Opsin-Binding Ligands, Compositions and Methods of Use

Abstract

Compounds and compositions 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 - 15 . (canceled) 
     
     
         16 . A method of inhibiting the formation or accumulation of a visual cycle product, comprising contacting an opsin protein with a compound of Formula I, 
       
         
           
           
               
               
           
         
         wherein A is: 
       
       
         
           
           
               
               
           
         
         
           R 1  and R 2  are independently:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
           R 3  is:
 1) hydrogen, 
 2) —CH 3 , 
 3) —CH 2 CH 3 , or 
 4) deuterium; 
 
           R 4  is:
 1) hydrogen, 
 2) lower alkyl, 
 3) lower haloalkyl, or 
 4) deuterium; 
 
           R a  and R b  are each independently:
 1) hydrogen, or 
 2) —CH 3 ; 
 
           T is:
 1) —CH 2 —, 
 2) —CH 2 CH 2 —, or 
 3) absent; 
 
           R i  and R j  are each independently:
 1) hydrogen, 
 2) hydroxyl, or 
 3) lower alkyl; 
 
           or R i  and R j  taken together are oxo (═O); 
           B is:
 1) oxygen, 
 2) NR 5 , or 
 3) CR q R s ; 
 R q  and R s  are each independently: 
 1) hydrogen, 
 2) hydroxyl, or 
 3) lower alkyl; 
 
           R 5  is:
 1) hydrogen, or 
 2) lower alkyl; 
 
           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 
 R e  and R f  when taken together are: 
 1) —OCH 2 O—, or 
 2) —OCF 2 O—; 
 
           and provided that if R 1  and/or R 2  are hydrogen then each of R a  and R b  must be selected from methyl or ethyl 
           including all pharmaceutically acceptable salts, solvates and hydrates thereof. 
         
       
     
     
         17 . The method of  claim 16 , wherein said visual cycle product is a toxic visual cycle product. 
     
     
         18 . The method of  claim 17 , wherein said toxic visual cycle product is lipofuscin or N-retinylidene-N-retinylethanolamine (A2E). 
     
     
         19 . The method of  claim 16 , wherein said compound reduces mislocalization of said opsin protein. 
     
     
         20 . The method of  claim 16 , wherein said opsin protein is present in a cell. 
     
     
         21 . The method of  claim 20 , wherein said cell is a cone cell or rod cell. 
     
     
         22 . The method of  claim 20 , wherein said cell is present in a mammalian eye. 
     
     
         23 . A method of inhibiting the formation or accumulation of a visual cycle product, comprising contacting an opsin protein with a compound selected from the group consisting of:
 3-(trifluoromethyl)-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 1);   3-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 2);   3-((2,6,6-trimethylcyclohex-1-enyl)methylamino)benzamide (Compound 3);   3-((2,6,6-trimethylcyclohex-1-enyl)methylamino)benzonitrile (Compound 4);   3-chloro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 5);   1-methyl-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 6);   1-fluoro-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 7);   1-chloro-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 8);   1-(trifluoromethyl)-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 9);   3-fluoro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 10);   N-methyl-3-(trifluoromethyl)-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 11);   3-(trifluoromethyl)-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 12);   3-fluoro-N-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 13);   3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzonitrile (Compound 14);   4-fluoro-3-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 15);   1-(3-fluorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 16);   1-(3-fluorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanone (Compound 17);   1-(3-chlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 18);   1-(3-chlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanone (Compound 19);   1-(3-(trifluoromethyl)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 20);   2-m-tolyl-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 21);   2-(3-(trifluoromethyl)phenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 22);   2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 23);   2-fluoro-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzonitrile (Compound 24);   1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 25);   1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 26);   1-(3,4-dichlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 27);   2-fluoro-1-methyl-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 28);   1,2-difluoro-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 29);   2-(3,4-dimethylphenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 30);   3-methoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 31);   N-((6,6-dimethylcyclohex-1-enyl)methyl)-3-fluoroaniline hydrochloride (Compound 32);   N-((6,6-dimethylcyclohex-1-enyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 33);   N-((2,2-dimethylcyclohexyl)methyl)-3-fluoroaniline hydrochloride (Compound 34);   N-((2,2-dimethylcyclohexyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 35);   3-methyl-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 36);   3-chloro-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 37);   3-fluoro-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 38);   3-fluoro-N-methyl-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 39);   3-ethoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 40),   3-isopropoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 41);   1-ethyl-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 42);   1-methoxy-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 43);   1-ethoxy-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 44);   (R)-2-m-tolyl-1-((1R,6S)-2,2,6-trimethylcyclohexyl)ethanol (Compound 45);   2-m-tolyl-1-((1R,6S)-2,2,6-trimethylcyclohexyl)ethanone (Compound 46);   3-ethyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 47);   N-((2,6,6-trimethylcyclohex-1-enyl)methyl)benzo[d][1,3]dioxol-5-amine hydrochloride (Compound 48);   2,2-difluoro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)benzo[d][1,3]dioxol-5-amine hydrochloride (Compound 49);   1-fluoro-3-((2,5,5-trimethylcyclopent-1-enyl)methoxy)benzene (Compound 50);   3-fluoro-N-((2,5,5-trimethylcyclopent-1-enyl)methyl)aniline hydrochloride (Compound 51);   5-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzo[d][1,3]dioxole (Compound 52);   1-fluoro-3-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 53);   1-chloro-3-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 54);   1,2-difluoro-4-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 55);   1-fluoro-3-((3,3,6,6-tetramethylcyclohex-1-enyl)methoxy) benzene (Compound 56);   3-fluoro-N-((3,3,6,6-tetramethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 57);   1-((3-fluorophenoxy)methyl)-7,7-dimethylcyclohept-1-ene (Compound 58);   N-((7,7-dimethylcyclohept-1-enyl)methyl)-3-fluoroaniline hydrochloride (Compound 59);   (3-fluorophenyl)((2,6,6-trimethylcyclohex-1-enyl)methyl) sulfane (Compound 60);   N-(7,7-dimethylcyclohept-1-enyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 61);   3-fluoro-N-methyl-N-((3,3,6,6-tetramethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 62);   3-fluoro-N-((2,2,5,5-tetramethylcyclohexyl)methyl)aniline hydrochloride (Compound 63);   (R)-2-(3-fluorophenyl)-1-((1R,6S)-2,2,6-trimethylcyclohexyl)ethanol (Compound 64); and   2-(3-fluorophenyl)-1-((1R,6S)-2,2,6-trimethylcyclohexyl) ethanone (Compound 65)   including all pharmaceutically acceptable salts, solvates and hydrates thereof.   
     
