Opsin-Binding Ligands, Compositions and Methods for 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 having the structure of Formula I 
       
         
           
           
               
               
           
         
         wherein X is:
 1) C(R i )(R j ), or 
 2) oxygen; 
 
         T is:
 1) CH 2 , 
 2) CH 2 CH 2 , or 
 3) absent; 
 
         R 1  and R 2  are independently:
 1) —CH 3 , or 
 2) —CH 2 CH 3 ; 
 
         R 3  is:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
         R 4  is:
 1) hydrogen, or 
 2) —CH 3 ; 
 
         R a  and R b  are each independently:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
         R i  and R j  are each independently:
 1) hydrogen, 
 2) deuteron, 
 3) hydroxyl, 
 4) fluoro, 
 5) alkoxy, 
 6) lower alkyl, or 
 7) lower haloalkyl; 
 
         or R i  and R j  can be taken together as oxo (═O): 
         B is: 
       
       
         
           
           
               
               
           
         
         
           7) cycloalkyl, 
           8) lower alkyl, or 
           9) lower haloalkyl; 
         
         R e , R f , R g , R h  and R k  are each independently:
 1) hydrogen, 
 2) lower alkyl, 
 3) lower haloalkyl, 
 4) halogen, 
 5) nitro, 
 6) hydroxy, 
 7) alkoxy, 
 8) nitrile, 
 9) carboxamido, 
 10) arylcarbonyl, 
 11) carbamoyl, 
 12) amidyl, 
 13) amino, 
 14) alkylcarbonyl, or 
 15) urea or 
 16) —C(NOH)NH 2 ; 
 
         R l , R m  and R n  are:
 1) —CR e , or 
 2) nitrogen; 
 
         but wherein at least one of R l , R m  and R n  is nitrogen, and 
         Z is:
 1) oxygen, or 
 2) sulfur; 
 
         including pharmaceutically acceptable salts, solvates and hydrates thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein X is CR i R j . 
     
     
         3 . The compound of  claim 2 , wherein R i  and R j  are taken together as oxo. 
     
     
         4 . The compound of  claim 2 , wherein R i  is hydroxyl and R j  is hydrogen. 
     
     
         5 . The compound of  claim 2 , wherein R 1  and R 2  are each independently methyl or ethyl. 
     
     
         6 . The compound of  claim 2 , wherein R 1  and R 2  are each methyl. 
     
     
         7 . The compound of  claim 2 , wherein R 3  is hydrogen or methyl. 
     
     
         8 . The compound of  claim 7 , wherein R 3  methyl. 
     
     
         9 . The compound of  claim 1 , wherein R 1  and R 2  are both methyl. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is methyl or hydrogen. 
     
     
         11 . The compound of  claim 10 , wherein R 3  is methyl. 
     
     
         12 . The compound of  claim 1 , wherein T is CH 2 . 
     
     
         13 . The compound of  claim 1 , wherein R a  and R b  are independently hydrogen or methyl. 
     
     
         14 . The compound of  claim 13 , wherein R a  and R b  are each hydrogen. 
     
     
         15 - 37 . (canceled) 
     
     
         38 . A composition, comprising a therapeutically effective amount of a compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         39 . (canceled)