| 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. |