Compositions, formulations and methods for treating ocular diseases
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. Combination therapy with antibodies and PK/PD data are also disclosed.
1. A method of treating an ocular condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound that activates Tie-2, wherein the compound is 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, and an agent that increases aqueous solubility of the compound that activates Tie-2, or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof as compared to solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof in absence of the agent, wherein the agent that increases solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof increases aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof by at least 10% at each of 5° C., ambient temperature, and 50° C., wherein the agent is a cyclodextrin.
2. The method of claim 1 , wherein the agent that improves the aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof comprises a 2-hydroxypropyl-β-cyclodextrin moiety.
3. The method of claim 1 , wherein the agent that improves the aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof comprises a sulfobutylether-β-cyclodextrin moiety.
4. The method of claim 1 , wherein the agent that improves the aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof comprises a surfactant moiety.
5. The method of claim 1 , wherein the agent that increases solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof increases aqueous solubility by at least 25%.
6. The method of claim 1 , wherein the agent that increases solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof increases aqueous solubility by at least 50%.
7. The method of claim 1 , wherein the therapeutically-effective amount is from about 0.1 mg to about 100 mg.
8. The method of claim 1 , wherein the therapeutically-effective amount is from about 0.5 mg to about 30 mg.
9. The method of claim 1 , wherein the compound that activates Tie-2, or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof, and the agent that improves the aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt thereof are coadministered in a unit dosage form.
10. The method of claim 9 , wherein the unit dosage form is administered subcutaneously.
11. The method of claim 9 , wherein the unit dosage form is administered to an eye.
12. The method of claim 1 , wherein the ocular condition is diabetic macular edema.
13. The method of claim 1 , wherein the ocular condition is diabetic retinopathy.
14. The method of claim 1 , wherein the ocular condition is macular degeneration.
15. The method of claim 1 , wherein the ocular condition is vascular leak in an eye of the subject.
16. The method of claim 1 , wherein the subject is a human.
17. The method of claim 1 , wherein:
Aryl 1 is substituted or unsubstituted phenyl;
Aryl 2 is substituted or unsubstituted heteroaryl; and
X is alkylene.
18. The method of claim 17 , wherein:
Aryl 1 is substituted phenyl;
Aryl 2 is substituted heteroaryl; and
X is methylene.
19. The method of claim 18 , wherein the compound that activates Tie-2 is a compound of the formula:
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.
20. The method of claim 19 , wherein:
Aryl 1 is para-substituted phenyl;
Aryl 2 is a substituted thiazole moiety;
X is methylene;
L 2 together with the nitrogen atom to which L 2 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.
21. The method of claim 20 , 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.
22. The method of claim 21 , 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.
23. The method of claim 21 , 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.
24. The method of claim 21 , 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.
25. The method of claim 1 , wherein the compound is:
26. The method of claim 1 , wherein the compound is:
27. The method of claim 21 , 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 alkyl.
28. The method of claim 1 , wherein the compound is:
29. The method of claim 18 , wherein the compound is:
30. The method of claim 20 , 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.
31. The method of claim 30 , 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.
32. The method of claim 30 , 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.
33. The method of claim 30 , 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.
34. The method of claim 1 , wherein the compound is:
35. The method of claim 1 , wherein the compound is:
36. The method of claim 26 , wherein the agent that improves the aqueous solubility of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof comprises a 2-hydroxypropyl-β-cyclodextrin moiety.
37. The method of claim 36 , wherein the condition is diabetic macular edema.
38. The method of claim 37 , wherein a plasma concentration in the subject of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof is no greater than 500 ng/mL at about 0.25 hours after the administration.
39. The method of claim 37 , wherein a plasma concentration in the subject of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof is about 50 ng/mL to about 350 ng/mL at about 0.25 hours after the administration; about 30 ng/mL to about 350 ng/mL at about 1 hour after the administration; about 10 ng/mL to about 200 ng/mL at about 2 hours after the administration; and about 0 ng/mL to about 50 ng/mL at about 4 hours after the administration.
40. The method of claim 37 , wherein a plasma concentration in the subject of the compound that activates Tie-2 or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof is:
a) for administration of a dose of about 5 mg, about 50 ng/mL to about 100 ng/mL at about 0.25 hours after the administration; about 30 ng/mL to about 80 ng/mL at about 1 hour after the administration; about 10 ng/mL to about 50 ng/mL at about 2 hours after the administration; and about 0 ng/mL to about 30 ng/mL at about 4 hours after the administration;
b) for administration of a dose of about 15 mg, about 120 ng/mL to about 180 ng/mL at about 0.25 hours after the administration; about 70 ng/mL to about 130 ng/mL at about 1 hour after the administration; about 20 ng/mL to about 70 ng/mL at about 2 hours after the administration; and about 0 ng/mL to about 40 ng/mL at about 4 hours after the administration;
c) for administration of a dose of about 22.5 mg, about 190 ng/mL to about 250 ng/mL at about 0.25 hours after the administration; about 170 ng/mL to about 240 ng/mL at about 1 hour after the administration; about 70 ng/mL to about 120 ng/mL at about 2 hours after the administration; and about 10 ng/mL to about 60 ng/mL at about 4 hours after the administration; and
d) for administration of a dose of about 30 mg, about 250 ng/mL to about 330 ng/mL at about 0.25 hours after the administration; about 270 ng/mL to about 330 ng/mL at about 1 hour after the administration; about 130 ng/mL to about 180 ng/mL at about 2 hours after the administration; and about 25 ng/mL to about 75 ng/mL at about 4 hours after the administration.
41. The method of claim 1 , wherein the administration is topical.
42. The method of claim 1 , wherein the administration is topical to an eye of the subject.
43. The method of claim 9 , wherein the unit dosage form is administered topically.
44. The method of claim 9 , wherein the unit dosage form is administered topically to an eye of the subject.
45. The method of claim 9 , wherein the unit dosage form is formulated as a drop.
46. The method of claim 9 , wherein the unit dosage form is formulated as a drop, wherein the drop is administered to an eye of the subject.
47. The method of claim 9 , wherein the unit dosage form is administered topically to an eye of the subject, wherein the therapeutically-effective amount of the compound that activates Tie-2, or the pharmaceutically-acceptable salt, tautomer, or zwitterion thereof is from about 15 mg to about 30 mg.
48. The method of claim 47 , wherein the unit dosage form is formulated as a drop.
49. The method of claim 48 , wherein the compound is:
50. The method of claim 49 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
51. The method of claim 50 , wherein the therapeutically-effective amount is about 30 mg.
52. The method of claim 50 , wherein the therapeutically-effective amount is about 15 mg.
53. The method of claim 48 , wherein the compound is:
54. The method of claim 53 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
55. The method of claim 54 , wherein the therapeutically-effective amount is about 30 mg.
56. The method of claim 54 , wherein the therapeutically-effective amount is about 15 mg.
57. The method of claim 48 , wherein the compound is:
58. The method of claim 57 , wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
59. The method of claim 58 , wherein the therapeutically-effective amount is about 30 mg.
60. The method of claim 58 , wherein the therapeutically-effective amount is about 15 mg.