24 HYDROXYVITAMIN D, ANALOGS AND USES THEREOF

• US 20060211661A1
• Filed: 06/02/2006
• Published: 09/21/2006
• Est. Priority Date: 05/29/1998
• Status: Abandoned Application

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Strugnell, Stephen, Bishop, Charles W., Knutson, Joyce C.
• Application Number:
  US11/421,968
• Publication Number:
  US 20060211661A1
• Time in Patent Office: Days
• US Class Current: 514/167
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61K 31/592 9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 3/02 Nutrients, e.g. vitamins, minerals
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 5/20 for decreasing, blocking or antagonising the activity of PTH
• 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

The invention provides 24-hydroxyvitamin D compounds and methods for their use in the treatment and prophylaxis of hyperparathyroidism and hyperproliferative diseases, and in the modulation of the immune and inflammatory responses as well as the treatment of bone depletive disorders.

Claims

1. A method of achieving an effect in a patient in need thereof comprising administering an effective amount of a vitamin D compound wherein the effect is treating bone loss, treating hyperproliferation, or modulating the immune or inflammatory response, and wherein said vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIB;

wherein R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ is lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

2. The method of claim 1, wherein said vitamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

3. The method of claim 1, wherein the effect is treating bone loss.

4. The method of claim 1, wherein the effect is treating hyperproliferation.

5. The method of claim 1, wherein the effect is modulating the immune response.

6. The method of claim 1, wherein the effect is modulating the inflammatory response.

7. The method of claim 1, wherein the vitamin D compound is 24-hydroxyvitamin D₂.

8. The method of claim 1, wherein the vitamin D compound is 24-hydroxyvitamin D₄.

9. A method of achieving an effect in a patient in need thereof comprising administering an effective amount of a vitamin D compound wherein the effect is treating bone loss, treating hyperparathyroidism, treating hyperproliferation, or modulating the immune or inflammatory response, and wherein said vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIA;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is 0 or 1;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ is lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

10. The method of claim 9, wherein said vitamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

11. The method of claim 9, wherein the effect is treating bone loss.

12. The method of claim 9, wherein the effect is treating hyperparathyroidism.

13. The method of claim 9, wherein the effect is treating hyperproliferation.

14. The method of claim 9, wherein the effect is modulating the immune response.

15. The method of claim 9, wherein the effect is modulating the inflammatory response.

16. A method of achieving an effect in a patient in need thereof comprising administering an effective amount of a previtamin D compound, wherein the effect is treating bone loss, treating hyperproliferation, or modulating the immune or inflammatory response, wherein said previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

17. The method of claim 16, wherein said previtamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

18. The method of claim 16, wherein the effect is treating bone loss.

19. The method of claim 16, wherein the effect is treating hyperproliferation.

20. The method of claim 16, wherein the effect is modulating the immune response.

21. The method of claim 16, wherein the effect is modulating the inflammatory response.

22. The method of claim 16 wherein Z is a side chain of formula IIA.

23. The method of claim 16 wherein Z is a side chain of formula IIB.

24. The method of claim 23 wherein the previtamin D is 24-hydroxyprevitamin D₂.

25. The method of claim 23 wherein the previtamin D is 24-hydroxyprevitamin D₄.

26. The method of claim 16 wherein Z is a side chain of formula IIC.

27. The method of claim 16 wherein Z is a side chain of formula IID.

28. The method of claim 16 wherein Z is a side chain of formula IIE.

29. The method of claim 16 wherein Z is a side chain of formula IIF.

30. A method of treating hyperparathyroidism comprising administering an effective amount of a previtamin D compound, wherein said previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIC, or IIE;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

31. The method of claim 30, wherein said previtamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

32. The method of claim 30 wherein Z is a side chain of formula IIA.

33. The method of claim 30 wherein Z is a side chain of formula IIC.

34. The method of claim 30 wherein Z is a side chain of formula IIE.

35. A method of achieving an effect in a patient in need thereof comprising administering an effective amount of a vitamin D compound, wherein the effect is increasing or maintaining bone mass or bone mineral content, inhibiting hyperproliferative effects, inducing or enhancing cell differentiation, and wherein the vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

36. The method of claim 35, wherein said vitamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

37. The method of claim 35, wherein the effect is increasing or maintaining bone mass or bone mineral content.

38. The method of claim 35, wherein the effect is inhibiting hyperproliferative effects.

39. The method of claim 35, wherein the effect is inducing or enhancing cell differentiation.

40. The method of claim 35 wherein Z is a side chain of formula IIA.

41. The method of claim 35 wherein Z is a side chain of formula IIB.

42. The method of claim 41 wherein the vitamin D is 24-hydroxyvitamin D₂.

43. The method of claim 41 wherein the vitamin D is 24-hydroxyvitamin D₄.

44. The method of claim 35 wherein Z is a side chain of formula IIC.

45. The method of claim 35 wherein Z is a side chain of formula IID.

46. The method of claim 35 wherein Z is a side chain of formula IIE.

47. The method of claim 35 wherein Z is a side chain of formula IIF.

48. A method of lowering elevated parathyroid hormone levels or maintaining lowered parathyroid hormone levels in a patient in need thereof comprising administering an effective amount of a vitamin D compound, wherein the vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIA, IIC, or IIE;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

