Method of locking 1alpha-OH of vitatmin D compounds in axial orientation

• US 20030040508A1
• Filed: 09/11/2002
• Published: 02/27/2003
• Est. Priority Date: 05/21/1998
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Sicinski, Rafal R.
• Granted Patent: US 6,890,914 B2
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/24 : the ring system containing nine carbon atoms, e.g. perhydroindane
• CPC Class Codes: C07C 401/00 : Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Abstract

A method of modifying or altering the structure of a 1α-hydroxylated vitamin D compound to increase its biological activity by altering the conformational equilibrium of the A-ring to favor a chair conformation that presents the 1α-hydroxyl in the axial orientation. This is accomplished by either locking the A-ring chair conformation in a geometry having an axially orientated 1α-hydroxyl, or by the addition of one or more substituents to the A-ring which interact with other substituents in the molecule or on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1α-hydroxyl in the axial orientation.

Claims

1. A method of modifying the calcemic activity of a 1α

-hydroxylated vitamin D compound to increase in vivo activity, comprising;

altering the conformational equilibrium of the A-ring of a 1α

-hydroxylated vitamin D compound to favor a chair conformation for said A-ring that presents the 1α

-hydroxyl in an axial orientation.

2. The method of claim 1 wherein the step of altering conformational equilibrium comprises locking the chair conformation of the A-ring in a geometry having an axially orientated 1α

-hydroxyl.

3. The method of claim 2 wherein the step of locking comprises adding an anchoring bond system to the A-ring.

4. The method of claim 3 wherein the anchoring bond system comprises substituents attached to carbon 2 and carbon 3 of the A-ring that have a trans-diequatorial orientation.

5. The method of claim 3 wherein the A-ring and anchoring bond system has the following structure:

6. The method of claim 3 wherein the anchoring bond system comprises substituents attached to carbon 3 and carbon 4 of the A-ring that have a trans-diequatorial orientation.

7. The method of claim 3 wherein the A-ring and anchoring bond system has the following structure:

8. The method of claim 2 wherein the step of locking comprises adding a flattening bond system to the A-ring.

9. The method of claim 8 wherein the A-ring and flattening bond system has the following structure:

10. The method of claim 2 wherein the step of locking comprises adding a bridged bond system to the A-ring.

11. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 2 and carbon 4 of the A-ring that have a cis-1,3-diaxial orientation.

12. The method of claim 10 wherein the A-ring and bridged bond system has the following structure:

13. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 2 and carbon 10 of the A-ring that have a cis-1,3-diaxial orientation.

14. The method of claim 10 wherein the A-ring and bridged bond system has the following structure:

15. The method of claim 10 wherein the bridged bond system comprises substituents attached to carbon 4 and carbon 10 of the A-ring that have a cis-1,3-diaxial orientation.

16. The method of claim 10 wherein the A-ring and the bridged bond system has the following structure:

17. The method of claim 1 wherein the step of altering conformational equilibrium comprises modifying the A-ring by the addition of one or more substituents which interacts with other substituents on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1α

-hydroxyl in said axial orientation.

18. The method of claim 17 wherein the substituent attached to carbon 2 of the A-ring has a conformational free energy value greater than about 1.4 kcal/mol and the carbon 2 substituent has an equatorial orientation.

19. The method of claim 17 wherein the A-ring has the following structure:

20. The method of claim 17 wherein the A-ring has the following structure:

21. The method of claim 17 wherein the substituent attached to carbon 10 of the A-ring has a conformational free energy value greater than about 1.4 kcal/mol and the carbon 10 substituent has an axial orientation.

22. The method of claim 17 wherein the A-ring has the following structure:

23. A method of increasing the biological response of a 1α

-hydroxylated vitamin D compound comprising

evaluating the conformational equilibrium of the A-ring of a 1α

-hydroxylated vitamin D compound to determine to what extent said 1α

-hydroxyl is presented axially or equatorially; and

if presented primarily equatorially, modifying the A-ring by the addition of a substituent thereto which locks said A-ring in a chair conformation that maintains the 1α

-hydroxyl in said axial orientation;

or modifying the A-ring by the addition of a substituent thereto which provides a driving force to the A-ring to adopt a chair conformation which presents the 1α

-hydroxyl in said axial orientation.

24. The method of claim 23 wherein the step of modifying the A-ring comprises adding an anchoring bond system to the A-ring.

25. The method of claim 24 wherein the anchoring bond system is added between substituents attached to carbons 2 and 3 of the A-ring.

