Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use

Abstract

The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory drugs; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders.

What is claimed is:  
     
         1 . A method for treating, preventing or reducing inflammation, pain and fever in a patient in need thereof comprising administering to the patient a compostion comprising a pharmaceutically acceptable carrier and at least one compound selected from 2-(4-methyl-4-(nitrosothio)piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio)cyclohexyl)methyl}amino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl)methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-{methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 4-({methyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 2-(4-(nitrosothio)-4-piperdyl)ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate hydrochloride; 2-(2-(2-{2-((2,6-dichlorophenyl)amino) phenyl}acetoxy)ethoxy)ethyl 3-(N-{((nitrosothio)cyclohexyl)methyl}-N-benzylcarbamoyl) propanoate; 2-{4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate citrate; 2-(2-(tert-butyl)-5-(nitrosothio)-1,3-dioxan-5-yl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 5-(bis{((nitrosothio)cyclohexyl)methyl}amino)pentyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-({3-((2S)-2-(6-methyl(2-naphthyl))propanoyloxy)propyl}{((nitrosothio)cyclohexyl)methyl}amino)acetic acid; 3-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(4-(2-methylpropyl) phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl (2S)2-(6-methoxy(2-naphthyl)) propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(3(phenylcarbonyl)phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate citrate; 2-{methyl(2-methyl{((nitrosothiol) cyclohexyl)methyl}amino)ethyl 2-{2-((2,6 dichlorophenyl)amino) phenyl}acetate bis nitric acid salt; 2-{methyl(2methyl{((nitrosothiol)cyclohexyl)methyl}amino)ethyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(((dimethylamino)ethyl){((nitrosothio)cyclohexyl)methyl}amino)ethyl 2-{2-((2,6-dichorophenyl)amino)phenyl}acetate; 2-(4-methyl-4(nitrosothio)piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy) acetylamino)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; (2-({N-(2-methyl-2-(nitrosothio)propyl) carbamoyl}methoxy)acetyloxy)methyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-(4-(nitrosothio)-4-piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; {(3-(methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl)oxycarbonyl}methyl 2-{2-((2,6 dichlorophenyl)amino)phenyl}acetate; 2-{4-(3-methyl-3-(nitrosothio)butanoyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)methyl)phenyl}acetate; {4-(dicyclopropyl(nitrosothio)methyl)-1-methyl-4-piperidyl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate;2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-{methyl(2-methyl-2-(nitrosothio) propyl)amino}ethylthio)ethan-1-one hydrochloride; 2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-(methyl{((nitrosothio)cyclohexyl)methyl}amino)ethylthio)ethan-1-one; 4-({diethyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; (2R,3R)-2,3-dihydroxy-3-{N-(2-methyl-2 (nitrosothio)propyl)carbamoyl}propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-{1-(2-methyl-2-(nitrosothio)propyl)-4-piperidyl}ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; {(2S)-1-(2-methyl-2-(nitrosothio)propyl) pyrrolidin-2yl}methyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl 2-{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(2-{4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}ethoxy)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}methyl)phenyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-{(2-(2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetyloxy)ethyl){((nitrosothio)cyclohexyl)methyl}amino}acetic acid;2-(methyl{1-(2-methyl-2-(nitrosothio)propyl)(4-piperidyl)}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 3-{(4S)-4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {ethoxy(3-methyl-3-(nitrosothio) butoxy)phosphonyl}methyl (2S)-2-(6-methoxy (2-naphthyl)) propanoate; 6-(4-(2-methyl-2-(nitrosothio)propyl)amino}pyrimidin-2-ylthio)hexyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {(2S,5S)-5-(1-methyl-1-(nitrosothio) ethyl)-3,6-dioxopiperazin-2-yl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(N-methyl{1-(2-methyl-2-(nitrosothio)propyl)(4 piperidyl)}carbonylamino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}carbonyl)phenyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; and 3-((2S)-2-(6-methoxy (2-naphthyl) propanoyloxy)-2-oxopropyl-3-methyl-3-(nitrosothio) butanoate, or a pharmaceutically acceptable salt thereof.  
     
