2-Alkylidene-18,19-Dinor-Vitamin D Compounds

• US 20100179344A1
• Filed: 02/19/2010
• Published: 07/15/2010
• Est. Priority Date: 04/09/2004
• Status: Abandoned Application

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Barycki, Rafal, Plum, Lori A., DeLuca, Hector F., Grzywacz, Pawel, Sicinski, Rafal R.
• Application Number:
  US12/709,181
• Publication Number:
  US 20100179344A1
• Time in Patent Office: Days
• US Class Current: 558/428
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

2-alkylidene-18,19-dinor-vitamin D compounds are disclosed as well as pharmaceutical uses for these compounds and methods of synthesizing these compounds. These compounds are characterized by low bone calcium mobilization activity and high intestinal calcium transport activity. This results in novel therapeutic agents for the treatment and prophylaxis of diseases where bone formation is desired, particularly osteoporosis, as well as autoimmune diseases such as multiple sclerosis, diabetes mellitus and lupus. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent and for the treatment of skin diseases such as psoriasis. These compounds also increase both breaking strength and crushing strength of bones evidencing use in conjunction with bone replacement surgery such as hip and knee replacements.

Claims

1. A compound having the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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-, —

(CH₂)n-, or —

(CR₁R₂)—

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

2. The compound of claim 1 where R is a side chain of the formula

3. The compound of claim 1 where R is a side chain of the formula

4. The compound of claim 1 where R is a side chain of the formula

5. The compound of claim 1 where R is a side chain of the formula

6. The compound of claim 1 where R is a side chain of the formula

7. The compound of claim 1 where R is a side chain of the formula

8. The compound of claim 1 where R is a side chain of the formula

9. The compound of claim 1 where R is a side chain of the formula

10. The compound of claim 1 where R is a side chain of the formula

11. The compound of claim 1 where R is a side chain of the formula

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

14. The pharmaceutical composition of claim 13 wherein said effective amount comprises from about 0.01 μ

g to about 100 μ

g per gram of composition.

15. The pharmaceutical composition of claim 13 wherein said effective amount comprises from about 0.1 μ

g to about 50 μ

g per gram of composition.

16. The pharmaceutical composition of claim 13 containing (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.01 μ

g to about 100 μ

g.

17. The pharmaceutical composition of claim 13 containing (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃ in an amount from about 0.1 μ

g to about 50 μ

g.

12. (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

18. A compound having the formula:

19. A compound having the formula:

where X² is —

H or a hydroxy protecting group.

20. A compound having the formula:

21. A compound having the formula:

where X³ is —

H or a hydroxy protecting group.

22. 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 having the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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—

, —

(CH₂)_n—

or —

(CR₁R₂)—

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

23. The method of claim 22 where the disease is senile osteoporosis.

24. The method of claim 22 where the disease is postmenopausal osteoporosis.

25. The method of claim 22 where the disease is steroid-induced osteoporosis.

26. The method of claim 22 where the disease is low bone turnover osteoporosis.

27. The method of claim 22 where the disease is osteomalacia.

28. The method of claim 22 where the disease is renal osteodystrophy.

29. The method of claim 22 wherein the compound is administered orally.

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

31. The method of claim 22 wherein the compound is administered transdermally.

32. The method of claim 22 wherein the compound is administered in a dosage of from 0.01 μ

g to 100 μ

g per day.

33. The method of claim 22 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

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

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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—

, —

(CH₂)_n—

or (CR₁R₂)—

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

35. The method of claim 34 wherein the compound is administered orally.

36. The method of claim 34 wherein the compound is administered parenterally.

37. The method of claim 34 wherein the compound is administered transdermally.

38. The method of claim 34 wherein the compound is administered topically.

39. The method of claim 34 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

40. The method of claim 34 wherein said effective amount comprises about 0.01 μ

g/day to about 100 μ

g/day of said compound.

41. A method of treating leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a patient an effective amount of a compound having the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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—

, —

(CH₂)_n—

or (CR₁R₂)—

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

42. The method of claim 41 wherein the compound is administered orally.

43. The method of claim 41 wherein the compound is administered parenterally.

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

45. The method of claim 41 wherein the compound is administered in a dosage of from about 0.01 μ

g/day to about 100 μ

g/day.

46. The method of claim 41 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

47. A method of increasing the strength of a bone comprising administering to a patient in need of such treatment an effective amount of a compound having the formula:

where Y₁ and Y₂, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where X is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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—

, —

(CH₂)_n—

or (CR₁R₂)—

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

48. The method of claim 47 wherein the bone strength is cortical strength.

49. The method of claim 47 wherein the bone strength is trabecular strength.

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

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

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

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

g to 100 μ

g per day.

54. The method of claim 47 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

55. A method of treating an autoimmune disease comprising administering to a patient with said disease an effective amount of a compound having the formula

where Y₁ and Y₂ which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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-, —

(CH₂)n-, or —

(CR₁R₂)—

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

56. The method of claim 55 where the disease is multiple sclerosis.

57. The method of claim 55 where the disease is diabetes mellitus.

58. The method of claim 55 where the disease is lupus.

59. The method of claim 55 wherein the compound is administered orally.

60. The method of claim 55 wherein the compound is administered parenterally.

61. Them method of claim 55 wherein the compound is administered transdermally.

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

g/day to about 100 μ

g/day.

63. The method of claim 55 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.

64. A method of treating an inflammatory bowel disease comprising administering to a patient with said disease an effective amount of a compound having the formula

where Y₁ and Y₂ which the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R₆ and R₈, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group —

(CH₂)_x—

where x is an integer from 2 to 5, and where the group R is represented by the structure;

where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —

OY, —

CH₂OY, —

C≡

CY and —

CH═

CHY, where the double bond 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, ═

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-, —

(CH₂)n-, or —

(CR₁R₂)—

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

65. The method of claim 64 wherein the disease is Crohn'"'"'s disease.

66. The method of claim 64 wherein the disease is ulcerative colitis.

67. The method of claim 64 wherein the compound is administered orally.

68. The method of claim 64 wherein the compound is administered parenterally.

69. The method of claim 64 wherein the compound is administered transdermally.

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

g/day to about 100 μ

g/day.

71. The method of claim 64 wherein the compound is (20S)-2-methylene-18,19-dinor-1α

,25-dihydroxyvitamin D₃.