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 III′:
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 3 -C 30 alkenylR 16 , —NH—C 3 -C 30 alkynylR 16 , and —NH—C 5 —C 30 alkenylalkynylR 16 ,
(ii) an amine linked polypropylene glycol, an amine or amide linked polypropylene oxide, an amine or amide linked polylactic acid, an amine or amide linked poly(lactic-co-glycolic acid),
an amine or amide linked polyglycolic acid, a polyester, and a polyamide;
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; and
(iii) polypropylene glycol, polypropylene oxide, polylactic acid, poly(lactic-co-glycolic acid),
and polyglycolic acid;
R 17 is H or —C(O)A;
A is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
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 selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 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.
11. The compound of claim 9 , wherein x is 2 or 3.
12. The compound of claim 9 , wherein x is 4, 5, or 6.
13. The compound of claim 9 , wherein x is 7, 8, 9, or 10.
14. The compound of claim 9 , wherein x is 11, 12, 13, or 14.
15. The compound of claim 1 , wherein R 42 is
16. The compound of claim 15 , wherein R 15 is hydrogen.
17. The compound of claim 16 , wherein x is 1.
18. The compound of claim 16 , wherein x is 2 or 3.
19. The compound of claim 16 , wherein x is 4, 5, or 6.
20. The compound of claim 16 , wherein x is 7, 8, 9, or 10.
21. The compound of claim 16 , wherein x is 11, 12, 13, or 14.
22. The compound of claim 1 of formula:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 of formula:
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 of formula:
or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
26. 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.
27. The method according to claim 26 , wherein the disorder is glaucoma.
28. The method of claim 26 , wherein the disorder is related to an increase in intraocular pressure (IOP).
29. The method of claim 26 , wherein the age-related macular degeneration is wet age-related macular degeneration.
30. The method of claim 26 , wherein the host is a human.
31. The method of claim 28 , wherein the disorder is optic nerve damage caused by high intraocular pressure (IOP).
32. The method of claim 26 , wherein the compound is administered via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, epi scleral, posterior juxtascleral, circumcorneal, or tear duct injection.
33. The method of claim 32 , wherein the compound is administered via intravitreal injection.
34. The method of claim 32 , wherein the compound is administered via subchoroidal injection.