Formulations of tie-2 activators and methods of use thereof

Abstract

Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTPβ. Further disclosed are formulations to increase the efficacy of the compounds that activate Tie-2 and inhibit HPTPβ.

1 .- 127 . (canceled) 
     
     
         128 . A pharmaceutical composition comprising, in a unit dosage form: a Tie-2 activator; and a pharmaceutically-acceptable excipient that releases the Tie-2 activator from the unit dosage form at a rate that is about zero order with respect to the Tie-2 activator;
 wherein the Tie-2 activator is a compound of the formula:   
       
         
           
           
               
               
           
         
         wherein: 
         Aryl 1  is an aryl group which is substituted or unsubstituted; Aryl 2  is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or 
       
       
         
           
           
               
               
           
         
          wherein:
 L 2  is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2  is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R a  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R b  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R c  is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d  forms a ring that is substituted or unsubstituted; 
 R d  is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R c  forms a ring that is substituted or unsubstituted; and 
 R g  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, 
 
         or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof. 
       
     
     
         129 . The pharmaceutical composition of  claim 128 , wherein:
 Aryl 1  is substituted or unsubstituted phenyl;   Aryl 2  is substituted or unsubstituted heteroaryl; and   X is alkylene.   
     
     
         130 . The pharmaceutical composition of  claim 128 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein
 Aryl 1  is para-substituted phenyl; 
 Aryl 2  is substituted heteroaryl; 
 X is methylene; 
 L 2  is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2  is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond; 
 R a  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; 
 R b  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; 
 R c  is H or alkyl which is substituted or unsubstituted; and 
 R d  is H or alkyl which is substituted or unsubstituted. 
 
     
     
         131 . The pharmaceutical composition of  claim 130 , wherein Aryl 2  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R e  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and 
 R f  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. 
 
     
     
         132 . The pharmaceutical composition of  claim 128 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt or zwitterion thereof. 
       
     
     
         133 . The pharmaceutical composition of  claim 128 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt or zwitterion thereof. 
       
     
     
         134 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutical composition is in the form of a solution, a drop, or a gel. 
     
     
         135 . The pharmaceutical composition of  claim 134 , wherein the pharmaceutical composition is in the form of a solution. 
     
     
         136 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutical composition is formulated for administration to an eye. 
     
     
         137 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutical composition is formulated for intravenous administration, intravitreal administration, or intraocular administration. 
     
     
         138 . The pharmaceutical composition of  claim 137 , wherein the pharmaceutical composition is formulated for intravitreal administration. 
     
     
         139 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutically-acceptable excipient releases the Tie-2 activator from the unit dosage form without an initial burst of the Tie-2 activator. 
     
     
         140 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutically-acceptable excipient releases the Tie-2 activator from the unit dosage form over a period of at least one month. 
     
     
         141 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutically-acceptable excipient is a biodegradable polymer. 
     
     
         142 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutically-acceptable excipient is a cellulose. 
     
     
         143 . The pharmaceutical composition of  claim 128 , wherein the pharmaceutically-acceptable excipient is hydrophobically modified poly(vinylpyrrolidone). 
     
     
         144 . The pharmaceutical composition of  claim 128 , wherein the Tie-2 activator is an inhibitor of HPTPβ. 
     
     
         145 . A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a pharmaceutical composition of  claim 128 . 
     
     
         146 . The method of  claim 145 , wherein the administering is by intravitreal administration. 
     
     
         147 . The method of  claim 145 , wherein the condition is selected from the group consisting of vision loss, acute kidney injury, influenza, myocardial ischemia, macular degeneration, glaucoma, and primary open angle glaucoma.