     
         2 . A method for treating or reversing a gastrointestinal, renal or other toxicity resulting from the use of a nonsteroidal antiinflammatory compound by a patient comprising administering to the patient a compostion comprising a pharmaceutically acceptable carrier and at least one compound selected from 2-(4-methyl-4-(nitrosothio)piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio)cyclohexyl)methyl}amino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl)methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3{methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 4-({methyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 2-(4-(nitrosothio)-4-piperdyl)ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate hydrochloride; 2-(2-(2-{2-((2,6-dichlorophenyl)amino)phenyl}acetoxy)ethoxy)ethyl 3-(N-{((nitrosothio)cyclohexyl)methyl}-N-benzylcarbamoyl) propanoate; 2-{4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate citrate; 2-(2-(tert-butyl)-5-(nitrosothio)-1,3-dioxan-5-yl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 5-(bis{((nitrosothio)cyclohexyl)methyl}amino)pentyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-({3-((2S)-2-(6-methyl(2-naphthyl))propanoyloxy)propyl}{((nitrosothio)cyclohexyl)methyl}amino)acetic acid; 3-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(4-(2-methylpropyl)phenyl) propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl (2S)2-(6-methoxy(2-naphthyl)) propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(3(phenylcarbonyl)phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate citrate; 2-{methyl(2 -methyl{((nitrosothiol) cyclohexyl)methyl}amino)ethyl 2-{2-((2,6 dichlorophenyl)amino) phenyl}acetate bis nitric acid salt; 2-{methyl(2 methyl}((nitrosothiol)cyclohexyl) methyl}amino)ethyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(((dimethylamino)ethyl){((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichiorophenyl)amino)phenyl}acetate; 2-(4-methyl-4 (nitrosothio)piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl (2S)-2-(6-methoxy (2-naphthyl))propanoate; 2-(2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy) acetylamino)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; (2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy)acetyloxy)methyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 2-(4-(nitrosothio)-4-piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; {(3-(m-ethyl}((nitrosothio) cyclohexyl)methyl}amino)propyl)oxycarbonyl}methyl 2-{2-((2,6 dichlorophenyl)amino)phenyl}acetate; 2-{4-(3-methyl-3-(nitrosothio)butanoyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)methyl) phenyl}acetate; {4-(dicyclopropyl(nitrosothio)methyl)-1-methyl-4-piperidyl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate;2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-{methyl(2-methyl-2-(nitrosothio)propyl)amino}ethylthio)ethan-1-one hydrochloride; 2-{2-((2,6-dichlorophenyl) amino)phenyl}-1-(2-(methyl}((nitrosothio)cyclohexyl)methyl}amino)ethylthio)ethan-1-one; 4-({diethyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; (2R,3R)-2,3-dihydroxy-3-{N-(2-methyl-2(nitrosothio)propyl)carbamoyl}propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-{1-(2-methyl-2-(nitrosothio)propyl)-4-piperidyl}ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; {(2S)-1-(2-(nitrosothio)propyl)pyrrolidin-2yl}methyl 2-}2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl 2-{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(2-{4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}methyl)phenyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-{(2-(2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetyloxy)ethyl){((nitrosothio)cyclohexyl)methyl}amino}acetic acid;2-(methyl{1-(2-methyl-2-(nitrosothio)propyl)(4-piperidyl)}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 3-{(4S)-4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {ethoxy(3-methyl-3-(nitrosothio) butoxy)phosphonyl}methyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 6-(4-{(2-methyl-2-(nitrosothio)propyl)amino}pyrimidin-2-ylthio)hexyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {(2S,5S)-5-(1-methyl-1-(nitrosothio) ethyl)-3,6-dioxopiperazin-2-yl}methyl (2S)-2-((6-methoxy(2-naphthyl))propanoate; 2-(N-methyl{1-(2-methyl-2-(nitrosothio)propyl)(4 piperidyl)}carbonylamino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)phenyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; and 3-((2S)-2-(6-methoxy(2-naphthyl) propanoyloxy)-2-oxopropyl-3-methyl-3-(nitrosothio) butanoate, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . A method for treating or preventing a gastrointestinal disorder in a patient in need thereof comprising administering to the patient a compostion comprising a pharmaceutically acceptable