MACROCYCLIC LACTONE COMPOUNDS AND METHODS FOR THEIR USE

• US 20080234309A1
• Filed: 03/11/2008
• Published: 09/25/2008
• Est. Priority Date: 09/13/2006
• Status: Active Grant

• Current Assignee: Elixir Medical Corporation
• Original Assignee: Elixir Medical Corporation
• Inventors: Yan, John, Zheng, Xiaoxia, Bhat, Vinayak D.
• Granted Patent: US 8,088,789 B2
• Time in Patent Office: Days
• US Class Current: 514/291
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/4525 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

wherein R¹, R², R³, R⁵, R⁶, R⁸, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ are each independently a member selected from the group consisting of H, C_1-6 alkyl, OH and C_1-6 hydroxyalkyl; R⁴, R⁷ and R⁹ are each independently selected from the group consisting of C_1-6 alkoxy and OH; R¹⁰ is a member selected from the group consisting of H, —OH, —OP(O)Me₂,

—O—(CH₂)_n—OH and —O—(CH₂)_m—O—(CH₂)_o—CH₃, wherein subscripts n and m are each independently from 2 to 8 and subscript o is from 1 to 6; each of L¹ and L⁴ are independently selected from the group consisting of:

wherein each M⁸ is independently a member selected from the group consisting of C_1-6 alkyl, OH and C_1-6 hydroxyalkyl; each of L² and L³ are independently selected from the group consisting of:

and
salts, hydrates, isomers, metabolites, N-oxides and prodrugs thereof.

Claims

1. A method of treating an ophthalmic condition or disease by administering to a subject in need thereof, a therapeutically effective amount of a compound of the formula:

2. The method of claim 1, wherein the ophthalmic condition or disease is a member selected from the group consisting of disorders of the eyelid, disorders of the lacrimal system and orbit, tear duct blockage, disorders of conjunctiva, disorders of the sclera, cornea, iris and ciliary body, disorders of the lens, disorders of the choroid and retina, Age-related Macular Degeneration (AMD), Diabetic Macular Edema (DME), glaucoma, disorders of the vitreous body and globe, disorders of the optic nerve and visual pathways, disorders of the ocular muscles, binocular movement, accommodation and refraction, visual disturbances and blindness.

3. The method of claim 1, wherein the method of treating is selected from the group consisting of inhibiting cell proliferation, preventing inflammation, preventing neovascularization, protecting neurovascular system, and preventing immune response after transplantation.

4. The method of claim 1, wherein the compound is administered via an implant, an injection or an eye drop.

5. The method of claim 4, wherein administration is to the ocular body of the eye, the intraocular body of the eye or the intravitreal body of the eye.

6. The method of claim 4, wherein administration is via the implant.

7. The method of claim 6, wherein the compound is released from the implant via osmotic pressure or diffusion.

8. The method of claim 1, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

9. The method of claim 8, wherein R⁴ is OH.

10. The method of claim 9, wherein

R¹, R⁶ and R⁸ are each methyl;

R², R³ and R⁵ are each H;

R⁴ and R¹⁰ are each OH;

R⁷ and R⁹ are each OMe;

M¹, M², M³, M⁴ and M⁵ are each H;

M⁶ and M⁷ are each methyl;

L¹ and L⁴ are each

11. The method of claim 1, wherein the compound is co-administered with at least one therapeutic agent.

12. The method of claim 11, wherein the therapeutic agent is a member selected from the group consisting of an anti-platelet, anti-thrombotic, anti-inflammatory, anti-angiogenic, anti-proliferative, immunosuppressant and anti-cancer agent.

13. The method of claim 11, wherein the therapeutic agent is a member selected from the group consisting of lucentis, avastin, macugan, volociximab, olopatadine, mydriatcs, dexamethasone, pilocarpine, tropicamide, quinolone, galentamine, fluocinolone acetonide, triamcinolone acetonide, atropine, atropine sulfate, atropine hydrochloride, atropine methylbromide, atropine metliylnitrate, atropine hyperduric, atropine N-oxide, phenylephrine, phenylephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, hydroxyamphetamine hydrochloride, hydroxyamphetamine iodide, cyclopentolate, cyclopentolate hydrochloride, homatropine, homatropine hydrobromide, homatropine hydrochloride, homatropine methylbromide, scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine methylbromide, scopolamine methylnitrate, scopolamine N-oxide, tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, pilocarpine, isopilocarpine, physostigmine, stearyl ammonium chloride and benzyl ammonium chloride.