49. The method of claim 48, wherein said vitamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

50. The method of claim 48 wherein Z is a side chain of formula IIA.

51. The method of claim 48 wherein Z is a side chain of formula IIC.

52. The method of claim 48 wherein Z is a side chain of formula IIE.

53. A method of achieving an effect in a patient in need thereof comprising administering an effective amount of a previtamin D compound, wherein the effect is increasing or maintaining bone mass or bone mineral content, inhibiting hyperproliferative effects, inducing or enhancing cell differentiation, wherein said previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

54. The method of claim 53, wherein said previtamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

55. The method of claim 53, wherein the effect is increasing or maintaining bone mass or bone mineral content.

56. The method of claim 53, wherein the effect is inhibiting hyperproliferative effects.

57. The method of claim 53, wherein the effect is inducing or enhancing cell differentiation.

58. The method of claim 53 wherein Z is a side chain of formula IIA.

59. The method of claim 53 wherein Z is a side chain of formula IIB.

60. The method of claim 59 wherein the previtamin D is 24-hydroxyprevitamin D₂.

61. The method of claim 59 wherein the previtamin D is 24-hydroxyprevitamin D₄.

62. The method of claim 53 wherein Z is a side chain of formula IIC.

63. The method of claim 53 wherein Z is a side chain of formula IID.

64. The method of claim 53 wherein Z is a side chain of formula IIE.

65. The method of claim 53 wherein Z is a side chain of formula IIF.

66. A method of lowering elevated parathyroid hormone levels or maintaining lowered parathyroid hormone levels in a patient in need thereof comprising administering an effective amount of a previtamin D compound, wherein said previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIC or IIE;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

67. The method of claim 66, wherein said previtamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

68. The method of claim 66 wherein Z is a side chain of formula IIA.

69. The method of claim 66 wherein Z is a side chain of formula IIC.

70. The method of claim 66 wherein Z is a side chain of formula IIE.

71. A pharmaceutical composition comprising an effective amount of a substantially pure, synthesized vitamin D compound and a pharmaceutically acceptable carrier, wherein the vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

72. The pharmaceutical compound of claim 71, wherein the compound is in an effective amount to lower elevated parathyroid hormone level or maintain lowered parathyroid hormone level when administered to a human.

73. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IIA.

74. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IIB.

75. The pharmaceutical compound of claim 74 wherein the vitamin D is 24-hydroxyvitamin D₂.

76. The pharmaceutical compound of claim 74 wherein the vitamin D is 24-hydroxyvitamin D₄.

77. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IIC.

78. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IID.

79. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IIE.

80. The pharmaceutical compound of claim 71 wherein Z is a side chain of formula IIF.

81. The pharmaceutical compound of claim 71 wherein the compound is orally administrable.

82. A pharmaceutical composition comprising an effective amount of a substantially pure, synthesized previtamin D compound and a pharmaceutically acceptable carrier, wherein the previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

83. The pharmaceutical compound of claim 82, wherein the compound is in an effective amount to lower or maintain lowered parathyroid hormone level when administered to a human.

84. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IIA.

85. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IIB.

86. The pharmaceutical compound of claim 85 wherein the previtamin D is 24-hydroxyprevitamin D₂.

87. The pharmaceutical compound of claim 85 wherein the previtamin D is 24-hydroxyprevitamin D₄.

88. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IIC.

89. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IID.

90. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IIE.

91. The pharmaceutical compound of claim 82 wherein Z is a side chain of formula IIF.

92. The pharmaceutical compound of claim 91 wherein the compound is orally administrable.

93. An article of manufacture comprising a tablet or capsule comprising a vitamin D compound and a pharmaceutically acceptable carrier, wherein the vitamin D compound is a compound of formula (I):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methylene group if Y is double bonded to the A-ring or a methyl group or hydrogen if Y is single bonded; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

94. An article of manufacture comprising a tablet or capsule comprising a previtamin D compound and a pharmaceutically acceptable carrier, wherein the previtamin D compound is a compound of formula (III):

wherein Z is a side chain of formula IIA, IIB, IIC, IID, IIE or IIF;

wherein a dotted line along the side chain represents an optional additional C—

C bond;

m is zero or an integer which is 1;

n is an integer which is 1 or 2;

q is zero or an integer which is 1 or 2;

A is carbon, oxygen, sulfur or nitrogen;

r is 1 and s is zero when A is nitrogen;

r and s are 1 when A is carbon;

r and s are zero when A is sulfur or oxygen;

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23, R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

R⁴ and R⁷ are independently lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

R¹ and R² are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, lower fluoroalkenyl, lower cycloalkyl or taken together with the carbon to which they are bonded form a C₃-C₈ cyclocarbon ring;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.