carrier and at least one compound selected from 2-(4-methyl-4-(nitrosothio)piperidyl) ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl)methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3{methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; 4-({methyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 2-(4-(nitrosothio)-4-piperdyl)ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate hydrochloride; 2-(2-(2-{2-((2,6-dichlorophenyl)amino) phenyl}acetoxy)ethoxy)ethyl 3-(N-{((nitrosothio)cyclohexyl)methyl}-N-benzylcarbamoyl) propanoate; 2-{4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate citrate; 2-(2-(tert-butyl)-5-(nitrosothio)-1,3-dioxan-5-yl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 5-(bis{((nitrosothio)cyclohexyl)methyl}amino)pentyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-({3-((2S)-2-(6-methyl(2-naphthyl))propanoyloxy)propyl}{((nitrosothio)cyclohexyl)methyl}amino)acetic acid; 3-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl }acetate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl }acetate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(4-(2-methylpropyl) phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl (2S)2-(6-methoxy(2-naphthyl))propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(3(phenylcarbonyl)phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate citrate; 2-{methyl(2-methyl{((nitrosothiol) cyclohexyl)methyl}amino)ethyl 2-{2-((2,6 dichlorophenyl)amino)phenyl}acetate bis nitric acid salt; 2-{methyl(2methyl{((nitrosothiol)cyclohexyl) methyl}amino)ethyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(((dimethylamino)ethyl){((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichorophenyl) amino)phenyl}acetate; 2-(4-methyl-4(nitrosothio)piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl (2S)-2-(6-methoxy (2-naphthyl))propanoate; 2-(2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy) acetylamino)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; (2-({N-(2-methyl-2-(nitrosothio)propyl) carbamoyl}methoxy)acetyloxy)methyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 2-(4-(nitrosothio)-4-piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate hydrochloride; {(3-(methyl{((nitrosothio) cyclohexyl)methyl}amino)propyl) oxycarbonyl}methyl 2-{2-((2,6dichlorophenyl) amino)phenyl}acetate; 2-{4-(3-methyl-3-(nitrosothio)butanoyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)methyl) phenyl}acetate; {4-(dicyclopropyl(nitrosothio)methyl)-1-methyl-4-piperidyl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate;2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-{methyl(2-methyl-2-(nitrosothio) propyl)amino}ethylthio)ethan-1-one hydrochloride; 2-{2-((2,6-dichlorophenyl) amino)phenyl}-1-(2-(methyl{((nitrosothio)cyclohexyl)methyl}amino) ethylthio)ethan-1-one; 4-({diethyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; (2R,3R)-2,3-dihydroxy-3-{N-(2-methyl-2(nitrosothio)propyl)carbamoyl}propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-{1-(2-methyl-2-(nitrosothio)propyl)-4-piperidyl}ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; {(2S)-1-(2-methyl-2-(nitrosothio)propyl) pyrrolidin-2yl}methyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl 2-{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(2-{4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}ethoxy)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 4-({4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}methyl)phenyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-{(2-(2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetyloxy)ethyl){((nitrosothio)cyclohexyl)methyl}amino}acetic acid;2-(methyl{1-(2-methyl-2-(nitrosothio)propyl)(4-piperidyl)}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 3-{(4S)-4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2S )-2-(6-methoxy(2-naphthyl))propanoate; {ethoxy(3-methyl-3-(nitrosothio) butoxy)phosphonyl}methyl (2S)-2-(6-methoxy (2-naphthyl)) propanoate; 6-(4-{(2-methyl-2-(nitrosothio)propyl)amino}pyrimidin-2-ylthio)hexyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {(2S,5S)-5-(1-methyl-1-(nitrosothio) ethyl)-3,6-dioxopiperazin-2-yl}methyl (2S)-2(6-methoxy(2-naphthyl))propanoate; 2-(N-methyl{1-(2-methyl-2-(nitrosothio)propyl)(4 piperidyl)}carbonylamino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}carbonyl)phenyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; and 3-((2S)-2-(6-methoxy(2-naphthyl) propanoyloxy)-2-oxopropyl-3-methyl-3-(nitrosothio) butanoate, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The method of  claim 3 , wherein the gastrointestinal disorder is a peptic ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a stress ulcer, a bleeding peptic ulcer, short bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.  
     
