Novel traps in the treatment of macular degeneration

Abstract

pharmaceutical compositions, and methods of use for treating, reducing a symptom of or reducing the risk of macular degeneration.

What is claimed is: 
     
         1 - 32 . (canceled) 
     
     
         33 . A method of treating a retinal disorder associated with accumulation of A2E or lipofuscin, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A and R are attached to adjacent carbon atoms on the phenyl ring, and together with the two carbon atoms to which they are attached, form a five-membered heteroaryl ring containing one nitrogen atom and one oxygen atom, wherein the heteroaryl ring is substituted with X; 
         X is C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl, aryl, aryl substituted with C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; 
         n 1  is 1 or 2; 
         T 1  is halogen; and 
         each D is independently C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or two D, together with the carbon atom to which they are attached, form a C 3 -C 6  carbocyclic ring or a saturated heterocycle selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein “*” denotes the position of the carbon atom to which the two D are attached. 
       
     
     
         34 . The method of  claim 33 , wherein X is C 3 -C 6  cycloalkyl, aryl, or aryl substituted with C 1 -C 6  alkyl. 
     
     
         35 . The method of  claim 33 , wherein X is C 1 -C 10  alkyl, or C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl. 
     
     
         36 . The method of  claim 33 , wherein each D is independently C 1 -C 6  alkyl. 
     
     
         37 . The method of  claim 36 , wherein each D is methyl. 
     
     
         38 . The method of  claim 33 , wherein n 1  is 1. 
     
     
         39 . The method of  claim 33 , wherein the compound is of formula (Ia), (Ib), (Ic), or (Id): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl, aryl, aryl substituted with C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; 
         n 1  is 1 or 2; 
         each T 1  is independently F or C 1 ; and 
         each D is independently C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or two D, together with the carbon atom to which they are attached, form a C 3 -C 6  carbocyclic ring or a saturated heterocycle selected from 
       
       
         
           
           
               
               
           
         
         wherein “*” denotes the position of the carbon atom to which the two D are attached. 
       
     
     
         40 . The method of  claim 41 , wherein X is C 3 -C 6  cycloalkyl, aryl, or aryl substituted with C 1 -C 6  alkyl; each T 1  is independently F or C 1 ; and each D is methyl. 
     
     
         41 . The method of  claim 40 , wherein X is aryl, aryl substituted with methyl, or cyclopropyl; n 1  is 1; and T 1  is Cl. 
     
     
         42 . The method of  claim 41 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 41 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The method of  claim 33 , wherein the retinal disease is macular degeneration. 
     
     
         45 . The method of  claim 44  wherein the retinal disease is dry age related macular degeneration. 
     
     
         46 . The method of  claim 44  wherein the retinal disease is geographic atrophy secondary to dry age related macular degeneration. 
     
     
         47 . The method of  claim 44  wherein the retinal disease is wet age related macular degeneration. 
     
     
         48 . The method of  claim 44  wherein the retinal disease is Stargardt's disease. 
     
     
         49 . A method of treating a retinal disorder associated with accumulation of A2E or lipofuscin, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A and R are attached to adjacent carbon atoms on the phenyl ring, and together with the two carbon atoms to which they are attached, form a five-membered heteroaryl ring containing one nitrogen atom and one oxygen atom, wherein the heteroaryl ring is substituted with X; 
         X is C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl, or aryl substituted with C 1 -C 6  alkyl; 
         n 1  is 1 or 2; 
         each T 1  is independently halogen, C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl, or cyano; and 
         each D is independently C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or two D, together with the carbon atom to which they are attached, form a C 3 -C 6  carbocyclic ring or a saturated heterocycle selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein “*” denotes the position of the carbon atom to which the two D are attached. 
       
     
     
         50 . The method of  claim 49 , wherein X is C 3 -C 6  cycloalkyl or aryl substituted with C 1 -C 6  alkyl. 
     
     
         51 . The method of  claim 49 , wherein X′ is C 1 -C 10  alkyl, or C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl. 
     
     
         52 . The method of  claim 49 , wherein each D is independently C 1 -C 6  alkyl. 
     
     
         53 . The method of  claim 52 , wherein each D is methyl. 
     
     
         54 . The method of  claim 49 , wherein n 1  is 1. 
     
     
         55 . The method of  claim 49 , wherein T 1  is halogen. 
     
     
         56 . The method of  claim 49 , wherein the compound is of formula (Ia), (Ib), (Ic), or (Id): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkyl, or aryl substituted with C 1 -C 6  alkyl; 
         n 1  is 1 or 2; 
         each T 1  is independently F, Cl, C 1 -C 10  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 10  alkyl substituted with C 3 -C 6  cycloalkyl, or cyano; and 
         each D is independently C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, or two D, together with the carbon atom to which they are attached, form a C 3 -C 6  carbocyclic ring or a saturated heterocycle selected from 
       
       
         
           
           
               
               
           
         
         wherein “*” denotes the position of the carbon atom to which the two D are attached. 
       
     
     
         57 . The method of  claim 56 , wherein X is C 3 -C 6  cycloalkyl, or aryl substituted with C 1 -C 6  alkyl; each T 1  is independently F, Cl, methyl, cyclopropyl, cyclobutyl, or cyano; and each D is methyl. 
     
     
         58 . The method of  claim 57 , wherein X is aryl substituted with methyl or cyclopropyl; n 1  is 1; and T 1  is Cl. 
     
     
         59 . The method of  claim 49 , wherein the retinal disease is macular degeneration. 
     
     
         60 . The method of  claim 59  wherein the retinal disease is dry age related macular degeneration. 
     
     
         61 . The method of  claim 59  wherein the retinal disease is geographic atrophy secondary to dry age related macular degeneration. 
     
     
         62 . The method of  claim 59  wherein the retinal disease is wet age related macular degeneration. 
     
     
         63 . The method of  claim 59 , wherein the retinal disease is Stargardt's disease.