Hptp-beta inhibitors

Abstract

Disclosed herein are compounds effective for activation of Tie-2 and inhibition of HPTP-beta. The compounds can provide effective therapy for conditions associated with angiogenesis, for example, ocular conditions. Formulations for increased solubility are disclosed.

1 - 49 . (canceled) 
     
     
         50 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 Aryl 1  is phenyl that is substituted or unsubstituted; 
 Aryl 2  is a substituted or unsubstituted thiazole moiety; 
 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 ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; 
 L is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L is bound forms an amide linkage, a carbamate linkage, a ureido 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, 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, 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, R b , and R d  forms a ring that is substituted or unsubstituted; and 
 R d  is H or alkyl which is substituted or unsubstituted, or together with any of L, R b , and R c  forms a ring that is substituted or unsubstituted, 
 
       or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof, wherein the compound has a purity of at least about 99.3%. 
     
     
         51 . The compound of  claim 50 , wherein:
 Aryl 1  is para-substituted phenyl;   X is methylene;   L together with the nitrogen atom to which L is bound forms a carbamate linkage;   R a  is alkyl, which is substituted or unsubstituted;   R b  is arylalkyl, which is substituted or unsubstituted;   R c  is H; and   R d  is H.   
     
     
         52 . The compound of  claim 51 , wherein Aryl 1  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 ureido 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 ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. 
 
     
     
         53 . The compound of  claim 52 , wherein:
 Aryl 1  is 4-phenylsulfamic acid;   R a  is alkyl, which is substituted or unsubstituted;   R b  is arylalkyl, which is substituted or unsubstituted;   R e  is H; and   R f  is heteroaryl.   
     
     
         54 . The compound of  claim 50 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The compound of  claim 50 , wherein the purity is chemical purity. 
     
     
         56 . The compound of  claim 50 , wherein the purity is optical purity. 
     
     
         57 . The compound of  claim 50 , wherein the purity is at least about 99.5%. 
     
     
         58 . The compound of  claim 50 , wherein the purity is at least about 99.9%. 
     
     
         59 . The compound of  claim 50 , wherein the compound is stable for at least about 4 weeks at about 25° C. or higher. 
     
     
         60 . The compound of  claim 50 , wherein the compound is stable for at least about 4 weeks at about 50° C. or higher. 
     
     
         61 . The compound of  claim 50 , wherein the compound is stable for at least about 3 months at about 25° C. or higher. 
     
     
         62 . The compound of  claim 50 , wherein the compound is formulated as a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically-effective amount of the compound, and a pharmaceutically-effective excipient. 
     
     
         63 . A method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Aryl 1  is phenyl that is substituted or unsubstituted; 
 Aryl 2  is a substituted or unsubstituted thiazole moiety; 
 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 ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; 
 L is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L is bound forms an amide linkage, a carbamate linkage, a ureido 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, 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, 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, R a , R b , and R d  forms a ring that is substituted or unsubstituted; and 
 R d  is H or alkyl which is substituted or unsubstituted, or together with any of L, R b , and R c  forms a ring that is substituted or unsubstituted, 
 
       or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof, wherein the compound has a purity of at least about 99.3%. 
     
     
         64 . The method of  claim 63 , wherein:
 Aryl 1  is para-substituted phenyl;   X is methylene;   L together with the nitrogen atom to which L is bound forms a carbamate linkage;   R a  is alkyl, which is substituted or unsubstituted;   R b  is arylalkyl, which is substituted or unsubstituted;   R c  is H; and   R d  is H.   
     
     
         65 . The method of  claim 64 , 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 ureido 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 ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. 
 
     
     
         66 . The method of  claim 65 , wherein:
 Aryl 1  is 4-phenylsulfamic acid;   R a  is alkyl, which is substituted or unsubstituted;   R b  is arylalkyl, which is substituted or unsubstituted;   R e  is H; and   R f  is heteroaryl.   
     
     
         67 . The method of  claim 63 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 63 , wherein the purity is chemical purity. 
     
     
         69 . The method of  claim 63 , wherein the purity is optical purity. 
     
     
         70 . The method of  claim 63 , wherein the purity is at least about 99.5%. 
     
     
         71 . The method of  claim 63 , wherein the purity is at least about 99.9%. 
     
     
         72 . The method of  claim 63 , wherein the compound is stable for at least about 4 weeks at about 25° C. or higher. 
     
     
         73 . The method of  claim 63 , wherein the compound is stable for at least about 4 weeks at about 50° C. or higher. 
     
     
         74 . The method of  claim 63 , wherein the compound is stable for at least about 3 months at about 25° C. or higher.