Opsin-binding ligands, compositions and methods of use

Abstract

Compounds are disclosed that are useful for treating ophthalmic conditions caused by or related to production of toxic visual cycle products that accumulate in the eye, such as dry adult macular degeneration, as well as conditions caused by or related to the misfolding of mutant opsin proteins and/or the mis-localization of opsin proteins. Compositions of these compounds alone or in combination with other therapeutic agents are also described, along with therapeutic methods of using such compounds and/or compositions. Methods of synthesizing such agents are also disclosed.

1 . A compound of Formula I, 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
         R a  and R h  are each independently:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
         R 3′  and R 5  are each independently:
 1) hydrogen, or 
 2) lower alkyl; and 
 
         R 4  is:
 1) hydrogen, 
 2) cycloalkyl, or 
 3) phenyl; 
 
         wherein if either R 1  or R 2  is hydrogen then each of R a  and R b  is selected from methyl and ethyl, including pharmaceutically acceptable salts, solvates and hydrates thereof. 
       
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein each of R 1  and R 2  is independently methyl or ethyl and each of R a  and R b  is independently hydrogen or methyl. 
     
     
         6 . The compound of  claim 5 , wherein each of each of R 1  and R 2  is methyl and each of R a  and R b  is hydrogen. 
     
     
         7 .- 49 . (canceled) 
     
     
         50 . A method of treating or preventing an ophthalmic condition in a subject at risk thereof, comprising administering to the subject an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently:
 1) hydrogen, 
 2) —CH 3 ; or 
 1) —CH 2 CH 3 ; 
 
         R a  and R b  are each independently:
 1) hydrogen, 
 2) CH 3 , or 
 3) —CH 2 CH 3 ; 
 
         R 3′  and R 5  are each independently:
 1) hydrogen, or 
 2) lower alkyl; and 
 
         R 4  is:
 1) hydrogen, 
 2) cycloalkyl, or 
 3) phenyl; 
 
         wherein if either R 1  or R 2  is hydrogen then each of R a  and R h  is selected from methyl and ethyl, including pharmaceutically acceptable salts, solvates and hydrates thereof. 
       
     
     
         51 . The method of  claim 50 , wherein said ophthalmic condition is an ocular protein mislocalization disorder. 
     
     
         52 . The method of  claim 50 , wherein said ophthalmic condition is selected from the group consisting of wet or dry age related macular degeneration (ARMD), retinitis pigmentosa (RP), a retinal or macular dystrophy, Stargardt's disease, Sorsby's dystrophy, autosomal dominant drusen, Best's dystrophy, peripherin mutation associate with macular dystrophy, dominant form of Stargart's disease, North Carolina macular dystrophy, light toxicity, normal vision loss related aging and normal loss of night vision related to aging. 
     
     
         53 . The method of  claim 50 , wherein said ophthalmic condition is retinitis pigmentosa (RP). 
     
     
         54 . The method of  claim 53 , wherein said RP is caused by aberrant opsin-folding. 
     
     
         55 .- 80 . (canceled) 
     
     
         81 . A method of treating or preventing an ophthalmic condition in a subject at risk thereof, comprising administering to the subject an effective amount of a compound of selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                 
                   Name 
                   Structure 
                 
                     
                 
                   7,7-dimethyl-5,6,7,7a-tetrahydro- 1H-inden-2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (−)-4,4,7,7-tetramethyl-5,6,7,7a- tetrahydro-1H-inden-2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (+)-4,4,7,7-tetramethyl-5,6,7,7a- tetrahydro-1H-inden-2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   4,4-dimethyl-5,6,7,7a-tetrahydro- 1H-inden-2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   4,4,7,7-tetramethyl-5,6,7,7a- tetrahydro-1H-inden-2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aS,7aS)-3a,7,7- trimethylhexahydro-1H-inden- 2(3H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aR,7aS)-3,3a,7,7-tetramethyl- 3a,4,5,6,7,7a-hexahydro-1H-inden- 1-one oxime 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   2,7,7-trimethyl-2,3,4,5,6,7- hexahydro-1H-isoindol-1-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aR,7aS)-3,3a,7,7-tetramethyl- 3a,4,5,6,7,7a-hexahydro-1H-inden- 1-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3R,3aR)-3,4,4-trimethyl- 2,3,3a,4,5,6-hexahydro-1H-inden- 1-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (3aR,7aS)-4,4,7,7- tetramethylhexahydro-1H-inden- 2(3H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(1R,7aS)-1,4,4-trimethyl- 5,6,7,7a-tetrahydro-1H-inden- 2(4H)-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(1R,3aR,7aS)-2,3,3a,7,7- pentamethyl-3a,4,5,6,7,7a- hexahydro 1H inden-1-ol 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aS,7aS)-2,3,4,4-tetramethyl- 3a,4,5,6,7,7a-hexahydro-1H-inden- 1-one 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aS,7aS)-3a,7,7- trimethyloctahydro-1H-inden-2-ol 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   (±)-(3aS,7aS)-3a,7,7- trimethylhexahydro-1H-inden- 2(3H)-one oxime 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof.