19-Nor-Vitamin D Analogs with 1,2-Dihydrofuran Ring

• US 20100009944A1
• Filed: 07/10/2008
• Published: 01/14/2010
• Est. Priority Date: 07/10/2008
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Plum, Lori A., DeLuca, Hector F., Clagett-Dame, Margaret, Sokolowska, Katarzyna, Sicinski, Rafal R., Glebocka, Agnieszka
• Granted Patent: US 7,879,829 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Abstract

19-nor-vitamin D analogs having an additional dihydrofuran ring connecting the 1α-oxygen and carbon-2 of the A-ring of the analog, and pharmaceutical uses therefore, are described. These compounds exhibit selective in vitro and in vivo activities, making them therapeutic agents for the treatment or prophylaxis of autoimmune diseases, some types of cancers, secondary hyperparathyroidism, psoriasis, or other skin diseases.

Claims

1. A compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

2. The compound of claim 1 wherein Y is hydrogen.

3. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 1 together with a pharmaceutically acceptable excipient.

4. The pharmaceutical composition of claim 3 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

5. The pharmaceutical composition of claim 3 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

6. 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

7. A pharmaceutical composition containing an effective amount of 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ together with a pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7 wherein said effective amount comprises from about 0.01 μ

g to about 1000 μ

g per gram of composition.

9. The pharmaceutical composition of claim 7 wherein said effective amount comprises from about 0.1 μ

g to about 500 μ

g per gram of composition.

10. A method of treating psoriasis comprising administering to a subject with psoriasis an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

11. The method of claim 10 wherein the compound is administered orally.

12. The method of claim 10 wherein the compound is administered parenterally.

13. The method of claim 10 wherein the compound is administered transdermally.

14. The method of claim 10 wherein the compound is administered topically.

15. The method of claim 10 wherein the compound is administered rectally.

16. The method of claim 10 wherein the compound is administered nasally.

17. The method of claim 10 wherein the compound is administered sublingually.

18. The method of claim 10 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

19. The method of claim 10 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

20. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a subject with said disease an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

21. The method of claim 20 wherein the compound is administered orally.

22. The method of claim 20 wherein the compound is administered parenterally.

23. The method of claim 20 wherein the compound is administered transdermally.

24. The method of claim 20 wherein the compound is administered rectally.

25. The method of claim 20 wherein the compound is administered nasally.

26. The method of claim 20 wherein the compound is administered sublingually.

27. The method of claim 20 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

28. The method of claim 20 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

29. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants, comprising administering to a subject with said disease an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

30. The method of claim 29 wherein the compound is administered orally.

31. The method of claim 29 wherein the compound is administered parenterally.

32. The method of claim 29 wherein the compound is administered transdermally.

33. The method of claim 29 wherein the compound is administered rectally

34. The method of claim 29 wherein the compound is administered nasally.

35. The method of claim 29 wherein the compound is administered sublingually.

36. The method of claim 29 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

37. The method of claim 29 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

38. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a subject with said disease an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

39. The method of claim 38 wherein the compound is administered orally.

40. The method of claim 38 wherein the compound is administered parenterally.

41. The method of claim 38 wherein the compound is administered transdermally.

42. The method of claim 38 wherein the compound is administered rectally.

43. The method of claim 38 wherein the compound is administered nasally.

44. The method of claim 38 wherein the compound is administered sublingually.

45. The method of claim 38 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

46. The method of claim 38 wherein the compound 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

47. A method of treating a skin condition selected from the group consisting of wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration and insufficient sebum secretion which comprises administering to a subject with said skin condition an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

48. The method of claim 47 wherein the compound is administered orally.

49. The method of claim 47 wherein the compound is administered parenterally.

50. The method of claim 47 wherein the compound is administered transdermally.

51. The method of claim 47 wherein the compound is administered topically.

52. The method of claim 47 wherein the compound is administered rectally.

53. The method of claim 47 wherein the compound is administered nasally.

54. The method of claim 47 wherein the compound is administered sublingually.

55. The method of claim 47 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

56. The method of claim 47 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

57. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

58. The method of claim 57 wherein the compound is administered orally.

59. The method of claim 57 wherein the compound is administered parenterally.

60. The method of claim 57 wherein the compound is administered transdermally.

61. The method of claim 57 wherein the compound is administered rectally.

62. The method of claim 57 wherein the compound is administered nasally.

63. The method of claim 57 wherein the compound is administered sublingually.

64. The method of claim 57 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

65. The method of claim 57 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

66. A method of treating obesity of an animal, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal comprising administering to an animal in need thereof an effective amount of a compound having the formula:

where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;

where Z in the above side chain structure is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —

COR⁵ and a radical of the structure;

where m and n, independently, represent the integers from 0 to 5, where R¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C_1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R², R³, and R⁴, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C_1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R¹ and R², taken together, represent an oxo group, or an alkylidene group having a general formula C_kH_2k—

where k is an integer, the group ═

CR²R³, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R³ and R⁴, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R⁵ represents hydrogen, hydroxy, protected hydroxy, or C_1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —

CH(CH₃)—

, —

(CH₂)_m—

, —

CR₁R₂—

or —

(CH₂)_n—

at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

67. The method of claim 66 wherein the compound is administered orally.

68. The method of claim 66 wherein the compound is administered parenterally.

69. The method of claim 66 wherein the compound is administered transdermally.

70. The method of claim 66 wherein the compound is administered rectally.

71. The method of claim 66 wherein the compound is administered nasally.

72. The method of claim 66 wherein the compound is administered sublingually.

73. The method of claim 66 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 1000 μ

g/day.

74. The method of claim 66 wherein the compound is 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D₃ having the formula:

75. The method of claim 66 wherein the animal is a human.

76. The method of claim 66 wherein the animal is a domestic animal.

77. The method of claim 66 wherein the animal is an agricultural animal.