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Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof

A technology for pharmaceutical preparations and compounds is applied in the application field of preparing non-steroidal anti-inflammatory drugs, and can solve the problems of reduced medicinal effect, limited sterilization conditions and effects of injections, and large changes in the structure of ibuprofen, and the like, To achieve the effect of rapid onset and long drug action time

Active Publication Date: 2013-03-27
山东华鲁制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the obtained compound has enhanced the binding effect on COX-2, the inhibitory effect of the compound on COX-2 and COX-1 is reduced after structural modification, and the medicinal effect has decreased. Larger changes in structure lead to changes in pharmacological activity
[0012] 2. The ibuprofen compound compound obtained through ibuprofen coupling, esterification, etc., has undergone major changes in the structure of ibuprofen, and its medicinal effect has also decreased. It may be this kind of ibuprofen compound compound drug In the process of metabolism in the body, the pharmacological effect is changed, resulting in the reduction of the anti-inflammatory or analgesic effect of ibuprofen
[0013] 3. Synthesis of ketoprofen or suprofen or phenoxyibuprofen with halogenated benzene derivatives and cyanoacetate derivatives, which can enhance the pharmacological effects in a certain aspect, such as analgesia or anti-inflammation, but the drug Changes in toxicity, increased adverse reactions to gastrointestinal irritation
The ibuprofen-arginine mixture injection is easily affected by temperature, which reduces the stability of the drug and limits the sterilization conditions and effects of the injection

Method used

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  • Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof
  • Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof
  • Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097]Add 10.3g (0.05mol) of ibuprofen and 8g of potassium bicarbonate to a 250mL three-necked flask, add 110mL of acetone while stirring, add 13.4g (0.08mol) of 1-bromoethyl acetate dropwise at room temperature, and continue to The mixture was stirred and reacted for 5 h, diluted by adding 200 mL of ethyl acetate, the reaction solution was transferred to a separatory funnel, washed with a 3% by weight aqueous solution of sodium carbonate (2×100 mL), the organic layer was separated, dried over anhydrous sodium sulfate, Remove the desiccant by filtration, add activated carbon to reflux for decolorization for 20 minutes, remove the activated carbon by filtration, concentrate the filtrate under normal pressure until no liquid distills out, distill the residue under reduced pressure, collect fractions at 164-166°C / 2mmHg, and obtain 12.6 g of colorless liquid. The colorless liquid is the target product ibuprofen-1-acetoxyethyl ester, and the yield relative to the raw material ibupro...

Embodiment 2

[0103] Add 103g (0.5mol) of ibuprofen and 100g of potassium bicarbonate to a 2500mL three-necked bottle, add 1000mL of acetone while stirring, add 134g (0.8mol) of 1-bromoethyl acetate dropwise at room temperature, and continue to store at 40°C. Stir the reaction for 3h, add 2000mL ethyl acetate to dilute, transfer the reaction solution into a separatory funnel, wash with a sodium carbonate solution with a concentration of 3% by weight (2×800mL), separate the organic layer, dry over anhydrous sodium sulfate, and filter Remove the desiccant, add activated carbon to reflux for decolorization for 20min, remove the activated carbon by filtration, concentrate the filtrate under normal pressure until no liquid is distilled out, distill the residue under reduced pressure, collect 164~166℃ / 2mmHg fractions, and obtain 130g of colorless liquid, which is subjected to IR, 1 HNMR and MS (ESI) spectrograms confirmed that the colorless liquid was the target product ibuprofen-1-acetoxyethyl es...

Embodiment 3

[0105] Add 2060g (10mol) of ibuprofen and 240g of potassium bicarbonate to a 5L three-necked flask, add 1L of acetone while stirring, add 2345g (14mol) of 1-bromoethyl acetate dropwise at room temperature, and continue to stir the reaction at 25°C 3h, add 1L ethyl acetate to dilute, transfer the reaction solution into a separatory funnel, wash with 3% by weight sodium carbonate solution (2×5000mL), separate the organic layer, dry over anhydrous sodium sulfate, filter to remove the dry Add activated carbon to reflux for decolorization for 20min, remove the activated carbon by filtration, concentrate the filtrate under normal pressure until no liquid is distilled out, distill the residue under reduced pressure, collect 164~166℃ / 2mmHg fractions, and obtain 2642g of colorless liquid, which is tested by IR, 1 HNMR and MS (ESI) spectrograms confirmed that the colorless liquid was the target product ibuprofen-1-acetoxyethyl ester, and the yield relative to the raw material ibuprofen w...

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Abstract

Disclosed are compounds based on ibuprofen, their preparation methods, uses and pharmaceutical preparation. The compounds have structures shown as formula(1), wherein m, n are integers and fulfill the requirement of 0.n.6, 0.m.6, respectively. The preparation methods for the compounds based on ibuprofen are as follows: contacting and reacting 2-(4-isobutyl phenyl)-propionic acid and an ester of an organic acid solution in the presence of a catalyst and under substitution reaction conditions. The present compounds can be used to prepare nonsteroidal anti-inflammatory drugs. The preparation can be preparation of fat emulsion, liposome, and dry emulsion and so on.

Description

technical field [0001] The invention relates to an ibuprofen-based compound, its preparation method and its application in the preparation of non-steroidal anti-inflammatory drugs. Background technique [0002] Ibuprofen, whose chemical name is 2-(4-isobutylphenyl)propionic acid, has functions such as analgesia, anti-inflammatory and antipyretic, and is the most widely used non-steroidal anti-inflammatory drug (NSAIDs) in the world at present. ). However, since ibuprofen inhibits cyclooxygenase (Cyclooxygenase, COX) COX-1 stronger than COX-2, long-term use can cause serious gastrointestinal side effects (including gastrointestinal bleeding, perforation or pyloric obstruction, etc. ) up to 20% to 50%, this risk may be fatal for some patients. The US FDA report pointed out that: NSAIDs can induce upper gastrointestinal ulcers, hemorrhage or perforation. The incidence rate is 1% in patients treated with NSAIDs for 3-6 months, and 2%-4% in patients treated with NSAIDs for 1 y...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/612C07C67/10A61K31/222A61P29/00
CPCC07C67/11C07C69/612C07C67/10A61K9/127A61K9/1075A61K9/0019A61P29/00
Inventor 苏庆冷国庆侯文阁宋志光陈曦
Owner 山东华鲁制药有限公司
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