Methods and compositions for treating opthalmic conditions with retinol derivatives

Abstract

Compounds that cause reversible night blindness may be used to treat ophthalmic conditions associated with the overproduction of waste products that accumulate during the course of the visual cycle. We describe methods and compositions using such compounds and their derivatives to treat, for example, the macular degenerations and dystrophies or to alleviate symptoms associated with such ophthalmic conditions. Such compounds and their derivatives may be used as single agent therapy or in combination with other agents or therapies.

1 . A method for treating Stargardt disease comprising administering to a human in need thereof a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein X 1  is selected from the group consisting of NR 2 , O, S, CHR 2 ; R 1  is (CHR 2 )x-L 1 —R 3 , wherein x is 0, 1, 2, or 3; L 1  is a single bond or —C(O)—; R 2  is a moiety selected from the group consisting of H, (C 1 -C 4 )alkyl, F, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )alkoxy, —C(O)OH, —C(O)—NH 2 , —(C 1 -C 4 )alkylamine, —C(O)—(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )fluoroalkyl, —C(O)—(C 1 -C 4 )alkylamine, and —C(O)—(C 1 -C 4 )alkoxy; and R 3  is H or a moiety, optionally substituted with 1-3 independently selected substituents, selected from the group consisting of (C 2 -C 7 )alkenyl, (C 2 -C 7 )alkynyl, aryl, (C 3 -C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, and a heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof; provided that R 3  is not H when both x is 0 and L 1  is a single bond. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein X 1  is NR 2  and R 2  is H or (C 1 -C 4 )alkyl. 
     
     
         4 . The method of  claim 1 , wherein x is 0. 
     
     
         5 . The method of  claim 1 , wherein R 3  is an aryl optionally substituted with one substituent selected from the group consisting of halogen, OH, O(C 1 -C 4 )alkyl, NH(C 1 -C 4 )alkyl, O(C 1 -C 4 )fluoroalkyl, and N[(C 1 -C 4 )alkyl] 2 . 
     
     
         6 . The method of  claim 1 , wherein said compound is 4-hydroxyphenylretinamide or 4-methoxyphenylretinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein said composition is systemically formulated for oral, intravenous, iontophoretic administration or administration by injection. 
     
     
         9 . The method of  claim 1 , wherein the Stargardt disease is associated with deposition of lipofuscin pigment granules in RPE cells. 
     
     
         10 . The method of  claim 1 , wherein the compound reduces serum vitamin A levels. 
     
     
         11 . The method of  claim 1 , wherein the compound reduces A2E or lipofuscin in RPE. 
     
     
         12 . The method of  claim 1 , wherein the human is a carrier of mutant ABCA4 or ELOV4 gene. 
     
     
         13 . A method for treating or preventing diseases or conditions in a human carrying mutant ABCA4 or ELOV4 gene, comprising administering to a human in need thereof a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X 1  is selected from the group consisting of NR 2 , O, S, CHR 2 ; R 1  is (CHR 2 )x-L 1 -R 3 , wherein x is 0, 1, 2, or 3; L 1  is a single bond or —C(O)—; R 2  is a moiety selected from the group consisting of H, (C 1 -C 4 )alkyl, F, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )alkoxy, —C(O)OH, —C(O)—NH 2 , —(C 1 -C 4 )alkylamine, —C(O)—(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )fluoroalkyl, —C(O)—(C 1 -C 4 )alkylamine, and —C(O)—(C 1 -C 4 )alkoxy; and R 3  is H or a moiety, optionally substituted with 1-3 independently selected substituents, selected from the group consisting of (C 2 -C 7 )alkenyl, (C 2 -C 7 )alkynyl, aryl, (C 3 -C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, and a heterocycle; or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof; provided that R 3  is not H when both x is 0 and L 1  is a single bond. 
       
     
     
         14 . The method of  claim 13 , wherein X 1  is NR 2  and R 2  is H or (C 1 -C 4 )alkyl. 
     
     
         15 . The method of  claim 13 , wherein x is 0. 
     
     
         16 . The method of  claim 13 , wherein R 3  is an aryl optionally substituted with one substituent selected from the group consisting of halogen, OH, O(C 1 -C 4 )alkyl, NH(C 1 -C 4 )alkyl, 0(C 1 -C 4 )fluoroalkyl, and N[(C 1 -C 4 )alkyl] 2 . 
     
     
         17 . The method of  claim 13 , wherein said compound is 4-hydroxyphenylretinamide or 4-methoxyphenylretinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 13 , wherein said diseases or conditions comprise recessive retinitis pigmentosa, cone-rod dystrophy, recessive cone-rod dystrophy or non-exudative age-related muscular degeneration. 
     
     
         19 . The method of  claim 13 , wherein said composition is systemically formulated for oral, intravenous, iontophoretic administration or administration by injection. 
     
     
         20 . The method of  claim 13 , wherein the Stargardt disease is associated with deposition of lipofuscin pigment granules in RPE cells. 
     
     
         21 . The method of  claim 13 , wherein the compound reduces serum vitamin A levels. 
     
     
         22 . The method of  claim 13 , wherein the compound reduces A2E or lipofuscin in RPE.