Method of locking 1α-OH of vitamin D compounds in axial orientation

• US 6,506,912 B2
• Filed: 10/31/2001
• Issued: 01/14/2003
• Est. Priority Date: 05/21/1998
• Status: Expired due to Fees

• 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.
• Primary Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US10/001,623
• Publication Number:
  US 20020068723A1
• Time in Patent Office: 440 Days
• Field of Search: 514/167, 514/449, 514/452, 514/451, 514/453, 514/463, 514/456, 514/464, 514/465, 514/461, 514/466, 514/469, 549/268, 549/269, 549/270, 549/271, 549/346, 549/347, 549/350, 549/351, 549/356, 549/357, 549/362, 549/366, 549/429, 549/430, 549/434, 549/407, 549/510, 549/511, 549/263, 549/266, 549/267
• US Class Current: 549/449
• 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 structured 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 compound having the formula:

where R₁ and R₂ are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents and where R₁ and R₂, taken together, represent an oxo group, or a group —

CH₂)_m—

where m is an integer having a value of from 2 to 5, and wherein n is an integer having a value of from 1 to 4, and wherein any of the groups CR₁R₂—

in the formula (CR₁R₂)_n may be replaced by an oxygen, sulfur or nitrogen atom, and R is represented by the structure below

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, —

COR₁₀ and a radical of the structure;

where x and y, independently, represent the integers from 0 to 5, where R₆ 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 R₇, R₈, and R₉, 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 R₆ and R₇, taken together, represent an oxo group, or an alkylidene group, ═

CR₇R₈, or the group —

(CH₂)_p—

, where p is an integer from 2 to 5, and where R₈ and R₉, taken together, represent an oxo group, or the group —

(CH₂)_q—

, where q is an integer from 2 to 5, and where R₁₀ 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)_x, —

(CR₆R₇)—

or —

(CH₂)_y—

at positions 20, 22; and

23, respectively, may be replaced by an oxygen or sulfur atom.

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

3. The pharmaceutical composition of claim 2 in dosage unit form.

4. The pharmaceutical composition of claim 3 comprising about 0.01 μ

g to about 100 μ

g of said at least one compound.

5. The pharmaceutical composition of claim 2 in topical form.

6. The pharmaceutical composition of claim 2 in oral form.

7. A 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 1.

8. The method of claim 7 where the disease is senile osteoporosis.

9. The method of claim 7 where the disease is postmenopausal osteoporosis.

10. The method of claim 7 where the disease is steroid-induced osteoporosis.

11. The method of claim 7 where the disease is low bone turnover osteoporosis.

12. The method of claim 7 where the disease is osteomalacia.

13. The method of claim 7 where the disease is renal osteodystrophy.

14. The method of claim 7 where the disease is rickets.

15. The method of claim 7 where the disease is vitamin D resistant rickets.

16. The method of claim 7 wherein the compound is administered orally.

17. The method of claim 7 wherein the compound is administered parenterally.

18. The method of claim 7 wherein the compound is administered transdermally.

19. The method of claim 7 wherein the compound is administered in a dosage of from 0.1 μ

g to 50 μ

g per day.

20. 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 1.

21. The method of claim 20 where the disease is psoriasis.

22. The method of claim 20 where the disease is a cancer selected from the group consisting of leukemia, colon cancer, breast cancer and prostate cancer.

23. The method of claim 20 where the disease is a skin disorder selected from the group consisting of dermatitis, eczema and keratosis.

24. 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 1.

25. The method of claim 24 where the disease is multiple sclerosis.

26. The method of claim 24 where the disease is diabetes mellitus.

27. The method of claim 24 where the disease is transplant rejection.

28. A method of treating rheumatoid arthritis comprising administering to a patient with rheumatoid arthritis an effective amount of a compound as claimed in claim 1.

29. A method of treating asthma comprising administering to a patient with asthma an effective amount of a compound as claimed in claim 1.

30. A method of treating hypertension comprising administering to a patient with hypertension an effective amount of a compound as claimed in claim 1.

31. A method of treating hypocalcemia comprising administering to a patient with hypocalcemia an effective amount of a compound as claimed in claim 1.

32. A method of treating hypoparathroidism comprising;

administering to a patient with hypoparathyroidism an effective amount of a compound as claimed in claim 1.

33. A method of treating female infertility which comprises administering to a female mammal in need thereof an effective amount of a compound as claimed in claim 1.

34. A method of treating acne comprising administering to a patient with acne an effective amount of a compound as claimed in claim 1.

35. A method of treating alopecia comprising administering to a patient with alopecia an effective amount of a compound as claimed in claim 1.

36. 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 in need thereof by topical, oral or parenteral means an effective amount of a compound as claimed in claim 1.