     
         24 . (canceled) 
     
     
         25 . A method of treating or preventing an ophthalmic condition in a subject at risk thereof or afflicted therewith, comprising administering to the subject an effective amount of a compound having the structure of Formula I 
       
         
           
           
               
               
           
         
         wherein A is: 
       
       
         
           
           
               
               
           
         
         
           R 1  and R 2  are independently:
 1) hydrogen, 
 2) —CH 3 , or 
 3) —CH 2 CH 3 ; 
 
           R 3  is:
 1) hydrogen, 
 2) —CH 3 , 
 3) —CH 2 CH 3 , or 
 4) deuterium; 
 
           R 4  is:
 1) hydrogen, 
 2) lower alkyl, 
 3) lower haloalkyl, or 
 4) deuterium; 
 
           R a  and R b  are each independently:
 1) hydrogen, or 
 2) —CH 3 ; 
 
           T is:
 1) —CH 2 —, 
 2) —CH 2 CH 2 —, or 
 3) absent; 
 
           R i  and R j  are each independently:
 1) hydrogen, 
 2) hydroxyl, or 
 3) lower alkyl; 
 
           or R i  and R j  taken together are oxo (═O); 
           B is:
 1) oxygen, 
 2) NR 5 , or 
 3) CR q R s ; 
 R q  and R s  are each independently: 
 1) hydrogen, 
 2) hydroxyl, or 
 3) lower alkyl; 
 
           R 5  is:
 1) hydrogen, or 
 2) lower alkyl; 
 
           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 
 R e  and R f  when taken together are: 
 1) —OCH 2 O—, or 
 2) —OCF 2 O—; 
 
           and provided that if R 1  and/or R 2  are hydrogen then each of R a  and R b  must be selected from methyl or ethyl 
           including all pharmaceutically acceptable salts, solvates and hydrates thereof. 
         
       
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25 , 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 Stargardt's disease, North Carolina macular dystrophy, light toxicity, normal vision loss related aging and normal loss of night vision related to aging. 
     