     
         5 . A method for treating an inflammatory disease or disorder in a patient in need thereof comprising administering to the patient a compostion comprising a pharmaceutically acceptable carrier and at least one compound selected from 2-(4-methyl-4-(nitrosothio)piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl)methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3{methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; 4-({methyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 2-(4-(nitrosothio)-4-piperdyl)ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate hydrochloride; 2-(2-(2-{2-((2,6-dichlorophenyl)amino) phenyl}acetoxy)ethoxy)ethyl 3-(N-{((nitrosothio)cyclohexyl)methyl}-N-benzylcarbamoyl) propanoate; 2-{4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate citrate; 2-(2-(tert-butyl)-5-(nitrosothio)-1,3-dioxan-5-yl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 5-(bis{((nitrosothio)cyclohexyl)methyl}amino)pentyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-({3-((2S)-2-(6-methyl(2-naphthyl))propanoyloxy)propyl}{((nitrosothio)cyclohexyl)methyl}amino)acetic acid; 3-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(4-(2-methylpropyl) phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl (2S) 2-(6-methoxy(2-naphthyl)) propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(3 (phenylcarbonyl)phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate citrate; 2-{methyl(2-methyl{((nitrosothiol) cyclohexyl)methyl}amino)ethyl 2-{2-((2,6 dichlorophenyl)amino) phenyl}acetate bis nitric acid salt; 2-{methyl(2 methyl{((nitrosothiol)cyclohexyl) methyl}amino)ethyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(((dimethylamino)ethyl){((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichorophenyl) amino)phenyl}acetate; 2-(4-methyl-4 (nitrosothio)piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl (2S)-2-(6-methoxy (2-naphthyl))propanoate; 2-(2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy) acetylamino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; (2-({N-(2-methyl-2-(nitrosothio)propyl) carbamoyl}methoxy)acetyloxy)methyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 2-(4-(nitrosothio)-4-piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate hydrochloride; {(3-(methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl) oxycarbonyl}methyl 2-{2-((2,6 dichlorophenyl) amino)phenyl}acetate; 2-{4-(3-methyl-3-(nitrosothio)butanoyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)methyl)phenyl}acetate; {4-(dicyclopropyl(nitrosothio)methyl)-1-methyl-4-piperidyl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate;2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-{methyl(2-methyl-2-(nitrosothio) propyl)amino}ethylthio)ethan-1-one hydrochloride; 2-{2-((2,6-dichlorophenyl) amino)phenyl}-1-(2-(methyl{((nitrosothio)cyclohexyl)methyl}amino) ethylthio)ethan-1-one; 4-({diethyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; (2R,3R)-2,3-dihydroxy-3-{N-(2-methyl-2(nitrosothio)propyl)carbamoyl}propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-{1-(2-methyl-2-(nitrosothio)propyl)-4-piperidyl}ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; {(2S)-1-(2-(nitrosothio)propyl) pyrrolidin-2yl}methyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl 2-{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(2-{4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}ethoxy)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 4-({4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}methyl)phenyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-{(2-(2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetyloxy)ethyl){((nitrosothio)cyclohexyl)methyl}amino}acetic acid;2-(methyl{1-(2-methyl-2-(nitrosothio)propyl)(4-piperidyl)}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 3-{(4S)-4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {ethoxy(3-methyl-3-(nitrosothio) butoxy)phosphonyl}methyl (2S)-2-(6-methoxy (2-naphthyl)) propanoate; 6-(4-{(2-methyl-2-(nitrosothio)propyl)amino}pyrimidin-2-ylthio)hexyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {(2S,5S)-5-(1-methyl-1-(nitrosothio) ethyl)-3,6-dioxopiperazin-2-yl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(N-methyl{1-(2-methyl-2-(nitrosothio)propyl)(4 piperidyl)}carbonylamino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}carbonyl)phenyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; and 3-((2S)-2-(6-methoxy (2-naphthyl) propanoyloxy)-2-oxopropyl-3-methyl-3-(nitrosothio) butanoate, or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The method of  claim 5 , wherein the inflammatory disease or disorder is reperfusion injury to an ischemic organ, a myocardial infarction, an inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, an organ transplant rejection, organ preservation, a female or male sexual dysfunction, a radiation-induced injury, asthma, atherosclerosis, thrombosis, platelet aggregation, restenosis, metastasis, influenza, incontinence, stroke, burn, trauma, acute pancreatitis, pyelonephritis, hepatitis, an autoimmune disease, an immunological disorder, senile dementia, insulin-dependent diabetes mellitus, disseminated intravascular coagulation, fatty embolism, Alzheimer's disease, adult or infantile respiratory disease, carcinogenesis or a hemorrhage in a neonate.  
     
