Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate

Abstract

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.

Description

technical field [0001] The present invention relates to positively charged and water-soluble prodrugs of aryl and heteroaryl propionic acids and their use in the treatment of any non-steroidal anti-inflammatory drug (NSAIAs) treatable condition in humans or animals. Specifically, the present invention aims to overcome the side effects caused by non-steroidal anti-inflammatory drugs. These prodrugs can be administered orally or transdermally. technical background [0002] Aryl and heteroaryl propionic acids include 2-aryl and heteroaryl propionic acids, 3-aryl and heteroaryl propionic acids and cyclized aryl and heteroaryl propionic acids. 2-(6-methoxy-2-naphthyl)propanoic acid (naproxen), α-methyl-4-(2-thienyl)phenylacetic acid (suprofen); α-methyl-(p-chloro Benzoyl)-5-methoxy-2-methylindole-3-acetic acid, 2-(2-fluoro-4-biphenyl)propionic acid (flurbiprofen), 6-chloro-α-methanol Base-9H-carbazole-2-acetic acid (carprofen), α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-aceti...

AI Technical Summary

Problems solved by technology

However, due to the slow skin penetration of these drugs, it is difficult to a

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