HPTP-β inhibitors
View Patent ↗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. A compound of formula:
wherein:
Aryl 1 is a phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted; and
Y is aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, 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.
2. The compound of claim 1 , wherein:
X is alkylene.
3. The compound of claim 2 , wherein:
X is methylene.
4. The compound of claim 3 , wherein the compound is of the formula:
wherein
X is methylene;
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;
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.
5. The compound of claim 4 , wherein the compound is of the formula:
6. The compound of claim 4 , wherein the compound is of the formula:
7. The compound of claim 4 , wherein:
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.
8. The compound of claim 7 , wherein Aryl 2 is:
9. The compound of claim 8 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, an alkoxy 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, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
10. The compound of claim 8 , wherein:
R e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and
R f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.
11. The compound of claim 8 , 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.
12. The compound of claim 1 , wherein the compound is:
13. The compound of claim 1 , wherein the compound is:
14. A pharmaceutical composition comprising two Tie-2 activators, wherein the two Tie-2 activators are stereoisomers of one another, wherein one of the Tie-2 activators is a compound of the formula:
wherein:
Aryl 1 is a phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted; and
Y is aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, 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; and
wherein the pharmaceutical composition is in a unit dosage form.
15. The pharmaceutical composition of claim 14 , wherein the stereoisomers are enantiomers of one another.
16. The pharmaceutical composition of claim 14 , wherein the stereoisomers are diastereomers of one another.
17. The pharmaceutical composition of claim 14 , wherein the two Tie-2 activators bind HPTP-beta.
18. The pharmaceutical composition of claim 14 , wherein the two Tie-2 activators inhibit HPTP-beta.
19. The pharmaceutical composition of claim 14 , wherein one of the Tie-2 activators is present in an amount that is no greater than 1% of the amount of the other Tie-2 activator.
20. The pharmaceutical composition of claim 14 , wherein one of the Tie-2 activators is a compound of the formula:
or a pharmaceutically-acceptable salt or zwitterion thereof.
21. The pharmaceutical composition of claim 14 , wherein the other of the Tie-2 activators is a compound of the formula:
or a pharmaceutically-acceptable salt or zwitterion thereof.
22. A pharmaceutical composition comprising a Tie-2 activator and a stereoisomer of the Tie-2 activator, wherein the stereoisomer of the Tie-2 activator is a compound of the formula:
wherein:
Aryl 1 is a phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted; and
Y is aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, 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; and
wherein the stereoisomer activates Tie-2 with a potency that is from about 0.001% to about 100% the potency of the Tie-2 activator.
23. The pharmaceutical composition of claim 22 , wherein the stereoisomer of the Tie-2 activator is an enantiomer of the Tie-2 activator.
24. The pharmaceutical composition of claim 22 , wherein the stereoisomer of the Tie-2 activator is a diastereomer of the Tie-2 activator.
25. The pharmaceutical composition of claim 22 , wherein the stereoisomer activates Tie-2 with a potency that is from about 0.01% to about 10% the potency of the Tie-2 activator.
26. The pharmaceutical composition of claim 22 , wherein the stereoisomer activates Tie-2 with a potency that is from about 0.01% to about 1% the potency of the Tie-2 activator.
27. The pharmaceutical composition of claim 22 , wherein the stereoisomer activates Tie-2 with a potency that is from about 0.01% to about 0.5% the potency of the Tie-2 activator.
28. The pharmaceutical composition of claim 22 , wherein the stereoisomer binds HPTP-beta.
29. The pharmaceutical composition of claim 22 , wherein the stereoisomer inhibits HPTP-beta.
30. The pharmaceutical composition of claim 22 , wherein the Tie-2 activator is a compound of the formula:
wherein:
Aryl 1 is a phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted; and
Y is aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, 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 or zwitterion thereof.
31. The pharmaceutical composition of claim 22 , wherein the stereoisomer of the Tie-2 activator is a compound of the formula:
or a pharmaceutically-acceptable salt or zwitterion thereof.
32. The pharmaceutical composition of claim 22 , wherein the Tie-2 activator is a compound of the formula:
or a pharmaceutically-acceptable salt or zwitterion thereof.
33. A method comprising contacting with a reagent a compound of formula:
wherein:
Aryl 1 is a phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted;
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 e , 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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, R a , R b , and R e 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 salt, tautomer, or zwitterion thereof,
wherein a stereocenter of the compound or salt thereof inverts, thereby providing a stereoisomer of the compound or a salt, tautomer, or zwitterion of the stereoisomer, wherein the stereoisomer is a compound of the formula:
wherein:
Aryl 1 is a substituted carbocyclic aryl group phenylsulfamic acid group;
Aryl 2 is
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether 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;
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;
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, or a sulfone linkage, any of which is substituted or unsubstituted; and
Y is aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
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;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L, 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.
34. The method of claim 33 , wherein the reagent is a base.
35. The method of claim 33 , wherein the compound is:
36. The method of claim 35 , wherein the stereoisomer is: