Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders

Abstract

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.

We claim: 
     
         1 . A compound of Formula (C), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein, 
         A is selected from —O— or —CH 2 —; 
         Y is 
       
       
         
           
           
               
               
           
         
         R A  is OH, R B  is H; or optionally, R A  and R B  together form an oxo; 
         R 1  and R 2  are each independently selected from hydrogen, C 1 -C 4  alkyl, —C(═O)R 3 ; and 
         R 3  is selected from alkyl, alkoxy, or —OCH 2 OC(O)R 4 , wherein R 4  is an alkyl or alkoxy. 
       
     
     
         2 . The compound of  claim 1 , wherein A is —O—. 
     
     
         3 . The compound of  claim 1 , wherein A is —CH 2 —. 
     
     
         4 . The compound of  claim 1 , wherein R A  is OH and R B  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 1  and R 2  are both hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is hydrogen and R 2  is C 1 -C 4  alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is hydrogen and R 2  is —C(═O)R 3 . 
     
     
         8 . The compound of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
 (R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;   3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;   (1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol;   (1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol;   (R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;   3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide;   (R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethanone;   (R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol;   (1R)-3-Amino-1-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)propan-1-ol;   (1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-ol;   (R)-Methyl 4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;   (R)-3-Amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol;   (1R)-3-Amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol;   (R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1-oxide;   (R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propan-1-ol;   3-Amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)propan-1-one;   3-Amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propan-1-one;   3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl) methyl)sulfonyl)phenyl)propan-1-one;   3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;   (R)-3-Amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol;   (R)-tert-Butyl 4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;   (E)-3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine;   3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine;   (R)-3-(Methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;   1-((S)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-1-yl)ethanone;   5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;   4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;   6-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidin-2-one;   5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-one;   5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrrolidin-2-one;   N-(3-(3-Amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide;   3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane 1,1-dioxide;   (R)-1-(3-((1H-Pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol;   (R)-3-Amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol;   (R)-3-Amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propan-1-ol;   (R)-1-(3-(((1H-Indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol;   (R)-1-(3-((1H-Indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol;   (R)-3-Amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol;   3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine;   3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan-1-ol;   3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1-ol;   3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol;   3-Amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol;   3-Amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol;   (E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one;   1-(3-(3-Amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one;   3-Amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol;   (E)-1-(3-(2-(1H-Imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol;   1-(3-(2-(1H-Imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol;   (E)-3-Amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol;   3-Amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol;   (E)-3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-ol; and   3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol.   
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (C) as represented in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 10 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (C) as represented in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of  claim 10 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 13 , wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. 
     
     
         16 . The method of  claim 14 , wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy.