Nimesulide derivatives and preparation method and application thereof

A nimesulide and derivative technology, applied in the field of preparation of nimesulide derivatives, can solve the problems of mitochondrial permeability change, low nimesulide solubility, mitochondrial failure, etc., and achieve strong feasibility and repeatability Sexuality, cost reduction, and high production efficiency

Inactive Publication Date: 2019-04-12
山西康斯亚森生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nimesulide has good anti-inflammatory, analgesic and antipyretic effects, rapid oral absorption, quick onset, strong effect, rare reports of serious adverse reactions in cardiovascular and cerebrovascular, kidney, lung and skin and other organs and systems, gastrointestinal tolerance Nimesulide is well received, studies have confirmed that nimesulide is one of the drugs with the lowest risk of upper gastrointestinal bleeding, but it is comparable to other NSAIDs, and the solubility of nimesulide is low, which also leads to weakening of its efficacy
[0010] In the clinical application of nimesulide, there are occasional cases of severe liver damage caused by nimesulide, which may be because nimesulide interferes with the respiratory chain of mitochondria, leading to ATP exhaustion in mitochondria and changes in mitochondrial permeability, directly causing mitochondrial swelling and rupture

Method used

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  • Nimesulide derivatives and preparation method and application thereof
  • Nimesulide derivatives and preparation method and application thereof
  • Nimesulide derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The molecular formula of the nimesulide derivative in the present embodiment is: C 13 h 11 N 2 NaO 5 S;

[0074] The chemical structural formula is:

[0075]

[0076] Molecular weight: 330.03.

[0077]The synthetic route of the nimesulide derivative described in this example is:

[0078]

[0079] The preparation steps of the nimesulide derivative are:

[0080] Dissolve nimesulide in distilled water to make nimesulide aqueous solution, the concentration of nimesulide aqueous solution is 0.4g / ml, add the aqueous solution of sodium hydroxide to the nimesulide aqueous solution, the concentration of sodium hydroxide aqueous solution is 0.1g / ml, the molar ratio of nimesulide to sodium hydroxide added was 0.8:1, the system was heated up to 45°C, the insoluble matter was completely dissolved, and the stirring was continued for 1h, and after cooling to room temperature, it was transferred to an ice bath at 0°C. A yellow solid was precipitated, and the solid was was...

Embodiment 2

[0082] The molecular formula of the present embodiment nimesulide derivative is: C 13 h 11 N 2 KO 5 S;

[0083] The chemical structural formula is:

[0084]

[0085] Molecular weight: 346.00.

[0086] The synthetic route of the nimesulide derivative described in this example is:

[0087]

[0088] The preparation steps of the nimesulide derivative are:

[0089] Dissolve nimesulide in distilled water to make nimesulide aqueous solution, the concentration of nimesulide aqueous solution is 0.4g / ml, add the aqueous solution of potassium hydroxide to the nimesulide aqueous solution, the concentration of potassium hydroxide aqueous solution is 0.1g / ml, the molar ratio of nimesulide to potassium hydroxide added is 0.8:1, the system is heated up to 45°C, the insoluble matter is completely dissolved, and the stirring is continued for 1h, cooled to room temperature and then transferred to an ice bath at 0°C, a large amount of A yellow solid was precipitated, and the solid w...

Embodiment 3

[0091] The molecular formula of the present embodiment nimesulide derivative is: C 13 h 14 N 2 o 3 S;

[0092] The chemical structural formula is:

[0093]

[0094] Molecular weight: 278.07.

[0095] The synthetic route of the nimesulide derivative described in this example is:

[0096]

[0097] The preparation steps of the nimesulide derivative are:

[0098] Mix nimesulide, tin and concentrated hydrochloric acid, the concentration of concentrated hydrochloric acid is 12mol / L, the molar ratio of nimesulide, tin and hydrochloric acid is 6:11:1, reflux at 85°C for 5h, pour it after the reaction is complete into ice water, filter out the solid and basify it with lye, and then recrystallize with a mixed solvent of methanol and chloroform to obtain a light brown solid that is a nimesulide derivative.

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Abstract

The invention relates to a preparation method of four nimesulide derivatives with the function of treating liver malignant tumors. According to the invention, a nimesulide solution and an acid or alkaline substance are subjected to displacement reaction to generate three salts with better water solubility and more stability, which are the nimesulide derivatives, or p-aminobenzonitrile is used as asubstrate, the fourth nimesulide derivative with higher bioavailability is generated through a series of redox reactions, four novel nimesulide derivatives are successfully prepared, all the four compounds are soluble in water, the solubility is better than that of the nimesulide, and better absorption rate and bioavailability are provided, and the hepatotoxicity of the four derivatives is not obviously different from that of the nimesulide at normal dose, and only one derivative is enhanced in liver toxicity at overdose. The inhibitory effect on BEL-7402 is no less than or even stronger thanthat of nimesulide when the four derivatives are co-cultured with CIK cells. The four nimesulide derivatives can be used for preparing drugs for inhibiting human liver cancer cells.

Description

technical field [0001] The invention relates to a preparation method of four kinds of nimesulide derivatives capable of treating liver malignant tumors. Background technique [0002] Liver cancer, referred to as hepatocellular carcinoma, is a common malignant tumor. In recent years, the incidence of this disease has been increasing worldwide. It currently ranks fifth among malignant tumors, and its mortality rate ranks third among malignant tumors. my country is a country with a high incidence of liver cancer. Liver cancer cases account for about 55% of the world's total. The mortality rate is second only to lung cancer, and the mortality rate of liver tumors in the age group of 30 to 44 ranks first among all kinds of cancer deaths. bit. Liver cancer is common in males. From the perspective of geographical distribution, the incidence rate in coastal areas is higher than that in inland areas, and in rural areas is higher than in urban areas. From the perspective of age group ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/08C07C303/40C07D209/48C07F5/02C07C255/54C07C253/30C07C303/38A61P35/00
CPCA61P35/00C07C253/30C07C303/38C07C303/40C07C311/08C07D209/48C07F5/025C07C255/54
Inventor 卢学春
Owner 山西康斯亚森生物科技有限公司
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