Targeting ocular diseases with novel ape1/ref-1 inhibitors

Abstract

Apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitors for inhibiting ocular diseases are disclosed herein.

What is claimed is: 
     
         1 . A method of inhibiting ocular neovascularization in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. 
     
     
         2 . The method as set forth in  claim 1 , wherein the APE1/Ref-1 inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, alkoxy, hydroxyl, and hydrogen; R 3  and R 6  are independently selected from the group consisting of a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl and an oxo; R 4  and R 5  are independently selected from the group consisting of an alkoxy and aryl, or both R 4  and R 5  taken together form a substituted or unsubstituted napthoquinone;
 X is selected from the group consisting of CH═CR 2  and NCH, wherein R 2  is selected from the group consisting of C 1 -C 10  alkyl and CF 3 CH 2 CH 2 ; and 
 Y is selected from the group consisting of N(Rz)R2 or NR{circumflex over ( )}OR{circumflex over ( )}, wherein each Rz is independently selected from the group consisting of C 1 -C 6  alkyl, heteroalkyl, cycloalkyl and cycloheteroalkyl, straight or branched chain or optionally substituted, or both Rz and R2 taken together with the attached nitrogen form an optionally substituted heterocycle; where each R{circumflex over ( )} is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cyclohexyl, and cycloheteroalkyl, each of which is optionally substituted, or both R{circumflex over ( )} are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle. 
 
     
     
         3 . The method as set forth in  claim 1  further comprising administering at least one additional therapeutic agent to the subject. 
     
     
         4 . The method as set forth in  claim 3 , wherein the additional therapeutic agent is selected from the group consisting of an anti-VEGF treatment, vitamins, minerals and combinations thereof. 
     
     
         5 . The method as set forth in  claim 4 , wherein the anti-VEGF treatment is selected from the group consisting of ranibizumab, bevacizumab, aflibercept, and combinations thereof. 
     
     
         6 . The method as set forth in  claim 1 , wherein the subject has a disease selected from the group consisting of retinopathy of prematurity (ROP), proliferative diabetic retinopathy (PDR), diabetic retinopathy, wet age-related macular degeneration (AMD), pathological myopia, hypertensive retinopathy, occlusive vasculitis, polypoidal choroidal vasculopathy, diabetic macular edema, uveitic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, retinal neovascularization, ocular histoplasmosis, neovascular glaucoma, retinoblastoma, and combinations thereof. 
     
     
         7 . A method of treating retinopathy of prematurity (ROP) in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. 
     
     
         8 . The method as set forth in  claim 7 , wherein the APE1/Ref-1 inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, alkoxy, hydroxyl, and hydrogen; R 3  and R 6  are independently selected from the group consisting of a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl and an oxo; R 4  and R 5  are independently selected from the group consisting of an alkoxy and aryl, or both R 4  and R 5  taken together form a substituted or unsubstituted napthoquinone;
 X is selected from the group consisting of CH═CR 2  and NCH, wherein R 2  is selected from the group consisting of C 1 -C 10  alkyl and CF 3 CH 2 CH 2 ; and 
 Y is selected from the group consisting of N(Rz)R2 or NR{circumflex over ( )}OR{circumflex over ( )}, wherein each Rz is independently selected from the group consisting of C 1 -C 6  alkyl, heteroalkyl, cycloalkyl and cycloheteroalkyl, straight or branched chain or optionally substituted, or both Rz and R2 taken together with the attached nitrogen form an optionally substituted heterocycle; where each R{circumflex over ( )} is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cyclohexyl, and cycloheteroalkyl, each of which is optionally substituted, or both R{circumflex over ( )} are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle 
 
     
     
         9 . The method as set forth in  claim 7  further comprising administering at least one additional therapeutic agent to the subject. 
     
     
         10 . The method as set forth in  claim 9 , wherein the additional therapeutic agent is selected from the group consisting of an anti-VEGF treatment, vitamins, minerals and combinations thereof. 
     
     
         11 . The method as set forth in  claim 10 , wherein the anti-VEGF treatment is selected from the group consisting of ranibizumab, bevacizumab, aflibercept, and combinations thereof. 
     
     
         12 . A method of treating wet age-related macular degeneration (AMD) in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. 
     
     
         13 . The method as set forth in  claim 12 , wherein the APE1/Ref-1 inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, alkoxy, hydroxyl, and hydrogen; R 3  and R 6  are independently selected from the group consisting of a substituted or unsubstituted alkoxy, a substituted or unsubstituted aryl and an oxo; R 4  and R 5  are independently selected from the group consisting of an alkoxy and aryl, or both R 4  and R 5  taken together form a substituted or unsubstituted napthoquinone;
 X is selected from the group consisting of CH═CR 2  and NCH, wherein R 2  is selected from the group consisting of C 1 -C 10  alkyl and CF 3 CH 2 CH 2 ; and 
 Y is selected from the group consisting of N(Rz)R2 or NR{circumflex over ( )}OR{circumflex over ( )}, wherein each Rz is independently selected from the group consisting of C 1 -C 6  alkyl, heteroalkyl, cycloalkyl and cycloheteroalkyl, straight or branched chain or optionally substituted, or both Rz and R2 taken together with the attached nitrogen form an optionally substituted heterocycle; where each R{circumflex over ( )} is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cyclohexyl, and cycloheteroalkyl, each of which is optionally substituted, or both R{circumflex over ( )} are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle 
 
     
     
         14 . The method as set forth in  claim 12  further comprising administering at least one additional therapeutic agent to the subject. 
     
     
         15 . The method as set forth in  claim 14 , wherein the additional therapeutic agent is selected from the group consisting of an anti-VEGF treatment, vitamins, minerals and combinations thereof. 
     
     
         16 . The method as set forth in  claim 15 , wherein the anti-VEGF treatment is selected from the group consisting of ranibizumab, bevacizumab, aflibercept, and combinations thereof.