26. The method of claim 24 wherein the anchoring bond system is added between substituents attached to carbons 3 and 4 of the A-ring.

27. The method of claim 23 wherein the step of modifying the A-ring comprises adding a flattening bond system to the A-ring.

28. The method of claim 27 wherein the flattening bond system is added between substituents attached to carbons 2 and 3 of the A-ring.

29. The method of claim 23 wherein the step of modifying the A-ring comprises adding a bridged bond system to the A-ring.

30. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 2 and 4 of the A-ring.

31. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 2 and 10 of the A-ring.

32. The method of claim 29 wherein the bridged bond system is added between substituents attached to carbons 4 and 10 of the A-ring.

33. The method of claim 23 wherein the step of modifying the A-ring comprises adding a substituent to carbon 2 of the A-ring having a conformational free energy value greater than about 1.4 kcal/mol.

34. The method of claim 23 wherein the step of modifying the A-ring comprises adding a substituent to carbon 10 of the A-ring having a conformational free energy value greater than about 1.4 kcal/mol.

35. A compound having the formula:

36. The compound of claim 35 having the formula:

37. The compound of claim 35 having the formula:

38. The compound of claim 35 having the formula:

39. The compound of claim 35 having the formula:

40. The compound of claim 35 having the formula:

41. The compound of claim 35 having the formula:

42. The compound of claim 35 having the formula:

43. The compound of claim 35 having the formula:

44. The compound of claim 35 having the formula:

45. A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 35 together with a pharmaceutically acceptable excipient.

46. The pharmaceutical composition of claim 45 in dosage unit form.

47. The pharmaceutical composition of claim 46 containing about 0.01 μ

g to about 100 μ

g of said at least one compound.

48. The pharmaceutical composition of claim 45 in topical form.

49. The pharmaceutical composition of claim 45 in oral form.

50. A method of treating metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.

51. The method of claim 50 where the disease is senile osteoporosis.

52. The method of claim 50 where the disease is postmenopausal osteoporosis.

53. The method of claim 50 where the disease is steroid-induced osteoporosis.

54. The method of claim 50 where the disease is low bone turnover osteoporosis.

55. The method of claim 50 where the disease is osteomalacia.

56. The method of claim 50 where the disease is renal osteodystrophy.

57. The method of claim 50 where the disease is rickets.

58. The method of claim 50 where the disease is vitamin D resistant rickets.

59. The method of claim 50 wherein the compound is administered orally.

60. The method of claim 50 wherein the compound is administered parenterally.

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

62. The method of claim 50 wherein the compound is administered in a dosage of from 0.1 μ

g to 50 μ

g per day.

63. A method of treating a disease characterized by abnormal cell proliferation or cell differentiation comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.

64. The method of claim 63 where the disease is psoriasis.

65. The method of claim 63 where the disease is a cancer selected from the group consisting of leukemia, colon cancer, breast cancer and prostate cancer.

66. The method of claim 63 where the disease is a skin disorder selected from the group consisting of dermatitis, eczema and keratosis.

67. A method of treating a disease characterized by an imbalance in the immune system comprising administering to a patient with said disease an effective amount of a compound as claimed in claim 35.

68. The method of claim 67 where the disease is multiple sclerosis.

69. The method of claim 67 where the disease is diabetes mellitus.

70. The method of claim 67 where the disease is transplant rejection.

71. A method of treating rheumatoid arthritis comprising administering to a patient with rheumatoid arthritis an effective amount of a compound as claimed in claim 35.

72. A method of treating asthma comprising administering to a patient with asthma an effective amount of a compound as claimed in claim 35.

73. A method of treating hypertension comprising administering to a patient with hypertension an effective amount of a compound as claimed in claim 35.

74. A method of treating hypocalcemia comprising administering to a patient with hypocalcemia an effective amount of a compound as claimed in claim 35.

75. A method of treating hypoparathroidism comprising administering to a patient with hypoparathyroidism an effective amount of a compound as claimed in claim 35.

76. A method of treating female infertility which comprises administering to a female mammal an effective amount of a compound as claimed in claim 35.

77. A method of treating acne comprising administering to a patient with acne an effective amount of a compound as claimed in claim 35.

78. A method of treating alopecia comprising administering to a patient with alopecia an effective amount of a compound as claimed in claim 35.

79. A method of treating skin conditions selected from the group consisting of lack of skin firmness, wrinkles, lack of dermal hydration and insufficient sebum secretion which comprises administering to a patient by topical, oral or parenteral means an effective amount of a compound as claimed in claim 35.