Methods of Using and Compositions Comprising Selective Cytokine Inhibitory Drugs for Treatment and Management of Macular Degeneration

Abstract

Methods of treating, preventing and/or managing macular degeneration are disclosed. Specific embodiments encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

1 . A method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.  
     
     
         2 . The method of  claim 1 , which further comprises administering to the patient a therapeutically or prophylactically effective amount of a second active agent.  
     
     
         3 . The method of  claim 2 , wherein the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound.  
     
     
         4 . The method of  claim 2 , wherein the second active agent is thalidomide, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2α or pentoxifylline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.  
     
     
         5 . The method of  claim 4 , wherein the antiangiogenesis compound is thalidomide.  
     
     
         6 . The method of  claim 1 , wherein the macular degeneration is wet macular degeneration, dry macular degeneration, age-related macular degeneration, age-related maculopathy, choroidal neovascularisation, retinal pigment epithelium detachment, atrophy of retinal pigment epithelium, Best's disease, vitelliform, Stargardt's disease, juvenile macular dystrophy, fundus flavimaculatus, Behr's disease, Sorsby's disease, Doyne's disease, honeycomb dystrophy, or macular damaging condition.  
     
     
         7 . The method of  claim 1 , wherein the selective cytokine inhibitory drug is stereomerically pure.  
     
     
         8 . A method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.  
     
     
         9 . The method of  claim 8 , wherein the 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide is enantiomerically pure.  
     
     
         10 . A method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl-amide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.  
     
     
         11 . The method of  claim 10 , wherein the cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide is enantiomerically pure.  
     
     
         12 . The method of  claim 1 , wherein the selective cytokine inhibitory drug is of formula (I):  
       
         
           
           
               
               
           
         
         wherein n has a value of 1, 2, or 3;  
         R 5  is o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, and halo;  
         R 7  is (i) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (iv) benzyloxy;  
         R 12  is —OH, alkoxy of 1 to 12 carbon atoms, or  
         
           
             
             
                 
                 
             
           
         
         R 8  is hydrogen or alkyl of 1 to 10 carbon atoms; and  
         R 9  is hydrogen, alkyl of 1 to 10 carbon atoms, —COR 10 , or —SO 2 R 10 , wherein R 10  is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.  
       
     
     
         13 . The method of  claim 12 , wherein the selective cytokine inhibitory drug is enantiomerically pure.  
     
     
         14 . The method of  claim 1 , wherein the selective cytokine inhibitory drug is of formula (II):  
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2 , when taken independently of each other, is hydrogen, lower alkyl, or R 1  and R 2 , when taken together with the depicted carbon atoms to which each is bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo;  
         R 3  is phenyl substituted with from one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C 4 -C 6 -cycloalkylidenemethyl, C 3 -C 10 -alkylidenemethyl, indanyloxy, and halo;  
         R 4  is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;  
         R 4  is hydrogen or alkyl of 1 to 6 carbon atoms;  
         R 5  is —CH 2 —, —CH 2 —CO—, —SO 2 —, —S—, or —NHCO—; and  
         n has a value of 0, 1, or 2.  
       
     
     
         15 . The method of  claim 14 , wherein the selective cytokine inhibitory drug is enantiomerically pure.  
     
     
         16 . The method of  claim 1 , wherein the selective cytokine inhibitory drug is of c formula (III):  
       
         
           
           
               
               
           
         
         wherein the carbon atom designated * constitutes a center of chirality; Y is C═O, CH 2 , SO 2 , or CH 2 C═O;  
         each of R 1 , R 2 , R 3 , and R 4 , independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR 8 R 9 ; or any two of R 1 , R 2 , R 3 , and R 4  on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene;  
         each of R 5  and R 6 , independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;  
         R 7  is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR 8′ R 9 ;  
         each of R 8  and R 9  taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R 8  and R 9  is hydrogen and the other is —COR 10  or —SO 2 R 10 , or R 8  and R 9  taken together are tetramethylene, pentamethylene, hexamethylene, or —CH 2 CH 2 X 1 CH 2 CH 2 — in which X 1  is —O—, —S— or —NH—; and  
         each of R 8′  and R 9′  taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R 8′  and R 9′  is hydrogen and the other is —COR 10′  or —SO 2 R 10′ , or R 8′  and R 9′  taken together are tetramethylene, pentamethylene, hexamethylene, or —CH 2 CH 2 X 2 CH 2 CH 2 — in which X 2  is —O—, —S—, or —NH—.  
       
     
     
         17 . The method of  claim 16 , wherein the selective cytokine inhibitory drug is enantiomerically pure.  
     
     
         18 . A method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during or after surgical intervention directed at reducing or avoiding a symptom of macular degeneration in the patient.  
     
     
         19 . The method of  claim 17 , wherein the surgical intervention is light therapy, laser therapy, radiation therapy, retinal pigment epithelium transplantation, or foveal translocation.  
     
     
         20 . A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active agent capable of reducing or avoiding a symptom of macular degeneration.  
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound.  
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the second active agent is thalidomide, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2α or pentoxifylline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.