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

An aryl and alkyl technology, applied in the field of positively charged water-soluble aryl and heteroaryl propionic acid prodrugs with fast skin penetration speed, can solve the problem of slow skin penetration

Active Publication Date: 2009-08-12
TECHFIELDS BIOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the slow skin penetration of these drugs, it is difficult to a

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0105] Synthesis of Diethylaminoethyl α-Methyl-4-(2-thienyl)phenylacetate Acetate

[0106] 28.1 g (0.1 mol) of α-methyl-4-(2-thienoyl)phenylacetyl chloride was dissolved in 100 ml of chloroform and cooled to 0°C. 15 ml of triethylamine and 11.7 g (0.1 mol) of diethylaminoethanol were added to the reaction solution. Stir at room temperature for 3 hours. The solvent was evaporated to dryness. The solid mixture evaporated to dryness was suspended in 300 ml of methanol, and 200 ml of 5% aqueous sodium bicarbonate solution was added with stirring, followed by stirring at room temperature for 3 hours. The mixture was evaporated to dryness. To the evaporated mixture was added 300 ml of methanol for dissolution. The solid was removed by filtration and washed with methanol. The solution was evaporated to dryness, and 200ml of chloroform was added to dissolve it. 6 g of acetic acid was added to the reaction solution with stirring. A small amount of solid formed was removed by fil...

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Abstract

The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, 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 -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, 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 NS AIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments.

Description

technical field [0001] The present invention relates to positively charged and water-soluble prodrugs of aryl and heteroaryl propionic acids and their use in the treatment of any non-steroidal 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] Aryl and heteroaryl propionic acids include 2-aryl and heteroaryl propionic acids, 3-aryl and heteroaryl propionic acids and cyclized aryl and heteroaryl propionic acids. 2-(6-methoxy-2-naphthyl)propanoic acid (naproxen), α-methyl-4-(2-thienyl)phenylacetic acid (suprofen); α-methyl-(p-chloro Benzoyl)-5-methoxy-2-methylindole-3-acetic acid, 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen), 6-chloro-α-methanol Base-9H-carbazole-2-acetic acid (carprofen), α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-aceti...

Claims

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Application Information

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IPC IPC(8): C07D209/12C07D491/04C07D209/82C07D263/57
CPCC07D263/57C07D209/46C07D333/32C07D333/22C07D491/04C07D209/08C07D209/88A61P1/02A61P1/08A61P11/06A61P15/00A61P17/00A61P19/02A61P19/08A61P25/02A61P25/04A61P25/06A61P27/02A61P27/06A61P27/16A61P29/00A61P35/00A61P43/00
Inventor 于崇曦徐丽娜
Owner TECHFIELDS BIOCHEM CO LTD
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