Compounds and compositions for the treatment of ocular disorders
The disclosure describes prodrugs and derivatives of prostaglandins, carbonic anhydrase inhibitors, kinase inhibitors, beta-adrenergic receptor antagonists and other drugs, as well as controlled delivery formulations containing such prodrugs and derivatives, for the treatment of ocular disorders.
1. A compound of Formula XIV:
or a pharmaceutically acceptable salt thereof;
wherein:
R 30 is selected from polyethylene glycol, polypropylene glycol, polypropylene oxide, polylactic acid, poly(lactic-co-glycolic acid),
R 31 is selected from hydrogen, A, —COOH, —C(O)A, aryl, alkyl, alkoxy, alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
aryloxy, polyethylene glycol, and
A is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, and alkyloxy; and
x is selected from an integer between 1 and 10.
2. The compound of claim 1 , wherein x is 1.
3. The compound of claim 1 , wherein x is 2, 3, 4, or 5.
4. The compound of claim 1 , wherein x is 6, 7, 8, or 9.
5. The compound of claim 1 , wherein x is 1, 2, or 3.
6. The compound of claim 1 ,
wherein:
R 31 is —C(O)A; and
A is aryloxy, alkyoxy, or alkyl.
7. The compound of claim 1 , wherein R 31 is
8. The compound of claim 1 ,
wherein:
R 30 is selected from
9. The compound of claim 8 , wherein R 30 is
10. The compound of claim 9 , wherein x is 1 or 2.
11. The compound of claim 9 , wherein x is 3.
12. The compound of claim 9 , wherein x is 4, 5, or 7.
13. The compound of claim 9 , where x is 8 or 9.
14. The compound of claim 9 , wherein x is 10.
15. The compound of claim 8 , wherein R 30 is
16. The compound of claim 15 ,
wherein:
R 31 is —C(O)A; and
A is aryloxy or alkoxy.
17. The compound of claim 16 , wherein x is 1, 2, 3, 4, or 5.
18. The compound of claim 16 , wherein x is 6, 7, 8, 9, or 10.
19. The compound of claim 8 , wherein R 30 is
20. The compound of claim 19 , wherein x is 1, 2, 3, 4, or 5.
21. The compound of claim 19 , wherein R 31 is —C(O)A.
22. The compound of claim 21 , wherein A is alkyl.
23. The compound of claim 19 , wherein R 31 is
24. The compound of claim 23 , wherein x is 1, 2, or 3.
25. The compound of claim 23 , wherein x is 4, 5, or 6.
26. The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 of the formula
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
32. A method for the treatment of an ocular disorder treatable with a tyrosine kinase inhibitor comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 1 to a host in need thereof wherein the disorder is selected from glaucoma, age-related macular degeneration (AMD), a disorder related to an increase in intraocular pressure (IOP), a disorder related to neuroprotection, or diabetic retinopathy.
33. The method of claim 32 , wherein the host is a human.
34. The method of claim 33 , wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).
35. The method of claim 33 , wherein the compound is administered via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, or tear duct injection.
36. The method of claim 35 , wherein the compound is administered via intravitreal injection.
37. The compound of formula:
or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition comprising a compound of claim 37 in a pharmaceutically acceptable carrier.
39. A method for the treatment of an ocular disorder treatable with a tyrosine kinase inhibitor comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 37 to a host in need thereof wherein the disorder is selected from glaucoma, age-related macular degeneration (AMD), a disorder related to an increase in intraocular pressure (IOP), a disorder related to neuroprotection, or diabetic retinopathy.
40. The method of claim 39 , wherein the host is a human.
41. The method of claim 40 , wherein the disorder is optic nerve damage caused by high intraocular pressure (TOP).
42. The method of claim 40 , wherein the compound is administered via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, circumcorneal, or tear duct injection.
43. The method of claim 42 , wherein the compound is administered via intravitreal injection.
44. The method according to claim 33 , wherein the disorder is glaucoma.
45. The method according to claim 33 , wherein the disorder is related to an increase in intraocular pressure (IOP).
46. The method according to claim 40 , wherein the disorder is glaucoma.
47. The method according to claim 40 , wherein the disorder is related to an increase in intraocular pressure (IOP).