Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate

Abstract

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.

Description

technical field [0001] The present invention relates to positively charged, water-soluble prodrugs of aryl anthranilic acids and related compounds and their use in the treatment of any nonsteroidal anti-inflammatory drug (NSAIAs) treatable condition in humans or animals. Specifically, the present invention is directed to overcoming the side effects associated with the use of non-steroidal anti-inflammatory drugs (NSAIAs). These prodrugs can be administered orally or transdermally. technical background [0002] 2-[(2,3-Dimethylphenyl)amino]benzoic acid (mefenamic acid), 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid (methyl chloride fenamic acid), 2-[[(3-trifluoromethyl)phenyl]amino]benzoic acid (flufenamic acid), 2-[[3-(trifluoromethyl)phenyl]amino]-3 -Picolinic acid (niflumic acid), 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunitin) and related compounds belong to non-steroidal anti-inflammatory drugs Arylanthranilic acids in inflammat...

AI Technical Summary

Problems solved by technology

However, due to the slow skin penetration of these drugs, it is difficult to achieve therapeutically effective plasma concentrations by means of formulations

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