Compositions and methods for treating ocular diseases

Abstract

Disclosed herein are compositions and methods for treating ocular diseases, inter alia, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, uveitis, and the like. These diseases or conditions are characterized by changes in the ocular vasculature whether progressive or non-progressive, whether a result of an acute disease or condition, or a chronic disease or condition.

1 - 172 . (canceled) 
     
     
         173 . A method for treating an ocular condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a HPTP-β inhibitor; and
 a therapeutically-effective amount of an anti-VEGF agent, wherein the anti-VEGF agent is ranibizumab, bevacizumab, or aflibercept. 
 
     
     
         174 . The method of  claim 173 , wherein the HPTP-β inhibitor has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R is a substituted or unsubstituted thiazolyl unit having the formula: 
       
         
           
           
               
               
           
         
         R 2 , R 3 , and R 4  are each independently: 
         i) hydrogen; 
         ii) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkyl; 
         iii) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkenyl; 
         iv) substituted or unsubstituted C 2 -C 6  linear or branched alkynyl; 
         v) substituted or unsubstituted C 6  or C 10  aryl; 
         vi) substituted or unsubstituted C 1 -C 9  heteroaryl; 
         vii) substituted or unsubstituted C 1 -C 9  heterocyclic; or 
         viii) R 2  and R 3  taken together to form a saturated or unsaturated ring having from 5 to 7 atoms; 
         wherein from 1 to 3 atoms can optionally be oxygen, nitrogen, or sulfur; 
         Z is a unit having the formula:
   -(L) n -R 1    
 
         R 1  is: 
         i) hydrogen; 
         ii) hydroxyl; 
         iii) amino; 
         iv) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkyl; 
         v) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkoxy; 
         vi) substituted or unsubstituted C 6  or C 10  aryl; 
         vii) substituted or unsubstituted C 1 -C 9  heterocyclic rings; or 
         viii) substituted or unsubstituted C 1 -C 9  heteroaryl rings; 
         L is a linking unit having the formula:
   -[Q] y [C(R 5a R 5b )] x [Q 1 ] z [C(R 6a R 6b )] w —
 
 
         Q and Q 1  are each independently: 
         i) —C(O)—; 
         ii) —NH—; 
         iii) —C(O)NH—; 
         iv) —NHC(O)—; 
         v) —NHC(O)NH—; 
         vi) —NHC(O)O—; 
         vii) —C(O)O—; 
         viii) —C(O)NHC(O)—; 
         ix) —O—; 
         x) —S—; 
         xi) —SO 2 —; 
         xii) —C(═NH)—; 
         xiii) —C(═NH)NH—; 
         xiv) —NHC(═NH)—; or 
         xv) —NHC(═NH)NH—; 
         R 5a  and R 5b  are each independently: 
         i) hydrogen; 
         ii) hydroxy; 
         iii) halogen; 
         iv) substituted or unsubstituted C 1 -C 6  linear or C 3 -C 6  branched alkyl; or 
         v) a unit having the formula:
   —[C(R 7a R 7b )] t R 8  
 
 
         R 7a  and R 7b  are each independently: 
         i) hydrogen; or 
         ii) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkyl; 
         R 8  is: 
         i) hydrogen; 
         ii) substituted or unsubstituted C 1 -C 6  linear, C 3 -C 6  branched, or C 3 -C 6  cyclic alkyl; 
         iii) substituted or unsubstituted C 6  or C 10  aryl; 
         iv) substituted or unsubstituted C 1 -C 9  heteroaryl; or 
         v) substituted or unsubstituted C 1 -C 9  heterocyclic; 
         R 6a  and R 6b  are each independently: 
         i) hydrogen; or 
         ii) C 1 -C 4  linear or C 3 -C 4  branched alkyl; 
         the index n is 0 or 1; the indices t, w, and x are each independently from 0 to 4; the indices y and z are each independently 0 or 1; or a pharmaceutically acceptable salt thereof. 
       
     
     
         175 . The method of  claim 173 , wherein the ocular condition is glaucoma. 
     
     
         176 . The method of  claim 173 , wherein the therapeutically-effective amount of the HPTP-β inhibitor is from about 0.5 mg to about 30 mg per treatment. 
     
     
         177 . The method of  claim 173 , wherein the therapeutically-effective amount of the HPTP-β inhibitor is from about 15 mg per treatment. 
     
     
         178 . The method of  claim 173 , wherein the anti-VEGF agent is ranibizumab. 
     
     
         179 . The method of  claim 177 , wherein the therapeutically-effective amount of ranibizumab is about 0.05 mg to about 1.5 mg. 
     
     
         180 . The method of  claim 173 , wherein the anti-VEGF agent is bevacizumab. 
     
     
         181 . The method of  claim 179 , wherein the therapeutically-effective amount of bevacizumab is about 0.1 mg to about 5 mg. 
     
     
         182 . The method of  claim 173 , wherein the anti-VEGF agent is aflibercept. 
     
     
         183 . The method of  claim 181 , wherein the therapeutically-effective amount of aflibercept is about 0.05 mg to about 5 mg. 
     
     
         184 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is subcutaneous. 
     
     
         185 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is topical. 
     
     
         186 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is subcutaneous. 
     
     
         187 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is intravitreal. 
     
     
         188 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is subconjunctival. 
     
     
         189 . The method of  claim 173 , wherein the administering of the HPTP-β inhibitor is to an eye of the subject. 
     
     
         190 . The method of  claim 173 , wherein the HPTP-β inhibitor is formulated as a drop. 
     
     
         191 . The method of  claim 173 , wherein the HPTP-β inhibitor is formulated as a drop, wherein the drop is administered to an eye of the subject. 
     
     
         192 . The method of  claim 173 , wherein the administration reduces central foveal thickness in an eye of the subject. 
     
     
         193 . The method of  claim 173 , wherein the subject is human. 
     
     
         194 . The method of  claim 173 , wherein the administering of the anti-VEGF agent is intravitreal. 
     
     
         195 . The method of  claim 173 , wherein the therapeutically-effective amount of the HPTP-3 inhibitor is from about 0.5 mg to about 30 mg per treatment, wherein the administering of the HPTP-β inhibitor is topical, wherein the HPTP-β inhibitor is formulated as a drop, wherein the therapeutically-effective amount of the anti-VEGF agent is about 0.05 mg to about 5 mg, and wherein the administering of the anti-VEGF agent is intravitreal. 
     
     
         196 . The method of  claim 195 , wherein the ocular condition is glaucoma.