Amelioration of cataracts, macular degeneration and other ophthalmic diseases

• US 20050131025A1
• Filed: 11/22/2004
• Published: 06/16/2005
• Est. Priority Date: 05/19/2003
• Status: Active Grant

• Current Assignee: Colby Pharmaceutical Company
• Original Assignee: Othera Holding, Inc.
• Inventors: Matier, William L., Patil, Ghanshyam
• Granted Patent: US 7,825,134 B2
• Time in Patent Office: Days
• US Class Current: 514/326
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears

Abstract

Ophthalmically acceptable compositions used in arresting the development of cataract, presbyopia, macular degeneration and other retinopathies, glaucoma, uveitis and various corneal disorders are disclosed. The compositions are also useful as a prophylactic treatment to prevent or delay development of age-related ocular disorders, which include cataracts, presbyopia, glaucoma and macular degeneration. The compositions comprise a pharmaceutically acceptable carrier or diluent and at least one compound having the formula:

• where R₁ and R₂ are, independently, H or C₁ to C₃ alkyl;
• R₃ and R₄ are, independently C₁ to C₃ alkyl; and
• where R₁ and R₂, taken together, or R₃ and R₄, taken together, or both may be cycloalkyl;
• R₅ is H, OH, or C₁ to C₆ alkyl;
• R₆ is or C₁ to C₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl;
• R₇ is C₁ to C₆ alkyl, alkenyl, alkynyl, or substituted alkyl or alkenyl or where R₆ and R₇, or R₅, R₆ and R₇, taken together, form a carbocycle or heterocycle having from 3 to 7 atoms in the ring.

Claims

1. A method of treating macular degeneration, retinopathy, glaucoma, presbyopia, conjunctival diseases, eyelid disorders, corneal disease or uveitis in a patient, the method comprising administering to the eye of such patient a composition comprising an ophthalmically acceptable carrier or diluent containing at least one compound having the formula:

2. The method of claim 1 wherein R₁, R₂, R₃, and R₄ are a C₁-C₃ alkyl.

3. The method of claim 2 wherein R₁, R₂, R₃, and R₄ are ethyl groups.

4. The method of claim 2 wherein R₁, R₂, R₃, and R₄ are methyl groups.

5. The method of claim 4 wherein:

each of R₅ is H or methyl,

R₆, is methyl substituted with benzyloxy or C₁-C₆ alkoxy; and

R₇ is methyl.

6. The method of claim 4 wherein:

each of R₅ is H or methyl,

R₆ and R₇ form a cyclopropyl group.

7. The method of claim 4 wherein:

R₅, R₆ and R₇ form a furanyl group.

8. The method of claim 4 wherein:

R₅ is H; and

R₆ and R₇ form a tetrahydrofuranyl group.

9. The method of claim 4 wherein:

R₅ is H; and

R₆ and R₇ form a cyclopropyl ring.

10. The method of claim 1, wherein the administration is via eye drops, eye wash or eye ointment.

11. The method of claim 1 further comprising administering a reducing agent to the patient.

12. The method of claim 11, wherein the reducing agent is coadministered with the composition.

13. The method of claim 11, wherein the reducing agent is administered separately from the composition.

14. The method of claim 11 wherein the reducing agent is a sulfhydryl compound.

15. The method of claim 14 further comprising coadministering mercaptopropionyl glycine, N-acetyl cysteine, β

-mercaptoethylamine, or glutathione to the patient.

16. The method of claim 11 wherein the reducing agent is administered via eye drops, eye wash or ophthalmic ointment.

17. The method of claim 1 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 0.1 μ

M to about 10 mM.

18. The method of claim 1 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 1 μ

M to about 5 mM.

19. The method of claim 1 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 25 μ

M to about 1 mM.

20. The method of claim 1 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 50 μ

M to about 100 μ

M.

59. The method of claim 1 wherein said disease or disorder is blepharitis.

60. The method of claim 1 wherein said disease or disorder is ocular rosacea.

61. The method of claim 1 wherein said disease or disorder is macular degeneration.

62. The method of claim 1 wherein said disease or disorder is retinopathy.

63. The method of claim 1 wherein said disease or disorder is glaucoma

64. The method of claim 1 wherein said disease or disorder is presbyopia.

65. The method of claim 1 wherein said composition further comprises a second compound used to treat said macular degeneration, retinopathy, glaucoma, presbyopia, conjunctival diseases, eyelid disorders, corneal disease or uveitis.

