Pharmaceutical composition for preventing or treating macular degeneration

Abstract

The present invention provides a pharmaceutical composition for preventing or treating macular degeneration, which comprises benzopyran derivatives substituted with secondary amines including imidazole or pharmaceutically acceptable salts thereof as an active ingredient. The pharmaceutical composition of the present invention may be used in the form of eye drops.

1 . A method for preventing or treating macular degeneration comprising administering an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  represents H, CN, NO 2  or NH 2 , 
         R 2  represents 
       
       
         
           
           
               
               
           
         
         R 3  and R 4  are independent each other and represent H, Cl, Br, F, C 1 ˜C 3  straight or branched alkyl, OR b , CF 3 , OCF 3 , NO 2  or CO 2 R b , 
         R a  represents C 1 ˜C 4  straight or branched alkyl, 
         R b  represents H or C 1 ˜C 3  alkyl, and 
         * represents a chiral center. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of Formula 1 is selected from the group consisting of:
 (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-trifluoromethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-trifluoromethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-bromophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(2,4-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(2-isopropylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(2,3-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2R,3R,4S)-6-nitro-4-[N-(2,3-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(4-bromophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(4-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(4-fluorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(2-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(2-isopropylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(2-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(3-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-nitro-4-[N-(3-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-nitro-4-[N-(4-trifluoromethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-cyano-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(4-trifluoromethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-amino-4-[N-(4-trifluoromethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-amino-4-[N-(2,3-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-amino-4-[N-(4-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3R,4S)-6-amino-4-[N-(4-bromophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(2,3-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(2-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(4-methoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(2,4-dimethylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(2-isopropylphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(4-trifluoromethoxyphenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;   (2S,3S,4R)-6-amino-4-[N-(4-bromophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran; and   (2S,3S,4R)-6-amino-4-[N-(4-fluorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran.   
     
     
         3 . The method of  claim 1 , wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof is administered in the form of eye drop formulation to be delivered to the retina. 
     
     
         4 . The method of  claim 1 , wherein normal regeneration of corneal epithelial cells is not inhibited. 
     
     
         5 . An eye drop formulation for preventing or treating macular degeneration comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and * are the same as defined in  claim 1 . 
       
     
     
         6 . The eye drop formulation for preventing or treating macular degeneration of  claim 5 , in a solution form or a suspension form. 
     
     
         7 . The method of  claim 1 , comprising administering an effective amount of (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran or its pharmaceutically acceptable salt as an active ingredient. 
     
     
         8 . An eye drop formulation for preventing or treating macular degeneration, comprising (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran or its pharmaceutically acceptable salt as an active ingredient. 
     
     
         9 . The eye drop formulation for preventing or treating macular degeneration of  claim 8 , having in a solution form or a suspension form.