Positively charged water-soluble prodrugs of diflunisal and related compounds with fast skin penetration rates
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A kind of compound, technology of difluorophenyl, applied in the field of water-soluble prodrugs
Active Publication Date: 2015-09-16
TECHFIELDS BIOCHEM CO LTD
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However, it is difficult to achieve therapeutically effective plasma concentrations of these drugs in the host by way of formulation
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[0073] 1. Synthetic method of dimethylaminoethyl salicylsalicylate acetate
[0074] 31.8 g (0.1 mol) of acetylsalicylic acid 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. The mixture was stirred at room temperature for 3 hours. The reaction solvent is evaporated. The residue was dissolved in 300 ml of methanol, and 200 ml of 5% sodium bicarbonate aqueous solution was added to the reaction mixture. The mixture was stirred for 3 hours. The mixture was evaporated to dryness, and 300 ml of methanol was added to the residue with stirring. The solids were 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 solid was removed by filtration. 6 g of acetic acid was added to the reaction mixt...
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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 the positively charged water solubility of 5-(2,4-difluorophenyl)salicylic acid (diflunisal), salicylsalicylic acid (salicylic acid) or other salicylic acid analogs The prodrug and its application in the treatment of any diflunisal, salicylic acid and salicylic acid in the treatment of human or animal diseases. Specifically, the present invention is to overcome the side effects caused by using diflunisal, salicyl salicylate or salicylic acid. These prodrugs can be administered orally or transdermally. technical background [0002] Diflunisal and salicylic acid are two of many non-steroidal anti-inflammatory drugs of salicylic acid, which have been used clinically for more than 20 years. Diflunisal is one of the 200 most commonly prescribed drugs. Diflunisal has better anti-inflammatory effects than aspirin, and its biological half-life is also 3-4 times longer than that of aspirin (W.O. Faye, T.L. Lemke, D.A. Williams, Me...
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