14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

15. The composition of claim 14, wherein the compound is a compound of FIG. 2.

16. The composition of claim 14, wherein

R¹, R⁶ and R⁸ are each methyl;

R², R³ and R⁵ are each H;

R⁴ and R¹⁰ are each OH;

R⁷ and R⁹ are each OMe;

M¹, M², M³, M⁴ and M⁵ are each H;

M⁶ and M⁷ are each methyl;

L¹ and L⁴ are each

17. The composition of claim 14, wherein the pharmaceutically acceptable excipient is a member selected from the group consisting of a polymer, a solvent, an antioxidant, a binder, a filler, a disintegrant, a lubricant, a coating, a sweetener, a flavor, a stabilizer, a colorant, a metal, a ceramic and a semi-metal.

18. The composition of claim 17, wherein the pharmaceutically acceptable excipient is a polymer.

19. The composition of claim 18, wherein the polymer is selected from the group consisting of polyurethane, polyethylene imine, ethylene vinyl alcohol copolymer, silicone, C-flex, nylons, polyamide, polyimide, polytetrafluoroethylene (PTFE), parylene, parylast, poly(methacrylate), poly(vinyl chloride), poly(dimethyl siloxane), poly(ethylene vinyl acetate), polycarbonate, polyacrylamide gels, poly(methyl methacrylate), poly(n-butyl methacrylate), poly(butyl methacrylate) copolymer or blended with poly(ethylene vinyl acetate), poly(methyl methacrylate), poly(2-hydroxy ethyl methacrylate), poly(ethylene glycol methacrylates), poly(ethylene carbonate), Poly L lactide-glycolide copolymer, poly L lactide-trimethylene carbonate copolymer and Poly L-lactide.

20. The composition of claim 19, wherein the polymer is poly(n-butylmethacrylate).

21. The composition of claim 19, wherein the compound is present in an amount of at least 25% (w/w) in a mixture of the compound and the polymer.

22. The composition of claim 21, wherein the compound is present in an amount of at least 50% (w/w).

23. The composition of claim 21, wherein the compound is present in an amount of at least 75% (w/w).

24. The composition of claim 14, wherein less than about 5% of the compound is metabolized to rapamycin.

25. The composition of claim 14, wherein less than about 1% of the compound is metabolized to rapamycin.

26. The composition of claim 14, wherein less than about 0.1% of the compound is metabolized to rapamycin.

27. The composition of claim 14 in a dosage form, having a daily systemic dose of the compound of from about 0.1 mg to about 20 mg.

28. The composition of claim 27, wherein the daily systemic dose of the compound is from about 0.5 mg to about 10 mg.

29. The composition of claim 27, wherein the daily systemic dose of the compound is from about 1 mg to about 5 mg.

30. A device for intracorporeal use, the device comprising:

an implant; and

at least one source of a compound of claim 14.

31. The device of claim 30, wherein the device is configured to release the compound to a body lumen or organ within an intracorporeal body to inhibit cell proliferation.

32. The device of claim 31, wherein the device is configured to release the compound to a body lumen or organ within an intracorporeal body to inhibit smooth muscle cell proliferation and inflammation.

33. The device of claim 30, wherein the implant is a vascular prosthesis.

34. The device of claim 33, wherein the vascular prosthesis comprises an expandable structure.

35. The device of claim 33, wherein the vascular prosthesis comprises a stent, graft, or a scaffold formed at least in part from an open lattice.

36. The device of claim 35, wherein the vascular prosthesis is a stent.

37. The device of claim 34, wherein the vascular prosthesis has a luminal and a tissue facing surface, and wherein the compound is associated with at least one of the luminal or tissue facing surfaces.

38. The device of claim 30, wherein the amount of compound on the device is from about 1 nanogram/cm² to about 1000 microgram/cm².

39. The device of claim 38, wherein the amount of compound on the device is from about 1 microgram/cm² to about 500 microgram/cm².

40. The device of claim 38, wherein the amount of compound on the device is from about 10 microgram/cm² to about 400 microgram/cm².

41. The device of claim 30, wherein the concentration of the compound in adjacent tissue is from about 0.001 ng/gm tissue to about 1000 μ

g/gm tissue.

42. The device of claim 41, wherein the concentration of the compound in adjacent tissue is from about 1 ng/gm tissue to about 500 μ

g/gm tissue.

43. The device of claim 41, wherein the concentration of the compound in adjacent tissue is from about 100 ng/gm tissue to about 100 μ

g/gm tissue.

