H), 7.81 (s, 2H).

Embodiment 2

[0050] Example 2. Preparation of N-(5-sulfonamido-1,3,4-thiadiazol-2-yl)hept-6-yne amide (compound 2)

[0051]

[0052] 2

[0053] Dissolve 277 mg of 6-heptynoic acid in dichloromethane, add 2 equivalents of oxalyl chloride dropwise under ice-cooling, then add a drop of N,N-dimethylformamide, continue stirring for 6-8 h, spin dry for later use. Dissolve 360 ​​mg of compound 1 in N,N-dimethylformamide, add 316 mg of pyridine under ice-cooling, then add dropwise the solution of 6-heptynoyl chloride in N,N-dimethylformamide, and continue stirring for 6 h. The reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was spin-dried, and 0.42 g of white powder was obtained by silica gel column chromatography, with a yield of 73.7%.

[0054] 1 H NMR (600 MHz, DMSO- d 6 ) δ 13.0 (s, 1H), 8.32 (s, 2H), 2.78 (t, J =2.4 Hz, 1H), 2.55 (t, J = 7.2 Hz, 2H), 2.20–2.17 (m, 2H), 1.73–1.68 (m, 2H),1.50–1.45 (m, 2H).

Embodiment 3

[0055] Example 3. Preparation of 2-bromoethyl 2-acetoxybenzoate (compound 3a)

[0056]

[0057] 3a

[0058] Dissolve 360 ​​mg of aspirin in dichloromethane, add 2 equivalents of oxalyl chloride dropwise in an ice bath, then add a drop of N,N-dimethylformamide, continue stirring for 6-8 h, spin dry for later use. Dissolve 250 mg of 2-bromoethanol in dichloromethane, add 303 mg of triethylamine under ice-cooling, then add a solution of aspirinyl chloride in dichloromethane dropwise, continue stirring for 6 h, and monitor the reaction by thin-layer chromatography. After the reaction was finished, it was extracted with dichloromethane, the solvent was spin-dried, and 0.40 g of light yellow oil was obtained by silica gel column chromatography, with a yield of 70.2%.

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Abstract

The invention relates to an acetazolamide derivative, a preparation method thereof and an application of the acetazolamide derivative in preparation of a medicine for treating coronary heart disease.The acetazolamide derivative is an acetazolamide derivative I obtained by bonding a carbonic anhydrase inhibitor acetazolamide Ac and a non-steroidal anti-inflammatory drug which is represented by aspirin As and has a carboxylic acid group through a linking group, and the structural general formula is shown as a formula 1 shown in the specification, wherein in the formula 1, OOC-NSAID represents anon-steroidal anti-inflammatory drug in which one carboxylic acid proton is lost, representative are acetazolamide derivatives containing aspirin or indomethacin, and the acetazolamide derivative I has good activity of inhibiting carbonic anhydrase 9, can effectively improve myocardial anoxia injury in an anoxia microenvironment, and is applied to preparation of the medicine for treating coronaryheart disease.

Description

technical field [0001] The invention relates to an acetazolamide derivative and a preparation method thereof, and also relates to its application in the preparation of medicines for treating coronary heart disease. Background technique [0002] Coronary heart disease is myocardial damage caused by myocardial tissue ischemia (hypoxia at the cellular level) caused by organic stenosis or blockage of coronary arteries, also known as ischemic heart disease. According to data released by my country's Cardiovascular Disease Center in 2019, the number of people suffering from coronary heart disease and other cardiovascular diseases in China has reached 290 million, with high morbidity and mortality, which seriously threaten public health. Hypoxia is an important factor causing myocardial injury, but the efficacy of existing drugs is greatly reduced in the hypoxic microenvironment. Therefore, optimizing the structure of existing drug molecules around hypoxia and overcoming the influ...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D417/14A61P9/10
CPCC07D417/12C07D417/14A61P9/10
Inventor 苟少华周雯张斌
Owner SOUTHEAST UNIV
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