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Nonsteroidal antiinflammatories with nitric oxide donors and its preparation method

A non-steroidal anti-inflammatory drug, nitric oxide technology, applied in anti-inflammatory agents, pharmaceutical formulations, medical preparations with non-active ingredients, etc., can solve problems such as bleeding or even perforation, large side effects of the digestive tract, thromboembolism, etc.

Inactive Publication Date: 2007-10-17
江苏吴中苏药医药开发有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Among them, Class A has relatively large gastrointestinal side effects, and long-term use can lead to serious side effects such as gastrointestinal ulcers, bleeding and even perforation, which limits their wide application in clinical practice.
Class B has less gastrointestinal side effects than Class A. Although Class C has the lightest gastrointestinal side effects, it has been found to have cardiovascular side effects and the risk of thromboembolism in recent years. Rofecoxib has been withdrawn from the market in recent years, and celecoxib has also warned

Method used

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  • Nonsteroidal antiinflammatories with nitric oxide donors and its preparation method
  • Nonsteroidal antiinflammatories with nitric oxide donors and its preparation method
  • Nonsteroidal antiinflammatories with nitric oxide donors and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Ricofilone m-nitroxymethylphenyl acetate

[0033]

[0034] Dissolve 9.5 g (0.05 mol) of m-hydroxybenzyl bromide in 100 ml of acetonitrile, add 10 g (0.06 mol) of silver nitrate, and stir in the dark at 25°C for 18 hours, filter off the solid, spin the filtrate to dryness, and purify it by column chromatography, and use petroleum ether -eluted with ethyl acetate to obtain m-nitrooxymethylphenol, 4.5 g of yellow oily matter, yield 53%. Dissolve the oil in 30ml of dichloromethane, add 3.7g (0.027mol) of bromoacetic acid and 6g of DCC, stir at 25°C for 8 hours, filter, make sand from the filtrate, and purify by column to obtain m-nitroxymethylbenzene bromoacetic acid Ester, light brown oil 4.7g.

[0035] Dissolve 0.1g of sodium metal (0.00435mol) in 10ml of methanol, add 1.6g (0.0042mol) of ricofilon, spin dry after dissolving, dissolve the solid in 10ml of DMF, drop into the bromoacetic acid m-nitroxymethylphenyl 1.2g (0.0042mol) and DMF10ml solution, st...

Embodiment 2

[0036] Embodiment 2: Diclofenac m-nitrooxymethylphenyl acetate

[0037]

[0038] Dissolve 0.2g (0.0087mol) of sodium metal in 20ml of methanol, add 2.5g (0.00845mol) of diclofenac, spin dry after dissolving, dissolve the solid in 20ml of DMF, drop into 2.5g of m-nitrooxymethylphenyl bromoacetate ( 0.00845mol) and 20ml of DMF, stirred at 25°C for 4 hours, added 120ml of ethyl acetate, washed three times with water, dried, sanded, and eluted with petroleum ether-ethyl acetate to obtain 1.4g of a yellowish solid. (MS-ESI(+): 505[M+H] + ;IR: 1770, 1732, 1633, 1277cm -1 ; NMR (CDCl 3 ): 8.23 ​​(s, 1H), 6.82-7.40 (m, 11H), 6.00 (s, 2H), 4.82 (s, 2H), 3.76 (s, 2H)).

Embodiment 3

[0039] Embodiment 3: m-nitroxymethylphenyl acetate of clomethoxib

[0040]

[0041] Dissolve 0.25g of sodium metal (0.0109mol) in 10ml of methanol, add 3g of clomethoxib (0.0102mol), spin dry after dissolution, dissolve the solid in 10ml of DMF, and drop into 3g of m-nitrooxymethylphenyl bromoacetate (0.0102mol) and DMF10ml solution, stirred at 20°C for 4 hours, added 40ml of ethyl acetate, washed three times with water, made sand after drying, and eluted with petroleum ether-ethyl acetate to obtain 0.6g of yellow oil. (MS-ESI(+): 503[M+H] + ;IR: 1740, 1635, 1270cm -1 ; NMR (CDCl 3 ): 9.03(s, 1H), 6.52-7.38(m, 10H), 6.20(s, 2H), 4.98(s, 2H), 3.86(s, 2H)), 2.25(s, 3H)).

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Abstract

The invention relates to a non-steroidal anti-inflammatory drug with nitrogen oxide donor and a method for preparing same, which can be used to eliminate inflammation, relieve fever and stop pain, and can decrease the frequently seen side effect thereof on the gastrointestinal tract. The structure of which is A-O(X)-CO-O(y)-B-ONO2,wherein, A is the non-steroidal anti-inflammatory group; B is the connection group, when x=0, y=1; when x=1 then y=0. The the non-steroidal anti-inflammatory groups includes aspirin, diclofenac, indometacin, lumiracoxib, brufen, ketoprofen, naproxen, piroxicam, and meloxicam. The preparation process are that the bromhydrin (or hydroxybenzene) reacts with silver nitrate into hydroxy nitrate, then reacts with bromo acid into the connection group of nitrogen oxide donor, then connects with the non-steroidal anti-inflammatory drug; or the non-steroidal anti-inflammatory drug condensates with bromo acid into a bromide intermediate, then reacts with silver nitrate into the non-steroidal anti-inflammatory drug with nitrogen oxide donor.

Description

technical field [0001] The present invention relates to a non-steroidal anti-inflammatory drug with a nitric oxide donor and a preparation method thereof, which can be used for anti-inflammatory, antipyretic and analgesic, and can significantly reduce the common gastrointestinal effects of non-steroidal anti-inflammatory drugs. side effect. Background technique [0002] Non-steroidal anti-inflammatory drugs (NSAIDs) have been used in the treatment of arthritis and other diseases for more than 100 years. At present, hundreds of NSAIDs are on the market. About 30 million people in the world use these drugs to effectively relieve pain every day. , but their adverse reactions and allergic reactions to the gastrointestinal tract, liver, kidney, blood and nervous system also plague these patients. Therefore, the history of NSAIDs development is the history of continuous reduction of drug side effects and improvement of compliance. [0003] In 1971, the cyclooxygenase (COX) theor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K45/00A61P29/00A61K47/54
Inventor 武卫唐磊张荣久曹庆先华雯妍
Owner 江苏吴中苏药医药开发有限责任公司
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