2-Methylene-1Alpha,25-Dihydroxy-19,21-Dinorvitamin D3 Analogs and Uses Thereof

• US 20070238706A1
• Filed: 04/06/2007
• Published: 10/11/2007
• Est. Priority Date: 04/06/2006
• Status: Active Grant

• 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., Clagett-Dame, Margaret
• Granted Patent: US 7,648,973 B2
• Time in Patent Office: Days
• US Class Current: 514/63
• CPC Class Codes: A61K 8/342 Alcohols having more than seven atoms in an unbroken chain
• CPC Class Codes: A61K 8/585 Organosilicon compounds
• CPC Class Codes: A61K 8/63 Steroids; Derivatives thereof
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/20 : for decreasing, blocking or antagonising the activity of PTH
• CPC Class Codes: A61Q 19/06 : for countering cellulitis
• CPC Class Codes: A61Q 19/08 : Anti-ageing preparations
• 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

Compounds of formula I are provided where X₁, X₂ and X₃ are independently selected from H or hydroxy protecting groups. Such compounds are used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions.

Claims

1. A compound having the formula I

2. The compound of claim 1, wherein X₁, X₂ and X₃ are hydroxy protecting groups.

3. The compound of claim 2, wherein X₁, X₂ and X₃ are triethylsilyl or t-butyldimethylsilyl groups.

4. The compound of claim 1, wherein X₁, X₂ and X₃ is H and the compound has the formula II

5. A pharmaceutical composition, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 wherein the effective amount comprises from about 0.01 μ

g to about 1 mg of the compound per gram of the composition.

7. The pharmaceutical composition of claim 5 wherein the effective amount comprises from about 0.1 μ

g to about 500 μ

g of the compound per gram of the composition.

8. A method of treating a subject suffering from a biological condition, comprising administering an effective amount of the compound of claim 1 to the subject, wherein the biological condition is selected from a metabolic bone disease;

psoriasis;

leukemia;

colon cancer;

breast cancer;

prostate cancer;

skin cancer;

lung cancer;

multiple sclerosis;

lupus;

diabetes mellitus;

host versus graft reaction;

rejection of organ transplants;

an inflammatory disease selected from rheumatoid arthritis, asthma, or inflammatory bowel diseases;

a skin condition selected from wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, or insufficient sebum secretion;

renal osteodystrophy;

osteopenia;

or osteoporosis.

9. The method of claim 8, wherein the biological condition is renal osteodystrophy, vitamin D-resistant rickets, osteoporosis or psoriatic arthritis.

10. The method of claim 8, wherein the biological condition is selected from leukemia, colon cancer, breast cancer, skin cancer, lung cancer or prostate cancer.

11. The method of claim 8, wherein the biological condition is selected from multiple sclerosis, lupus, diabetes mellitus, host versus graft reaction, or rejection of organ transplants.

12. The method of claim 8, wherein the biological condition is selected from rheumatoid arthritis, asthma, or inflammatory bowel diseases selected from celiac disease, ulcerative colitis and Crohn'"'"'s disease.

13. The method of claim 8, wherein the biological condition is selected from wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, or insufficient sebum secretion.

14. The method of claim 8, wherein the compound is administered orally, parenterally, nasally, rectally, sublingually, transdermally or topically to the subject.

15. The method of claim 8, wherein the compound is administered intraperitoneally.

16. The method of claim 8, wherein the compound is administered in a dosage of from 0.01 μ

g per day to 1 mg per day.

17. A compound having the formula II

18. A pharmaceutical composition, comprising an effective amount of the compound of claim 17 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, wherein the effective amount comprises from about 0.01 μ

g to about 1 mg of the compound per gram of the composition.

20. The pharmaceutical composition of claim 18, wherein the effective amount comprises from about 0.1 μ

g to about 500 μ

g of the compound per gram of the composition.

21. A method of treating or preventing obesity of an animal, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal comprising administering to an animal in need thereof an effective amount of a compound having the formula:

22. The method of claim 21, wherein the compound is administered orally, parenterally, nasally, rectally, sublingually, transdermally or topically to the animal.

23. The method of claim 21, wherein the compound is administered in a dosage of from 0.01 μ

g per day to 1 mg per day.

24. The method of claim 21, wherein the compound is 2-methylene-1α

,25-dihydroxy-19,21-dinorvitamin D₃ having the formula;

25. The method of claim 21, wherein the animal is a human.

26. The method of claim 21, wherein the animal is a domestic animal.

27. The method of claim 21, wherein the animal is an agricultural animal.