| 摘要 |
The novel positively charged pro-drugs of arylanthranilic acids in the general formula (1) 'Structure 1' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. 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 -200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about -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 parent drugs in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and thus avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier. |