     
         28 .- 29 . (canceled) 
     
     
         30 . A method of treating or preventing an ophthalmic condition in a subject at risk thereof or afflicted therewith, comprising administering to the subject an effective amount of a compound selected from the group consisting of:
 3-(trifluoromethyl)-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 1);   3-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 2);   3-((2,6,6-trimethylcyclohex-1-enyl)methylamino)benzamide (Compound 3);   3-((2,6,6-trimethylcyclohex-1-enyl)methylamino)benzonitrile (Compound 4);   3-chloro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 5);   1-methyl-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 6);   1-fluoro-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 7);   1-chloro-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 8);   1-(trifluoromethyl)-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 9);   3-fluoro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 10);   N-methyl-3-(trifluoromethyl)-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 11);   3-(trifluoromethyl)-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 12);   3-fluoro-N-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline (Compound 13);   3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzonitrile (Compound 14);   4-fluoro-3-methyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 15);   1-(3-fluorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 16);   1-(3-fluorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanone (Compound 17);   1-(3-chlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 18);   1-(3-chlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanone (Compound 19);   1-(3-(trifluoromethyl)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 20);   2-m-tolyl-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 21);   2-(3-(trifluoromethyl)phenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 22);   2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 23);   2-fluoro-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzonitrile (Compound 24);   1-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 25);   1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 26);   1-(3,4-dichlorophenyl)-2-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 27);   2-fluoro-1-methyl-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 28);   1,2-difluoro-4-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 29);   2-(3,4-dimethylphenyl)-1-(2,6,6-trimethylcyclohex-1-enyl)ethanol (Compound 30);   3-methoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 31);   N-((6,6-dimethylcyclohex-1-enyl)methyl)-3-fluoroaniline hydrochloride (Compound 32);   N-((6,6-dimethylcyclohex-1-enyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 33);   N-((2,2-dimethylcyclohexyl)methyl)-3-fluoroaniline hydrochloride (Compound 34);   N-((2,2-dimethylcyclohexyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 35);   3-methyl-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 36);   3-chloro-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 37);   3-fluoro-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 38);   3-fluoro-N-methyl-N-(((1R,6S)-2,2,6-trimethylcyclohexyl)methyl)aniline hydrochloride (Compound 39);   3-ethoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 40);   3-isopropoxy-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 41);   1-ethyl-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 42);   1-methoxy-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzene (Compound 43);   1-ethoxy-3-((2,6,6-trimethylcyclohex-1-enyl)methoxy)benzene (Compound 44);   (R)-2-m-tolyl-1-((1R,6S)-2,2,6-trimethylcyclohexyl)ethanol (Compound 45);   2-m-tolyl-1-((1R,6S)-2,2,6-trimethylcyclohexyl)ethanone (Compound 46);   3-ethyl-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 47);   N-((2,6,6-trimethylcyclohex-1-enyl)methyl)benzo[d][1,3]dioxol-5-amine hydrochloride (Compound 48);   2,2-difluoro-N-((2,6,6-trimethylcyclohex-1-enyl)methyl)benzo[d][1,3]dioxol-5-amine hydrochloride (Compound 49);   1-fluoro-3-((2,5,5-trimethylcyclopent-1-enyl)methoxy)benzene (Compound 50);   3-fluoro-N-((2,5,5-trimethylcyclopent-1-enyl)methyl)aniline hydrochloride (Compound 51);   5-((2,6,6-trimethylcyclohex-1-enyl)methoxy) benzo[d][1,3]dioxole (Compound 52);   1-fluoro-3-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 53);   1-chloro-3-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 54);   1,2-difluoro-4-(((1R,6S)-2,2,6-trimethylcyclohexyl)methoxy) benzene (Compound 55);   1-fluoro-3-((3,3,6,6-tetramethylcyclohex-1-enyl)methoxy) benzene (Compound 56);   3-fluoro-N-((3,3,6,6-tetramethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 57);   1-((3-fluorophenoxy)methyl)-7,7-dimethylcyclohept-1-ene (Compound 58);   N-((7,7-dimethylcyclohept-1-enyl)methyl)-3-fluoroaniline hydrochloride (Compound 59);   (3-fluorophenyl)((2,6,6-trimethylcyclohex-1-enyl)methyl) sulfane (Compound 60);   N-((7,7-dimethylcyclohept-1-enyl)methyl)-3-fluoro-N-methylaniline hydrochloride (Compound 61);   3-fluoro-N-methyl-N-((3,3,6,6-tetramethylcyclohex-1-enyl)methyl)aniline hydrochloride (Compound 62);   3-fluoro-N-((2,2,5,5-tetramethylcyclohexyl)methyl)aniline hydrochloride (Compound 63);   (R)-2-(3-fluorophenyl)-1-((1R,6S)-2,2,6-trimethylcyclohexyl) ethanol (Compound 64); and   2-(3-fluorophenyl)-1-((1R,6S)-2,2,6-trimethylcyclohexyl) ethanone (Compound 65)   including all pharmaceutically acceptable salts, solvates and hydrates thereof.   
     
     
         31 . (canceled)