FORMULATIONS OF TIE-2 ACTIVATORS AND METHODS OF USE THEREOF
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.