Oculoselective drugs and prodrugs

1. A compound of Formula I:

wherein:

R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;

R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, or C 1 -C 10 alkoxy;

R 4 is H or W, provided that at least one of R 1 , R 2 , and R 4 is W;

R 5 is tetrahydrofuranyl,;

W is:

and

each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl;

or a stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R 1 and R 2 are each independently H or W.

3. A compound according to claim 1 of Formula Ia:

4. A compound according to claim 1 , wherein R 4 is W.

5. A compound according to claim 4 , wherein R 1 and R 2 are each H.

6. A compound according to claim 5 wherein R 3 is straight chain or branched C 1 -C 10 alkyl, R 5 is tetrahydrofuran-3-yl, and W is:

7. A compound according to claim 6 wherein W is:

8. A compound according to claim 4 wherein R 1 and R 2 are each aralkyl.

9. A compound according to claim 8 wherein R 4 is:

10. A compound according to claim 1 , wherein at least one of the R 6 substituents is other than H.

11. A compound according to claim 1 , wherein each R 6 is independently H,straight chain or branched C 1 -C 5 alkyl or straight chain or branched C 2 -C 6 alkoxyalkyl.

12. A compound according to claim 1 , wherein each R 6 is independently H, methyl, or CH 2 OCH 3 .

13. A compound according to claim 1 , wherein each W is independently:

14. A compound according to claim 5 , wherein each W is independently:

15. A compound according to claim 1 wherein R 3 is H or straight chain or branched C 1 -C 5 alkyl.

16. A compound according to claim 1 wherein R 3 is methyl.

17. A compound according to claim 1 , wherein R 5 is tetrahydrofuranyl.

18. A compound according to claim 17 , wherein R 5 is tetrahydrofuran-3-yl.

19. A compound according to claim 3 , wherein R 5 is tetrahydrofuran-3-yl.

20. A compound of Formula II:

wherein:

R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;

R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, or C 1 -C 10 alkoxy;

R 4 is H or W;

Z is —O— or —O(C═O)—;

R 5 is tetrahydrofuranyl;

W is:

each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl; and

R 7 is straight chain or branched alkyl, cycloalkyl, aryl, or aralkyl;

provided that:

when Z is —O(C═O)—, then R 5 is other than H;

or a stereoisomer or pharmaceutically acceptable salt thereof.

21. A compound according to claim 20 of formula II wherein R 4 is H.

22. A compound according to claim 20 , wherein R 1 and R 2 are each independently H or W.

23. A compound according to claim 20 , wherein R 1 , R 2 , and R 4 are each H.

24. A compound according to claim 20 , of Formula II(a):

25. A compound according to claim 20 , wherein R 4 is W.

26. A compound according to claim 25 , wherein R 1 and R 2 are each H.

27. A compound according to claim 26 wherein R 3 is straight chain or branched C 1 -C 10 alkyl, R 5 is tetrahydrofuran-3-yl, and W is:

28. A compound according to claim 27 wherein W is:

29. A compound according to claim 25 wherein R 1 and R 2 are each aralkyl.

30. A compound according to claim 25 wherein R 4 is:

31. A compound according to claim 20 , wherein at least one of the R 6 substituents is other than H.

32. A compound according to claim 20 , wherein each R 6 is independently H, straight chain or branched C 1 -C 5 alkyl or straight chain or branched C 2 -C 6 alkoxyalkyl.

33. A compound according to claim 20 , wherein each R 6 is independently H, methyl, or CH 2 OCH 3 .

34. A compound according to claim 20 , wherein each W is independently:

35. A compound according to claim 26 , wherein each W is independently:

36. A compound according to claim 20 wherein R 3 is H or straight chain or branched C 1 -C 5 alkyl.

37. A compound according to claim 20 wherein R 3 is methyl.

38. A compound according to claim 20 , wherein R 5 is tetrahydrofuranyl.

39. A compound according to claim 38 , wherein R 5 is tetrahydrofuran-3-yl.

40. A compound according to claim 20 , wherein W is:

41. A compound according to claim 1 , wherein R 5 is 3-alkyltetrahydrofuran-3-yl.

42. A compound according to claim 20 , wherein R 5 is 3-alkyltetrahydrofuran-3-yl.

43. A compound according to claim 1 , of the formula:

44. A compound according to claim 43 , of the formula:

45. A pharmaceutically acceptable salt of a compound according to claim 43 , of formula:

[A]·HX;

wherein A is a compound according to claim 43 and HX is an acid selected from the group consisting of hydrochloric, sulfuric, maleic, fumaric, oxalic, succinic, citric, and tartaric acids.

46. A process for producing a compound of formula IIIa:

wherein:

R 1 and R 2 are each independently H, W, or a phenoxyl protecting group;

R 3 is hydrogen, straight chain or branched C 1 -C 10 alkyl, cycloalkyl, amino, or C 1 -C 10 alkoxy,

R 4 is H or W, provided that at least one of R 1 , R 2 , and R 4 is W; and

Z is —O—, —O(C═O)—, or —NH(C═O)—;

R 5 is tetrahydrofuranyl,

W is:

each R 6 is independently H, straight chain or branched C 1 -C 10 alkyl, or straight chain or branched C 1 -C 10 alkoxyalkyl; and

R 7 is alkyl, cycloalkyl, aryl, or aralkyl;

provided that:

when Z is —O(C═O)—, then R 5 is other than H; and

when Z is —NH(C═O)—, then R 5 is other than H, and W is:

comprising contacting a compound of the formula:

wherein:

at least one of R 1 , R 2 , and R 4 is H;

with at least one compound of formula W−L, wherein each L is independently a leaving group;

to produce a compound of formula IIIa.

47. A pharmaceutical composition for treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 1 ; or a stereoisomer or pharmaceutically acceptable salt thereof.

48. The composition according to claim 47 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

49. The composition according to claim 47 , formulated as an eye drop, eye wash, or eye ointment.

50. The composition according to claim 47 , formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.

51. A method of treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises:

administering to the eye of the patient a composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 1 ; or a stereoisomer or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or reduce the symptoms of glaucoma, ocular hypertension, or optic neuropathy.

52. The method according to claim 51 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

53. The method according to claim 51 , wherein the composition is administered in an eye drop, eye wash, or eye ointment.

54. The method according to claim 51 , wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.

55. A pharmaceutical composition for treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 20 or a stereoisomer, or pharmaceutically acceptable salt thereof.

56. The composition according to claim 55 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

57. The composition according to claim 55 , formulated as an eye drop, eye wash, or eye ointment.

58. The composition according to claim 55 , formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.

59. A method of treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises administering to the eye of the patient a composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 20 , or a stereoisomer or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or reduce the symptoms of glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy.

60. The method according to claim 59 , wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

61. The method according to claim 59 , wherein the composition is administered in an eye drop, eye wash, or eye ointment.

62. The method according to claim 59 , wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.