Opsin-Binding Ligands, Compositions and Methods of Use

Abstract

Compounds and compositions of said compounds along with methods of use of compounds are disclosed for treating ophthalmic conditions related to mislocalization of opsin proteins, the misfolding of mutant opsin proteins and the production of toxic visual cycle products that accumulate in the eye. Compounds and compositions useful in the these methods, either alone or in combination with other therapeutic agents, are also described.

1 . A compound having the structure of Formula I
   A-B-Q-V   Formula I
   wherein A is:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         B is —(CH 2 ) n —, —CH═CH—, —CH 2 —N(R 22 )—, —CH 2 —O—, —C(O)—CH 2 —C(O)—, 
       
       
         
           
           
               
               
           
         
       
       or —C(O)NR 22 —, wherein n=0, 1 or 2;
 E is —N(R 22 )— or oxygen; 
 Q is —C(O)—, —(CH 2 ) a —, —S(O 2 )— or —CH 2 —C(O)—, wherein a is 1 or 2; 
 V is NR 21 R 22 , 
 
       
         
           
           
               
               
           
         
         wherein b is 1 or 2 and a is 1 or 2; 
         Y is NR 22 , N-Q-U, CR 22 R 23 , oxygen, S(O) n , N—C(S)—NR 22 R 23 , N—(C═N—CN)—NR 22 R 23 , N—(C═N—SO 2 CH 3 )—NR 22 R 23 , C═NOR 22 , C═N—NR 22 R 23  or C H -Q-U, n is 0, 1 or 2; 
         U is NR 22 R 23 , lower alkyl, haloalkyl, alkoxy, OR 22  or hydrogen; 
         X is hydrogen, alkyl, or —C≡CR 9 ; 
         R 1  and R 2  are independently —CH 3  or —CH 2 CH 3 ; 
         R 3  is hydrogen, —CH 3  or —CH 2 CH 3 ; 
         R a  and R b , are each independently hydrogen, deuterium or —CH 3 —; 
         R c  and R d , are each independently hydrogen, alkoxy, lower alkyl or alkenyl; 
         R 4  is —CH 3 , —CF 3 , —C 2 H 5  or —C 3 H 5 ; 
         R 5 , R 6  and R 7  are each independently hydrogen, lower alkyl, halogen, dialkylamine, nitro or dialkylamine; 
         Z is CR 3 , CH or nitrogen; 
         R 8  is —CH 2 — or —C(O)—; 
         R 9 , R 14  and R 16  are each independently hydrogen, or —CH 3 ; 
         R 10  is N—R 13 , sulfur or oxygen; 
         R 11  is ═N—, or ═C(CH 3 )—; 
         R 12  is lower alkyl, alkoxy or haloalkyl; 
         R 13  is phenyl, lower alkyl or haloalkyl; 
         R 15  is hydrogen or —C(O)CH 3 ; 
         R 17  and R 18  together are —(CH 2 ) 4 — or —CH═CH—CH═CH—; 
         R19 and R20 together are —CH2-C(CH3)2-CH2-C(O)— or —CH═CH—CH═CH—; 
         R 21  is hydrogen, —C(O)CH 3 , —CH 3  or —CH 2 CH 3 ; 
         R 22  and R 23  are each independently hydrogen or lower alkyl; 
         R 24  and R 25  are each independently hydrogen or —CH 3 ; 
         R 26  is NR 22 R 23  or alkoxy; 
         or wherein R 1  and R 2  taken together or R a  and R b  taken together along with the carbon to which they are attached are cyclopropyl; 
         or R 24  and R 25  taken together along with the two carbons to which they are attached are cyclopropyl; 
         or R 24  and R 25  taken together is oxo; 
         T is oxygen, —N(R 16 )— or sulfur; and 
         E is oxygen, —N(R 16 )—, sulfur or —C(O)—; 
         including pharmaceutically acceptable salts, solvates and hydrates thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein R a  and R b  are each independently hydrogen or methyl. 
     
     
         4 . The compound of  claim 2 , wherein R c  and R d  are each independently hydrogen or lower alkyl. 
     
     
         5 . The compound of  claim 1 , wherein V is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5 , wherein a and b are each 1, X is hydrogen, Y is C H —C(O)NR 22 R 23  or N—C(O)NR 22 R 23  wherein R 23 , R 24  and R 25  are all hydrogen. 
     
     
         7 . The compound of  claim 1 , wherein X is H, lower alkyl or —C≡CR 9 . 
     
     
         8 . The compound of  claim 1 , wherein Y is O or N—C(O)—NR 22 R 23 . 
     
     
         9 - 20 . (canceled) 
     
     
         21 . A method of reducing or inhibiting mislocalization of an opsin protein, comprising contacting an opsin protein with a compound of  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein said opsin protein is pressent in a rod cell or a cone cell. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 22 , wherein said cell is present in a mammalian eye. 
     
     
         25 . A method of inhibiting the formation or accumulation of a visual cycle product, comprising contacting an opsin protein with a compound of  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein said visual cycle product is lipofuscin or N-retinylidene-N-retinylethanolamine (A2E). 
     
     
         27 . 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  claim 1 . 
     
     
         28 . The method of  claim 27 , wherein said ophthalmic condition is an ocular protein mislocalization disorder. 
     
     
         29 . The method of  claim 27 , 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. 
     
     
         30 . The method of  claim 29 , wherein said ophthalmic condition disorder is ARMD. 
     
     
         31 . The method of  claim 29 , wherein said ophthalmic condition is retinitis pigmentosa (RP). 
     
     
         32 . (canceled) 
     
     
         33 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.