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 pharmaceutical composition comprising:
 a) a therapeutically-effective amount of a compound that enhances Ang1-induced phosphorylation of Tie2; and   b) a cyclodextrin,   
       wherein the composition is formulated as a unit dosage form. 
     
     
         174 . The composition of  claim 173 , wherein the therapeutically-effective amount of the compound is from about 5 mg to about 50 mg per dose. 
     
     
         175 . The composition of  claim 173 , wherein the therapeutically-effective amount of the compound is from about 0.5 mg to about 30 mg per dose. 
     
     
         176 . The composition of  claim 173 , wherein the therapeutically-effective amount of the compound is from about 1 mg to about 20 mg per dose. 
     
     
         177 . The composition of  claim 173 , The composition of  claim 173 , wherein the therapeutically-effective amount of the compound is about 1 mg. 
     
     
         178 . The composition of  claim 173 , formulated as an eye drop. 
     
     
         179 . The composition of  claim 173 , formulated as a drop. 
     
     
         180 . The composition of  claim 173 , wherein the compound 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  heterocyclyl; 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  heterocyclyl; or 
 viii) substituted or unsubstituted C 1 -C 9  heteroaryl; 
 
       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  heterocyclyl; 
 
       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 or zwitterion thereof. 
     
     
         181 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         182 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         183 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         184 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         185 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         186 . The composition of  claim 173 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof. 
     
     
         187 . The composition of  claim 173 , wherein the compound is a pharmaceutically-acceptable salt that has a lithium counterion. 
     
     
         188 . The composition of  claim 173 , wherein the compound is a pharmaceutically-acceptable salt that has a sodium counterion. 
     
     
         189 . The composition of  claim 173 , wherein the cyclodextrin is a β-cyclodextrin. 
     
     
         190 . The composition of  claim 173 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. 
     
     
         191 . A pharmaceutical composition comprising:
 a) a therapeutically-effective amount of a compound having the formula:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof; and
 b) hydroxypropyl-β-cyclodextrin. 
 
     
     
         192 . A pharmaceutical composition comprising:
 a) about 1 mg of a compound having the formula:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or zwitterion thereof; and
 b) hydroxypropyl-β-cyclodextrin, 
 
       wherein the composition is formulated as a unit dosage form.