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Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate

An aryl-based and alkyl-based technology, which can be used in medical preparations containing active ingredients, organic chemistry, pharmaceutical formulations, etc., and can solve problems such as slow skin penetration

Inactive Publication Date: 2009-08-12
于崇曦 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the slow rate of skin penetration of these drugs, it is difficult to achieve therapeutically effective plasma concentrations by means of formulations

Method used

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  • Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0084] Synthesis of 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid diethylaminoethyl acetate

[0085] 28.6 g (0.1 mol) of 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0 °C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol were added to the reaction mixture, and stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in 300ml of methanol, 200ml of 5% sodium bicarbonate solution was added, and stirred for 3 hours. The mixture was evaporated to dryness. 300 ml of methanol were added to the residue with stirring. The solid was removed by filtration and washed with methanol. The filtrate was evaporated to dryness, and the residue was dissolved in 200 ml of chloroform. 6 g of acetic acid was added to the reaction mixture with stirring. The solids were removed by filtration. An additional 6 g of acetic acid was added to the r...

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Abstract

The novel positively charged pro-drugs of aryl- and heteroarylacetic acids in the general formula(1) 'Structure 1' were designed and synthesized. The compounds of the general formula(1) 'Structure 1' indicated above can be prepared from functional derivatives of tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin 100 times faster than does tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, or related compounds. It takes 2-4 hours for tolmetin, zomepirac, etodolac, amfenac, bromofenac, alclofenac, fenclofenac, acemetacin, indomethacin, sulindac, fentiazac, lonazolac, bendazac, 6MNA, ibufenac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.

Description

technical field [0001] The present invention relates to positively charged and water soluble prodrugs of aryl and heteroaryl acetates and their use in the treatment of any nonsteroidal anti-inflammatory drug (NSAIAs) treatable condition in humans or animals. Specifically, the present invention aims to overcome the side effects caused by non-steroidal anti-inflammatory drugs. These prodrugs can be administered orally or transdermally. technical background [0002] 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (Tometine), 5-(4-chlorobenzoyl)-1,4-dimethyl-1H -Pyrrole-2-acetic acid (Zomenic acid), 1,8-Diethyl-1,3,4,9-tetrahydropyran-[3,4-b]indole-1-acetic acid (Etodolac) , 2-amino-3-benzoylphenylacetic acid (amfenac), 2-amino-3-(4-bromo-benzoyl)phenylacetic acid (bromfenac), 3-chloro-4-(2-propene Oxy)phenylacetic acid (alclofenac), 2-(2,4-dichlorophenoxy)-phenylacetic acid (fenchloric acid), 1-(4-chlorobenzoyl)-5-methoxy -2-Methyl-1H-indole-3-acetic acid carboxymethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12C07D491/04C07D231/12
CPCC07D231/56C07D209/28C07C219/10C07D491/04C07D231/12C07D277/30C07D207/337A61K38/05A61K38/13A61K2300/00
Inventor 于崇曦徐丽娜
Owner 于崇曦
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