Use of myeloperoxidase (mpo) inhibitors or pharmaceutically acceptable salts thereof to treat multiple sysyem atrophy (msa) 938

Abstract

The present invention relates to the use of MPO inhibitors for the treatment of multiple system atrophy. The present invention also relates to the use of MPO inhibitors for the treatment of Huntington's disease. The present invention also relates to the use of MPO inhibitors for neuroprotection.

1 - 7 . (canceled) 
     
     
         8 . A method for treating multiple system atrophy, comprising administering a pharmaceutically and pharmacologically effective amount of a MPO inhibitor or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. 
     
     
         9 . A method for treating Huntington's disease, comprising administering a pharmaceutically and pharmacologically effective amount of a MPO inhibitor or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. 
     
     
         10 . A method for neuroprotection, comprising administering a pharmaceutically and pharmacologically effective amount of a MPO inhibitor or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. 
     
     
         11 . The method according to any one of  claims 8  to  10 , wherein said MPO inhibitor or pharmaceutically acceptable salt thereof is selected from:
 1-butyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-isobutyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(pyridin-2-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(2-fluoro-benzyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[2-(2-methoxyethoxy)-3-propoxybenzyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(6-ethoxy-pyridin-2-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-piperidin-3-ylmethyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-butyl-4-thioxo-1,3,4,5-tetrahydro-2H-pyrrolo[3,2-d]pyrimidin-2-one; 
 1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(2-methoxy-2-methylpropyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(2-ethoxy-2-methylpropyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(piperidin-4-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(1-methylpiperidin-3-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(2-methoxybenzyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(3-methoxybenzyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(2,4-dimethoxybenzyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(3-chloropyridin-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-{[3-(2-ethoxyethoxy)pyridin-2-yl]methyl}-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-indol-3-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(5-chloro-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(5-fluoro-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-indol-6-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-indol-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(5-fluoro-1H-indol-3-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-imidazol-5-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-(1H-imidazol-2-ylmethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(5-chloro-1H-benzimidazol-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 1-[(4,5-dimethyl-1H-benzimidazol-2-yl)methyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; 
 7-bromo-1-isobutyl-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one; and 
 1-(3-chlorophenyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-c]pyrimidin-4-one. 
 
     
     
         12 . The method according to any one of  claims 8  to  10 , wherein said MPO inhibitor or pharmaceutically acceptable salt thereof is selected from:
 1,3-diisobutyl-8-methyl-6-thioxanthine; 
 1,3-dibutyl-8-methyl-6-thioxanthine; 
 3-isobutyl-1,8-dimethyl-6-thioxanthine; 
 3-(2-methylbutyl)-6-thioxanthine; 
 3-isobutyl-8-methyl-6-thioxanthine; 
 3-isobutyl-2-thioxanthine; 
 3-isobutyl-2,6-dithioxanthine; 
 3-isobutyl-8-methyl-2-thioxanthine; 
 3-isobutyl-7-methyl-2-thioxanthine; 
 3-cyclohexylmethyl-2-thioxanthine; 
 3-(3-methoxypropyl)-2-thioxanthine; 
 3-cyclopropylmethyl-2-thioxanthine; 
 3-isobutyl-1-methyl-2-thioxanthine; 
 3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; 
 3-(2-methoxy-ethyl)-2-thioxanthine; 
 3-(3-(1-morpholinyl)-propyl)-2-thioxanthine; 
 3-(2-furyl-methyl)-2-thioxanthine; 
 3-(4-methoxybenzyl)-2-thioxanthine; 
 3-(4-fluorobenzyl)-2-thioxanthine; 
 3-phenethyl-2-thioxanthine; 
 (+)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; 
 (−)-3-(2-tetrahydrofuryl-methyl)-2-thioxanthine; and 
 3-n-butyl-2-thioxanthine. 
 
     
     
         13 . The method according to any one of  claims 8  to  10 , wherein said MPO inhibitor or pharmaceutically acceptable salt thereof is selected from:
 3-(pyridin-2-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(pyridin-3-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(pyridin-4-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{[3-ethoxy-4-(2-ethoxyethoxy)pyridin-2-yl]methyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(5-fluoro-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(5-fluoro-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(1H-benzimidazol-2-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[1-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(5-chloro-1H-indol-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one and 
 3-[(4-fluoro-1H-indol-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-(1H-Benzimidazol-2-yl)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(1H-Pyrazol-3-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(5-Methylpyrazin-2-yl)methyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(3-Isopropylisoxazol-5-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(4-Methyl-1,2,5-oxadiazol-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(6-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(4-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(3-Butoxypyridin-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-(Pyridin-2-ylmethoxy)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(3,5-Dimethylisoxazol-4-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(1-Methyl-1H-indol-2-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-Phenyl-2-pyridin-2-ylethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(Quinolin-4-ylmethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[(6-Phenoxypyridin-3-yl)methyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[(Quinolin-4-ylmethyl)amino]ethyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(1-Methyl-1H-indol-3-yl)methyl]amino}ethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[Methyl(quinolin-4-ylmethyl)amino]ethyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-Aminopropyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-{2-[(Pyridin-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-{2-[(Pyridin-3-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[(Pyridin-4-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(6-Chloropyridin-3-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-[2-({[6-(Trifluoromethyl)pyridin-3-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-(2-{[(4,6-Dichloropyrimidin-5-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[2-(Dimethylamino)pyrimidin-5-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[(Quinolin-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-{2-[(Quinolin-3-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(1-tert-Butyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[1-(1,1-Dioxidotetrahydro-3-thienyl)-3,5-dimethyl-1H-pyrazol-4-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[(1H-Benzoimidazol-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[1-(Phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amino]propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-{2-[({1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}methyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate; 
 3-(2-{[(1-methyl-1H-pyrrol-2-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[1-(4-sec-Butylphenyl)-1H-pyrrol-2-yl]methyl}amino)propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[1-(3-Methoxyphenyl)-1H-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[2,5-Dimethyl-1-(1,3-thiazol-2-yl)-1H-pyrrol-3-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[4-(3-Chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[(1H-Imidazol-2-ylmethyl)amino]propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(1-Methyl-1H-imidazol-2-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(4-Bromo-1-methyl-1H-imidazol-5-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(1-Methyl-1H-indol-3-yl)methyl]amino}propyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 2-Thioxo-3-{2-[(1H-1,2,3-triazol-5-ylmethyl)amino]propyl}-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-[2-({[1-(Benzyloxy)-1H-imidazol-2-yl]methyl}amino)propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-(2-{[(6-Bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]amino}propyl}-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 3-{2-[({1-[2-(2-Methoxyphenoxy)ethyl]-1H-pyrrol-2-yl}methyl)amino]propyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one; 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]pyridine-2-carboxamide; 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]nicotinamide; 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)-ethyl]isonicotinamide; 
 N-[1-methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]-1,8-naphthyridine-2-carboxamide; 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]quinoline-2-carboxamide; 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]pyrimidine-2-carboxamide; and 
 N-[1-Methyl-2-(6-oxo-2-thioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)ethyl]-1H-imidazole-2-carboxamide trifluroaceate. 
 
     
     
         14 . A method according to any one of  claims 8  to  10 , wherein the daily dose of the MPO inhibitor or the pharmaceutically acceptable salt thereof is within the range of from 1 to 1000 mg.