Compounds and compositions for the treatment of ocular disorders

1. A compound of Formula IV′:

or a pharmaceutically acceptable salt thereof;

wherein:

R 42 is selected from

(i) —N═CH—C 3 -C 30 alkenylR 5 , —N═CH—C 3 -C 30 alkynylR 5 , —N═CH—C 3 -C 30 alkenylalkynylR 5 , —N═C 1 -C 30 alkylR 5 , —N═CH—C 3 -C 30 alkenyl, —N═CH—C 3 -C 30 alkynyl, —N═CH—C 3 -C 30 alkenylalkynyl, —N═C 1 -C 30 alkyl, —NHC 3 -C 30 alkenylR 5 , —NH—C 3 -C 30 alkynylR 5 , —NH—C 5 -C 30 alkenylalkynylR 5 , —NHC 0 -C 30 alkylR 5 , —NHC 3 -C 30 alkenylR 16 , —NH—C 3 -C 30 alkynylR 16 , —NH—C 5 -C 30 alkenylalkynylR 16 , and —NHC 0 -C 30 alkylR 16 ;

(ii) an imine, amine or amide linked unsaturated fatty acid residue selected from a derivative of linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, alpha-linolenic acid, stearidonic acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, euric acid, nervonic acid and mead acid;

(iii) an amine or amide linked polypropylene glycol, an amine or amide linked polypropylene oxide, an amine or amide linked polylactic acid, an amine or amide linked polylactic-co-glycolic acid),

an amine or amide linked polyglycolic acid, a polyester, and a polyamide; or

(iv) —NHC(O)C 1-20 alkyl, —NHC(O)C 1-20 alkenyl, —NHC(O)C 1-20 alkynyl, —NHC(O)(C 1-20 alkyl with at least one R 5 substituent on the alkyl chain), —NHC(O)(C 1-20 alkenyl with at least one R 5 substituent on the alkenyl chain) —NHC(O)(C 1-20 alkynyl with at least one R 5 substituent on the alkynyl chain), —NH(lactic acid) 2-20 C(O)C 1-20 alkyl, —NH(lactic acid) 2-10 C(O)C 1-20 alkyl, —NH(lactic acid) 4-20 C(O)C 1-20 alkyl, —NH(lactic acid) 2-20 C(O)C 1-10 alkyl, —NH(lactic acid) 2-20 C(O)C 4-10 alkyl, —NH(lactic acid) 2-20 C(O)OH, —NH(lactic acid) 2-10 C(O)OH, —NH(lactic acid) 4-20 C(O)OH, —NH(lactic acid) 2-10 C(O)OH, —NH(lactic acid) 4-10 C(O)OH, —NH(lactide-co-glycolide) 2-10 C(O)C 1-20 alkyl, —NH(lactide-co-glycolide) 4-10 C(O)C 1-20 alkyl, —NH(lactide-co-glycolide) 2-10 C(O)C 1-10 alkyl, —NH(lactide-co-glycolide) 2-10 C(O)C 4-20 alkyl, —NH(glycolic acid) 2-10 C(O)C 1-10 alkyl, —NH(glycolic acid) 4-10 C(O)C 1-10 alkyl, —NH(lactic acid) 4-10 C(O)C 1-10 alkyl, —NH(lactic acid) 2-10 C(O)C 1-10 alkyl, NH(lactic acid) 2-10 C(O)C 4-10 alkyl, —NH(lactic acid) 2-10 C(O)C 4-10 alkyl, and —NH(lactic acid) 2-10 C(O)C 4-10 alkyl;

R 15 is R 17 ;

R 16 is selected from:

(i) —C(O)C 3 -C 30 alkylR 5 , —C(O)C 3 -C 30 alkenylR 5 , —C(O)C 3 -C 30 alkynylR 5 , —C(O)C 3 -C 30 alkenylalkynylR 5 , —C(O)C 3 -C 30 alkyl, —C(O)C 3 -C 30 alkenyl, —C(O)C 3 -C 30 alkynyl, and —C(O)C 3 -C 30 alkenylalkynyl;

(ii) an unsaturated fatty acid residue selected from linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, alpha-linolenic acid, stearidonic acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, euric acid, nervonic acid, and mead acid; or

