POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLPROPIONIC ACIDS WITH VERY FAST SKIN PENETRATION RATE

摘要

The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids 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' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (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-drugs diffuses through human skin -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 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 drug in a few minutes. The prodrugs can be used medicinally in treating any NS AIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and 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 prodrugs enable naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.