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Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate

A compound and active ingredient technology, applied in the field of water-soluble prodrugs, can solve problems such as the treatment level of difficult diflunisal

Active Publication Date: 2009-08-05
TECHFIELDS BIOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult to achieve therapeutically effective plasma concentrations of diflunisal by means of formulations

Method used

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  • Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0073] 1. the synthetic method of diethylaminoethyl salicylate salicylate acetate

[0074] 31.8 g (0.1 mol) of acetylsalicyloyl salicylic acid chloride were 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. The mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off. The residue was dissolved in 300 ml of methanol, and 200 ml of 5% aqueous sodium bicarbonate was added to the reaction mixture. The mixture was stirred for 3 hours. The mixture was evaporated to dryness, and 300 ml of methanol were added to the residue with stirring. The solid was removed by filtration and washed with methanol. The solution was evaporated to dryness, and 200 ml of chloroform was added to the residue. 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 ac...

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Abstract

The novel positively charged pro-drugs of diflunisal, salicylsalicylic acid, and salicylic acid 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' or general formula(2) 'Structure 2' indicated above can be prepared from functional derivatives of diflunisal, salicylsalicylic acid, or salicylic acid, (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-drug, diethylaminoethyl 5-(2,4-difluorophenyl) salicylate. AcOH diffuses through human skin ~150 times faster than does diflunisal itself. 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 diflunisal, salicylsalicylic acid, or salicylic acid-treatable conditions in humans or animals and be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of diflunisal, salicylsalicylic acid, or salicylic acid, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables diflunisal, salicylsalicylic acid, or salicylic acid to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diflunisal, salicylsalicylic acid, or salicylic acid.

Description

technical field [0001] The present invention relates to positively charged water-soluble prodrugs of 5-(2,4-difluorophenyl)salicylic acid (diflunisal), salicylsalicylic acid or other salicylic acid analogues and their use in the treatment of Any use of diflunisal, salicylsalicylic acid and salicylic acid in treating diseases in humans or animals. Specifically, the present invention aims to overcome the side effects caused by the use of diflunisal, salicyl salicylate or salicylic acid. These prodrugs can be administered orally or transdermally. technical background [0002] Diflunisal and salicylsalicylic acid are two of the many salicylic acid NSAIDs that have been used clinically for more than 20 years. Diflunisal is one of the 200 most commonly prescribed drugs. The anti-inflammatory effect of diflunisal is better than that of aspirin, and its biological half-life is 3-4 times longer than that of aspirin (W.O.Faye, T.L.Lemke, D.A.Williams, Medicinal Chemistry, fourth ed...

Claims

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Application Information

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IPC IPC(8): C07C215/72C07C215/40C07C215/42C07C225/16
CPCC07C219/14C07C53/08C07C59/265C07C229/12C07C235/60C07C327/30
Inventor 于崇曦徐丽娜
Owner TECHFIELDS BIOCHEM CO LTD
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