(iii) polyethylene glycol, polypropylene glycol, polypropylene oxide, polylactic acid, poly(lactic-co-glycolic acid)

polyglycolic acid, or a polyester, poly amide, or other biodegradable polymer;

R 17 is H or —C(O)A;

A is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, and alkyloxy;

R 5 is selected from halogen, hydroxyl, cyano, mercapto, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, —S(O) 2 alkyl, —S(O)alkyl, —P(O)(Oalkyl) 2 , B(OH) 2 , —Si(CH 3 ) 3 , —COOH, —COOalkyl, and —CONH 2 ; and

x and y are selected from an integer between 1 and 30.

2. The compound of claim 1 , wherein x is 1, 2, or 3.

3. The compound of claim 1 , wherein x is 4 or 5.

4. The compound of claim 1 , where x is 6.

5. The compound of claim 1 , wherein x is 7, 8, 9, or 10.

6. The compound of claim 1 , wherein x is 11, 12, 13, or 14.

7. The compound of claim 1 , wherein R 15 is hydrogen.

8. The compound of claim 1 ,

wherein

R 42 is

9. The compound of claim 8 , wherein R 15 is hydrogen.

10. The compound of claim 9 , wherein x is 1, 2, or 3.

11. The compound of claim 9 , wherein x is 4, 5, or 6.

12. The compound of claim 9 , wherein x is 7, 8, 9, or 10.

13. The compound of claim 9 , wherein x is 11, 12, 13, or 14.

14. The compound of claim 1 , wherein R 42 is

15. The compound of claim 14 , wherein R 15 is hydrogen.

16. The compound of claim 15 , wherein x is 1, 2, or 3.

17. The compound of claim 15 , wherein x is 4, 5, or 6.

18. The compound of claim 15 , wherein x is 7, 8, 9, or 10.

19. The compound of claim 15 , wherein x is 11, 12, 13, or 14.

20. The compound of claim 1 , wherein R 42 is selected from —NH(lactide-co-glycolide) 2-10 C(O)C 1-20 alkyl, —NH(lactide-co-glycolide) 4-10 C(O)C 1-20 alkyl, —NH(lactide-co-glycolide) 2-10 C(O)C 1-10 alkyl, and —NH(lactide-co-glycolide) 2-10 C(O)C 4-20 alkyl.

21. The compound of claim 20 , wherein R 42 is —NH(lactide-co-glycolide) 2-10 C(O)C 1-20 alkyl.

22. The compound of claim 21 , wherein R 15 is hydrogen.

23. The compound of claim 20 , wherein R 42 is —NH(lactide-co-glycolide) 4-10 C(O)C 1-20 alkyl.

24. The compound of claim 23 , wherein R 15 is hydrogen.

25. The compound of claim 20 , wherein R 42 is —NH(lactide-co-glycolide) 2-10 C(O)C 1-10 alkyl.

26. The compound of claim 25 , wherein R 15 is hydrogen.

27. The compound of claim 20 , wherein R 42 is —NH(lactide-co-glycolide) 2-10 C(O)C 4-20 alkyl.

28. The compound of claim 27 , wherein R 15 is hydrogen.

29. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.

35. A method for the treatment of an ocular disorder treatable with a carbonic anhydrase 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.

36. The method of claim 35 , wherein the host is a human.

37. The method of claim 36 , wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).

38. The method of claim 36 , 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.

39. The method of claim 38 , wherein the compound is administered via intravitreal injection.

40. A compound of Formula:

or a pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising a compound of claim 40 in a pharmaceutically acceptable carrier.

42. A method for the treatment of an ocular disorder treatable with a carbonic anhydrase inhibitor comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of claim 40 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.

43. The method of claim 42 , wherein the host is a human.

44. The method of claim 43 , wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).

45. The method of claim 43 , 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.

46. The method of claim 45 , wherein the compound is administered via intravitreal injection.

47. The method according to claim 36 , wherein the disorder is glaucoma.

48. The method according to claim 36 , wherein the disorder is related to an increase in intraocular pressure (IOP).

49. The method according to claim 43 , wherein the disorder is glaucoma.

50. The method according to claim 43 , wherein the disorder is related to an increase in intraocular pressure (IOP).