44. The device of claim 30, wherein at least 75% of the compound is released from the device in a period from about 1 day to about 2 years.

45. The device of claim 30, wherein at least 90% of the compound is released from the device in a period from about 3 day to about 6 months.

46. The device of claim 30, wherein at least 90% of the compound is released from the device in a period from about 1 week to about 3 months.

47. The device of claim 30, wherein the device further includes a therapeutic agent.

48. The device of claim 47, wherein the therapeutic agent is a member selected from the group consisting of an anti-platelet, anti-thrombotic, anti-inflammatory, anti-angiogenic, anti-proliferative, immunosuppressant and anti-cancer agent.

49. The device of claim 47, wherein the therapeutic agent is released prior to, concurrent with, or subsequent to the release of the compound.

50. The device of claim 49, wherein the compound is released from a first source and the therapeutic agent is released from a second source.

51. The device of claim 49, wherein the compound and the therapeutic agent are released from a single source.

52. A method of inhibiting cell proliferation by administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 14.

53. The method of claim 52, wherein the compound of claim 14 is administered systemically, locally or via a combination thereof.

54. The method of claim 52, wherein the administration of the compound of claim 14 is via oral administration, administration as a suppository, topical contact, parenteral, intravascular, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, pulmonary, mucosal, transdermal, ophthalmic, subcutaneous administration or intrathecal administration.

55. The method of claim 52, wherein the administration of the compound of claim 14 is via delivery through a temporary device or an implant.

56. The method of claim 55, wherein the temporary device is selected from the group consisting of a catheter and a porous balloon.

57. The method of claim 55, wherein the implant is a vascular prosthesis.

58. The method of claim 57, wherein the vascular prosthesis comprises an expandable structure.

59. The method of claim 57, wherein the vascular prosthesis comprises a stent, graft, or scaffold formed at least in part from an open lattice.

60. The method of claim 52, wherein the IC₅₀ of the compound is from about 0.1 nM to about 1 μ

M.

61. The method of claim 60, wherein the IC₅₀ of the compound is from about 1 nM to about 0.5 μ

M.

62. The method of claim 60, wherein the IC₅₀ of the compound is from about 5 nM to about 100 nM.

63. The method of claim 52, wherein the effective dose of the compound is from about 0.1 mg to about 20 mg.

64. The method of claim 63, wherein the effective dose of the compound is from about 0.5 mg to about 10 mg.

65. The method of claim 63, wherein the effective dose of the compound is from about 1 mg to about 5 mg.

66. A compound of the formula:

67. The compound of claim 66, wherein R¹⁰ is

68. The compound of claim 67, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

69. The compound of claim 68, wherein R⁴ is OH.

70. The compound of claim 66, wherein R¹⁰ is

71. The compound of claim 70, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

72. The compound of claim 71, wherein R⁴ is OH.

73. The compound of claim 66, wherein R¹⁰ is —

OP(O)Me₂.

74. The compound of claim 73, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

75. The compound of claim 74, wherein R⁴ is OH.

76. The compound of claim 66, wherein R¹⁰ is

77. The compound of claim 76, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

78. The compound of claim 77, wherein R⁴ is OH.

79. The compound of claim 66, wherein R¹⁰ is

80. The compound of claim 79, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

81. The compound of claim 80, wherein R⁴ is OH.

82. The compound of claim 66, wherein the compound is a compound of FIG. 2.

83. The compound of claim 66, wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, M¹, M², M³, M⁴, M⁵, M⁶ and M⁷ is OH.

84. The compound of claim 83, wherein R⁴ is OH.

85. A method of making a compound of claim 66, the method comprising

contacting a macrocyclic lactone with an acid to replace an alkoxy group with a nucleophile, thereby making a compound of claim 66.

86. The method of claim 85, wherein the macrocyclic lactone is rapamycin.

87. The method of claim 86, wherein the nucleophile is a member selected from the group consisting of —

OH, —

SH and electron rich aromatic groups.

88. A method of making a compound of claim 66, the method comprising contacting a macrocyclic lactone with an epoxidation agent to modify an alkene group to an epoxide, thereby making a compound of claim 66.

89. The method of claim 88, wherein the macrocyclic lactone is rapamycin.

90. The method of claim 88, wherein the epoxidation agent is a member selected from the group consisting of a peracid and peroxide.

91. The method of claim 90, wherein the epoxidation agent is a member selected from the group consisting of a meta-chloro-peroxybenzoic acid and hydrogen peroxide.

92. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula:

93. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula: