| 摘要 |
The novel positively charged pro-drugs of diclofenac in the general formula (1), with X = O or S, were designed and synthesized. The compounds of the general formula (1) can be prepared from functional derivatives of diclofenac by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increase the solubility of the drugs in water, but also bond to the negative charge on the phosphate head group of membranes and push the pro-drug into the cytosol. Experimental results suggest that the pro-drug diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetate.AcOH diffuses through human skin 250 times faster than 2[(2,6-dichlorophenyl)amino]benzene acetic acid (diclofenac) and ethyl 2[(2,6-dichlorophenyl)amino]benzene acetate. 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 diclofenac-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 diclofenac, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables diclofenac to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of diclofenac. |
