24-Hydroxyvitamin D, analogs and uses thereof

• US 20010002397A1
• Filed: 01/03/2001
• Published: 05/31/2001
• Est. Priority Date: 05/29/1998
• Status: Active Grant

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Bone Care International Inc (Sanofi )
• Inventors: Bishop, Charles W., Knutson, Joyce C., Strugnell, Stephen
• Granted Patent: US 7,122,530 B2
• 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 comprising administering an effective amount of a vitamin D compound which is a 24-hydroxyvitamin D or a 24-hydroxyprevitamin D wherein the effect is treating or preventing bone loss or bone mineral content, hyperparathyroidism, hyperproliferation, or modulating the immune and inflammatory responses.

2. The method of

claim 1

, wherein said 24-hydroxyvitamin D is a compound of formula (I):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

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.

3. The method of

claim 1

, wherein said 24-hydroxyprevitamin D is a compound of formula (III):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

4. The method of

claim 1

wherein Z is a side chain of formula (IIA):

wherein a dotted line along the side chain represents an optional additional C-C bond and m is 0 or 1;

R¹ and R² are independently 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 cyclohydrocarbon ring;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

R⁵ and R⁶ are each hydrogen or taken together form a double bond between C-22 and C-23.

5. The method of

claim 1

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.

6. The method of

claim 5

, wherein said 24-hydroxyvitamin D is 24-hydroxyvitamin D₂;

24(S)-hydroxyvitamin D₂;

24-hydroxy-vitamin D₄;

24(R)-hydroxyvitamin D₄.

7. The method of

claim 1

wherein Z is a side chain of formula (IIC):

wherein n is an integer which is 1 or 2;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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; and

when A is carbon, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

8. The method of

claim 1

wherein Z is a side chain of formula (IID):

wherein R³, R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; and

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

9. The method of

claim 1

wherein Z is a side chain of formula (IIE):

wherein a dotted line along the side chain represents an optional additional C-C bond;

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

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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;

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

10. The method of

claim 9

wherein said 24-hydroxyvitamin D compound is 24—

OH—

25-ene-D₂; and

24—

OH—

25-oxo-D₂.

17. The method of

claim 1

wherein said 24-hydroxyvitamin D compound is administered in a dosage of about 3.5 μ

g to about 1000 μ

g/week.

26. The method of

claim 1

wherein said compound is administered in combination with a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

27. The method of

claim 26

wherein said bone agent is other vitamin D compounds, conjugated estrogens, sodium fluorides, biphosphonates, cobalamin, calcium receptor agonists, pertussin toxin, boron or DHEA.

11. A method of achieving an effect in a patient comprising administering an effective amount of a vitamin D compound which is a 24-hydroxyvitamin D or a 24-hydroxyprevitamin D wherein the effect is increasing or maintaining bone mass or bone mineral content, lowering or maintaining lowered parathyroid hormone level, inhibiting hyperproliferative effects, inducing or enhancing cell differentiation modulating immune response, and modulating inflammatory response.

12. The method of

claim 11

, wherein said 24-hydroxyvitamin D compound is a compound of formula (I):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

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.

13. The method of

claim 11

, wherein said 24-hydroxyprevitamin D is a compound of formula (III):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

14. A method of treating a human to alleviate the pathological effects of osteoporosis, hyperparathyroidism, psoriasis, skin cancer, breast cancer, colon cancer, prostate cancer, prostatic hyperplasia and immune response imbalance and inflammatory response in balance, wherein the method comprises administering to the human a vitamin D compound which is a 24-hydroxyvitamin D or a 24-hydroxyprevitamin D wherein said compound is administered to the human in an amount sufficient to increase or maintain bone mass or bone mineral content, lower or maintain lowered parathyroid hormone level, inhibit hyperproliferative effects, induce or enhance cell differentiation, modulate immune response and modulate inflammatory response in the human.

15. A pharmaceutical composition comprising an effective amount of a substantially pure, synthesized a 24-hydroxyvitamin D or a 24-hydroxyprevitamin D and a pharmaceutically acceptable carrier, adjuvant or vehicle.

16. The composition of

claim 15

, wherein the composition is orally administrable.

18. The composition of

claim 15

wherein the composition is further combined with a bone agent, a cytotoxic agent, an immune response regulating agent, an antiinflammatory agent or combinations thereof.

19. A 24-hydroxyvitamin D compound which is a compound of formula (I):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

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 provided that the compound of formula (I) is not 24-hydroxyvitamin D₂; and

X is hydrogen, lower alkyl or lower fluoroalkyl provided that the compound of formula (I) is not 24-hydroxyvitamin D₂.

21. The compound of

claim 19

wherein Z is a side chain of formula (IIC):

wherein n is an integer which is 1 or 2;

R ³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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; and

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

22. The compound of

claim 19

wherein Z is a side chain of formula (IIE):

wherein a dotted line along the side chain represents an optional additional C-C bond;

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

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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; and

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

20. A 24-hydroxyprevitamin D which is a compound of formula (Ill):

wherein Z represents a saturated or unsaturated, substituted or unsubstituted, straight-chain or branched C₄-C₁₈ hydrocarbon group in which the C-24 or equivalent position is hydroxylated;

Y is a methyl group or hydrogen; and

X is hydrogen, lower alkyl or lower fluoroalkyl.

23. The compound of

claim 20

, wherein Z is a side chain of formula (IIC):

wherein n is an integer which is 1 or 2;

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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;

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

24. The compound of

claim 20

, wherein Z is a side chain of formula (IIE):

wherein a dotted line along the side chain represents an optional additional C-C bond;

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

R³ is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl;

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

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; and

R⁹ and R¹⁰ are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl.

25. As an article of manufacture, a tablet having a relatively high absorption rate for vitamin D as measured by blood level of vitamin D over time after ingestion, comprising a vitamin D compound which is 24-hydroxyvitamin D or 24-hydroxyprevitamin D and a pharmaceutically acceptable carrier, adjuvant or vehicle.