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Anti-inflammatory analgesia mutual prodrug of non-steroidal antiinflammatory drug and preparation method thereof

A non-steroidal anti-inflammatory and prodrug technology, applied in the direction of anti-inflammatory agents, carboxylic acid amide preparation, non-central analgesics, etc., can solve the restrictions on the wide use of NSAID drugs, the inability to take oral administration, and the instability of the gastrointestinal system and other problems, to achieve good biological activity, high safety, and prolonged effect

Inactive Publication Date: 2015-06-17
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the prodrug has been marketed and has shown a good therapeutic effect in clinical application, it cannot be administered orally because it is unstable in the gastrointestinal system, and it needs to be administered by injection, which greatly limits the application of the NSAID drug. widely used

Method used

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  • Anti-inflammatory analgesia mutual prodrug of non-steroidal antiinflammatory drug and preparation method thereof
  • Anti-inflammatory analgesia mutual prodrug of non-steroidal antiinflammatory drug and preparation method thereof
  • Anti-inflammatory analgesia mutual prodrug of non-steroidal antiinflammatory drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Synthesis of synergistic prodrug paracetamol-flurbiprofen (AF)

[0030] Add 2g flurbiprofen (8.2mmol) in a 25ml single-necked round bottom flask, then add 15ml SOCl dropwise 2 , heated and stirred to reflux for 4-5 hours, and TLC detected that the conversion of flurbiprofen was complete and the reaction was stopped. Remove excess SOCl by distillation under reduced pressure 2 Finally, the flurbiprofen after acid chloride was transferred to a 50ml single-necked round bottom flask and dissolved in 20ml CH 2 Cl 21.24 g of acetaminophen (8.2 mmol) was dissolved in CH 2 Cl 2 in spare. Slowly add 8.2 mmol of acetaminophen in CH with a constant pressure dropping funnel 2 Cl 2 solution, remove the ice-water bath after the dropwise addition, stir and react at room temperature for 3 hours, and stop the reaction after the complete conversion of paracetamol as detected by TLC. The reaction solution is directly precipitated with ice water and filtered to obtain ...

Embodiment 2

[0032] Embodiment 2: the synthesis of synergistic prodrug paracetamol-ketoprofen (AK)

[0033] In a 50ml single-necked round bottom flask, add 2g of ketoprofen (8.0mmol) acid chloride and dissolve in 20ml CH 2 Cl 2 1.21 g of acetaminophen (8.0 mmol) was dissolved in CH 2 Cl 2 in spare. Slowly add 8.2 mmol of acetaminophen in CH with a constant pressure dropping funnel 2 Cl 2 solution, remove the ice-water bath after the dropwise addition, stir and react at room temperature for 3 hours, and stop the reaction after the complete conversion of paracetamol as detected by TLC. The reaction solution is directly precipitated with ice water, and then filtered to obtain a crude product, which is further crystallized with acetone to obtain acetaminophen-ketoprofen prodrug with a purity ≥ 99.5%. The synthesis process is as follows:

[0034]

Embodiment 3

[0035] Embodiment 3: Synthesis of synergistic prodrug acetaminophen-pirprofen (AP)

[0036] In a 50ml single-necked round bottom flask, add 2g of chlorinated pyrprofen (8.0mmol) and dissolve it in 20ml of CH 2 Cl 2 , stirred in an ice-water bath and added 1ml of triethylamine as an acid-binding agent. Dissolve 1.2 g of acetaminophen (8.0 mmol) in CH 2 Cl 2 Slowly add 8.2 mmol of acetaminophen in CH with a constant pressure dropping funnel. 2 Cl 2 solution, remove the ice-water bath after the dropwise addition, stir and react at room temperature for 3 to 4 hours, and stop the reaction after TLC detects that the conversion of the raw materials is complete. Afterwards, the reaction solution was directly applied to flash column chromatography (normal phase silica gel chromatography, 300-400 mesh), and washed with dichloromethane and dichloromethane-methanol (volume ratio 9:1, 4:1, 1:1) respectively. Remove 2 column volumes, collect the eluate of each section and suspend evap...

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Abstract

The invention relates to an anti-inflammatory analgesia mutual prodrug of a non-steroidal antiinflammatory drug, which is characterized in that two drug molecules having non-steroidal antiinflammatory analgesia or antipyretic analgesia effects to be connected through ester keys. The anti-inflammatory analgesia mutual prodrug has a structural formula shown in the description, wherein R1 is an alkyl group or an aromatic substituent group. Compared with the existing anti-inflammatory analgesia mutual prodrug, the anti-inflammatory analgesia mutual prodrug is obvious in pharmacological activity, high in safety and explicit in metabolic products and progress in human bodies.

Description

Technical field: [0001] The invention relates to the technical field of non-steroidal anti-inflammatory and analgesic synergistic prodrugs, and in particular provides a novel non-steroidal synergistic prodrug with antipyretic and analgesic, anti-inflammatory and analgesic activities as well as its preparation method and application. Background technique: [0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs with antipyretic and analgesic effects, most of which also have anti-inflammatory and anti-rheumatic effects. There are many types of NSAIDs, but they can be roughly divided into antipyretic and Pain relievers and anti-inflammatory pain relievers. It has been found that different types of NSAIDs have similar mechanisms of action. NSAID drugs all inhibit the activity of cyclooxygenase (Cyclooxygenase, COX), thereby inhibiting the production of prostacyclin (PGI1) and prostaglandin (PGE1) from arachidonic acid. , PGE2) and thromboxane A2 (TXA2), ulti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/25C07C231/12C07D207/20C07D209/46A61K31/4035A61K31/402A61K31/216A61P29/00A61P25/06A61P25/04A61P19/02
Inventor 杨凌葛广波刘兆明张延延曹云峰朱亮亮
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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