66. The method of claim 65 wherein said second compound is administered simultaneously.

67. The method of claim 65 wherein said second compound is administered sequentially.

21. A method of preventing or delaying development of cataract, presbyopia, glaucoma, age-related macular disorder or other age-related condition of the eye, the method comprising administering to the eye an eyedrop, eye wash or eye ointment comprising an ophthalmically acceptable carrier or diluent containing at least one compound having the formula:

22. The method of claim 21 wherein R₁, R₂, R₃, and R₄ are a C₁-C₃ alkyl.

23. The method of claim 22 wherein R₁, R₂, R₃, and R₄ are ethyl groups.

24. The method of claim 22 wherein R₁, R₂, R₃, and R₄ are methyl groups.

25. The method of claim 24 wherein:

each of R₅ is H or methyl,

R₆, is methyl substituted with benzyloxy or C₁-C₆ alkoxy; and

R₇ is methyl.

26. The method of claim 24 wherein:

each of R₅ is H or methyl,

R₆ and R₇ form a cyclopropyl group.

27. The method of claim 24 wherein:

R₅, R₆ and R₇ form a furanyl group.

28. The method of claim 24 wherein:

R₅ is H; and

R₆ and R₇ form a tetrahydrofuranyl group.

29. The method of claim 24 wherein:

R₅ is H; and

R₆ and R₇ form a cyclopropyl ring.

30. The method of claim 21 further comprising administering a reducing agent to the patient.

31. The method of claim 30, wherein the reducing agent is coadministered with the composition.

32. The method of claim 30, wherein the reducing agent is administered separately from the composition.

33. The method of claim 30 wherein the reducing agent is a sulfhydryl compound.

34. The method of claim 33 further comprising coadministering mercaptopropionyl glycine, N-acetyl cysteine, β

-mercaptoethylamine, or glutathione to the patient.

35. The method of claim 21 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 0.1 μ

M to about 10 mM.

36. The method of claim 21 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 1 μ

M to about 5 mM.

37. The method of claim 21 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 25 μ

M to about 1 mM.

38. The method of claim 21 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 50 μ

M to about 100 μ

M.

39. A method of protecting retinal pigment epithelium against photooxidative damage, the method comprising administering to the eye an eyedrop, eye wash or eye ointment comprising an ophthalmically acceptable carrier or diluent containing at least one compound having the formula:

40. The method of claim 39 wherein R₁, R₂, R₃, and R₄ are a C₁-C₃ alkyl.

41. The method of claim 40 wherein R₁, R₂, R₃, and R₄ are ethyl groups.

42. The method of claim 40 wherein R₁, R₂, R₃, and R₄ are methyl groups.

43. The method of claim 42 wherein:

each of R₅ is H or methyl,

R₆, is methyl substituted with benzyloxy or C₁-C₆ alkoxy; and

R₇ is methyl.

44. The method of claim 42 wherein:

each of R₅ is H or methyl,

R₆ and R₇ form a cyclopropyl group.

45. The method of claim 42 wherein:

R₅, R₆ and R₇ form a furanyl group.

46. The method of claim 42 wherein:

R₅ is H; and

R₆ and R₇ form a tetrahydrofuranyl group.

47. The method of claim 42 wherein:

R₅ is H; and

R₆ and R₇ form a cyclopropyl ring.

48. The method of claim 39 further comprising administering a reducing agent to the patient.

49. The method of claim 48, wherein the reducing agent is coadministered with the composition.

50. The method of claim 48, wherein the reducing agent is administered separately from the composition.

51. The method of claim 48 wherein the reducing agent is a sulfhydryl compound.

52. The method of claim 51 further comprising coadministering mercaptopropionyl glycine, N-acetyl cysteine, β

-mercaptoethylamine, or glutathione to the patient.

53. The method of claim 39 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 0.1 μ

M to about 10 mM.

54. The method of claim 39 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 1 μ

M to about 5 mM.

55. The method of claim 39 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 25 μ

M to about 1 mM.

56. The method of claim 39 wherein said compound is administered to achieve a concentration in the tissues and fluids of about 50 μ

M to about 100 μ

M.

57. A method for protecting hair follicles and preventing further hair loss comprising administering to a patient in need thereof a composition comprising a pharmaceutically acceptable carrier or diluent and at least one compound having the formula:

58. A method for protecting or treating rectal tissue from damage as a result of irradiation therapy comprising administering to a patient in need thereof a composition comprising a pharmaceutically acceptable carrier or diluent and and at least one compound having the formula: