Styrenyl Derivative Compounds for Treating 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 styrenyl derivative compounds, including but not limited to stilbene derivative compounds, and compositions comprising these compounds, that are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.

1 .- 84 . (canceled) 
     
     
         85 . A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound, or the pharmaceutically acceptable salt thereof, having a structure of Formula (A): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are hydrogen; 
         R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, —OR 12 , alkyl or fluoroalkyl; 
         R 7  and R 8  are hydrogen; 
         R 9  is hydrogen; 
         R 10  is hydrogen; 
         R 11  is 5-, 6-, or 7-member cycloalkyl; 
         each R 12  is independently selected from hydrogen or alkyl; 
         Z is W—Y, wherein 
         W is —C(R 14 )(R 15 )—; 
         Y is —C(R 16 )(R 17 )—; 
         R 14  and R 15  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , or —NR 18 R 19 ; or R 14  and R 15  together form an oxo; 
         R 16  and R 17  are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR 12 , or —NR 18 R 19 ; or R 16  and R 17  together form an oxo; and 
         each R 18  and R 19  is independently selected from hydrogen or alkyl. 
       
     
     
         86 . The method of  claim 85 , wherein R 11  is cyclohexyl. 
     
     
         87 . The method of  claim 85 , wherein R 14 , R 15 , R 16  and R 17  are each independently hydrogen, halogen, alkyl, fluoroalkyl —OR 12 , or —NR 18 R 19 , wherein each R 12  is independently hydrogen or alkyl. 
     
     
         88 . The method of  claim 85 , wherein R 3 , R 4 , R 5  and R 6  are each the same or different and independently hydrogen, halogen, —OR 12 , or alkyl. 
     
     
         89 . The method of  claim 85 , wherein the compound is selected from:
 (E)-3-(3-(2-cyclohexylvinyl)phenyl)propan-1-amine;   (E)-1-(3-(3-amino-1-hydroxypropyl)styryl)cyclohexanol;   (E)-1-(3-((1R,2R)-3-amino-1-hydroxy-2-methylpropyl)styryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-5-fluorostyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-2-fluorostyryl)cyclohexanol;   (1S,2S)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diol;   (1R,2R)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diol;   (E)-1-(5-(3-amino-1-hydroxypropyl)-2-methoxystyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-4-chlorostyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-4-methylstyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-5-methylstyryl)cyclohexanol;   (1S,2R)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)-propane-1,2-diol;   (E)-2-(3-(3-amino-1-hydroxypropyl)styryl)cyclohexanol;   (E)-1-(5-(3-amino-1-hydroxypropyl)-2-fluorostyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-5-methoxystyryl)cyclohexanol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-4-fluorostyryl)cyclohexanol;   (1R,2S)-3-amino-1-(3-((E)-2-(1-hydroxycyclohexyl)vinyl)phenyl)propane-1,2-diol;   (E)-1-(3-(3-amino-1-hydroxypropyl)-5-chlorostyryl)cyclohexanol; and   (E)-1-(3-(3-amino-1-hydroxypropyl)-2-methoxystyryl)cyclohexanol;   or the pharmaceutically acceptable salt thereof.   
     
     
         90 . A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound selected from:
 (E/Z)-3-(3-(2,6-dimethyl styryl)phenyl)prop-2-en-1-amine;   (E)-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-yn-1-amine; and   (E)-2-fluoro-3-(3-((E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)prop-2-en-1-amine;   or the pharmaceutically acceptable salt thereof.   
     
     
         91 . A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having a structure described by
 (E)-4-(3-(3-amino-1-hydroxypropyl)styryl)heptan-4-ol;   or the pharmaceutically acceptable salt thereof.   
     
     
         92 . The method of  claim 85  wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. 
     
     
         93 . The method of  claim 85  resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. 
     
     
         94 . The method of  claim 93 , wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). 
     
     
         95 . The method of  claim 90  wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. 
     
     
         96 . The method of  claim 90  resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. 
     
     
         97 . The method of  claim 96  wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). 
     
     
         98 . The method of  claim 91  wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy. 
     
     
         99 . The method of  claim 91  resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject. 
     
     
         100 . The method of  claim 99  wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).