     
         7 . A method for treating or preventing an ophthalmic disease or disorder in a patient in need thereof comprising administering to the patient a compostion comprising a pharmaceutically acceptable carrier and at least one compound selected from 2-(4-methyl-4-(nitrosothio)piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(methyl{((nitrosothio) cyclohexyl)methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3{methyl{((nitrosothio)cyclohexyl)methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; 4-({methyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 2-(4-(nitrosothio)-4-piperdyl)ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate hydrochloride; 2-(2-(2-{2-((2,6-dichlorophenyl)amino) phenyl}acetoxy)ethoxy)ethyl 3-(N-{((nitrosothio)cyclohexyl)methyl}-N-benzylcarbamoyl) propanoate; 2-{4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate citrate; 2-(2-(tert-butyl)-5-(nitrosothio)-1,3-dioxan-5-yl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 5-(bis{((nitrosothio)cyclohexyl)methyl}amino)pentyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-({3-((2S)-2-(6-methyl(2-naphthyl))propanoyloxy)propyl}{((nitrosothio)cyclohexyl)methyl}amino)acetic acid; 3-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)propyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(4-(2-methylpropyl) phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl (2S)2-(6-methoxy(2-naphthyl)) propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2-(3 (phenylcarbonyl)phenyl)propanoate citrate; 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 2{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate citrate; 2-{methyl(2-methyl{((nitrosothiol) cyclohexyl)methyl}amino)ethyl 2-{2-((2,6 dichlorophenyl)amino) phenyl}acetate bis nitric acid salt; 2-{methyl(2 methyl{((nitrosothiol)cyclohexyl)methyl}amino)ethyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(((dimethylamino)ethyl){((nitrosothio)cyclohexyl) methyl}amino)ethyl 2-{2-((2,6-dichorophenyl) amino)phenyl}acetate; 2-(4-methyl-4 (nitrosothio)piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(methyl{(1-methyl-4-(nitrosothio)(4-piperidyl))methyl}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 3-(4-methyl-4-(nitrosothio)piperidyl)propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(2-({N-(2-methyl-2-(nitrosothio)propyl)carbamoyl}methoxy) acetylamino)ethyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; (2-({N-(2-methyl-2-(nitrosothio)propyl) carbamoyl}methoxy)acetyloxy)methyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; 2-(4-(nitrosothio)-4-piperidyl)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate hydrochloride; {(3-(methyl{((nitrosothio) cyclohexyl)methyl}amino)propyl) oxycarbonyl}methyl 2-{2-((2,6 dichlorophenyl) amino)phenyl}acetate; 2-{4-(3-methyl-3-(nitrosothio)butanoyl)piperazinyl}ethyl 2-{2-((2,6-dichlorophenyl)methyl) phenyl}acetate; {4-(dicyclopropyl(nitrosothio)methyl)-1-methyl-4-piperidyl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate;2-{2-((2,6-dichlorophenyl)amino)phenyl}-1-(2-{methyl(2-methyl-2-(nitrosothio) propyl)amino}ethylthio)ethan-1-one hydrochloride; 2-{2-((2,6-dichlorophenyl) amino)phenyl}-1-(2-(methyl{((nitrosothio)cyclohexyl)methyl}amino) ethylthio)ethan-1-one; 4-({diethyl(2-methyl-2-(nitrosothio)propyl)amino}methyl)phenyl 2-{2-((2,6-dichlorophenyl) amino)phenyl}acetate; (2R,3R)-2,3-dihydroxy-3-{N-(2-methyl-2 (nitrosothio)propyl)carbamoyl}propyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-{1-(2-methyl-2-(nitrosothio)propyl)-4-piperidyl}ethyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; {(2S)-1-(2-methyl-2-(nitrosothio)propyl) pyrrolidin-2yl}methyl 2-{2-((2,6-dichlorophenyl)amino)phenyl}acetate; 2-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}ethoxy)ethyl 2-{1-((4-chlorophenyl) carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-(2-{4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}ethoxy)ethyl (2S)-2-(6-methoxy(2-naphthyl)) propanoate; 4-({4-(2-methyl-2-(nitrosothio) propyl)piperazinyl}methyl)phenyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 5-({4-(2-methyl-2-(nitrosothio)propyl)piperazinyl}carbonyl)-2 pyridyl 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetate; 2-{(2-(2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}acetyloxy)ethyl){((nitrosothio)cyclohexyl)methyl}amino}acetic acid;2-(methyl{1-(2-methyl-2-(nitrosothio)propyl)(4-piperidyl)}amino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 3-{(4S)-4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {ethoxy(3-methyl-3-(nitrosothio) butoxy)phosphonyl}methyl (2S)-2-(6-methoxy (2-naphthyl)) propanoate; 6-(4-{(2-methyl-2-(nitrosothio)propyl)amino}pyrimidin-2-ylthio)hexyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; {(2S,5S)-5-(1-methyl-1-(nitrosothio) ethyl)-3,6-dioxopiperazin-2-yl}methyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 2-(N-methyl{1-(2-methyl-2-(nitrosothio)propyl)(4 piperidyl)}carbonylamino)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate; 4-({4-(2-methyl-2-(nitrosothio)propyl) piperazinyl}carbonyl)phenyl 2-{2-((2,6-dichlorophenyl)amino) phenyl}acetate; and 3-((2S)-2-(6-methoxy (2-naphthyl) propanoyloxy)-2-oxopropyl-3-methyl-3-(nitrosothio) butanoate, or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The method of  claim 7 , wherein the ophthalmic disease or disorder is glaucoma, inflammation of the eye or elevation of intraocular pressure.  
     
     
         9 . The method of  claim 1 , wherein the composition is administered orally, topically, bucally, parentally, by inhalation, or by injection.  
     
     
         10 . The method of  claim 2 , wherein the composition is administered orally, topically, bucally, parentally, by inhalation, or by injection.  
     
     
         11 . The method of  claim 3 , wherein the composition is administered orally, topically, bucally, parentally, by inhalation, or by injection.  
     
     
         12 . The method of claims  5 , wherein the composition is administered orally, topically, bucally, parentally, by inhalation, or by injection.  
     
     
         13 . The method of  claim 7 , wherein the composition is administered topically