2-substituted-1α,25-dihydroxy-19,26,27-trinor vitamin D analogs and uses thereof

• US 8,404,666 B2
• Filed: 04/06/2007
• Issued: 03/26/2013
• Est. Priority Date: 04/06/2006
• 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., Plum, Lori A., Clagett-Dame, Margaret, Grzywacz, Pawel
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US11/697,434
• Publication Number:
  US 20070238704A1
• Time in Patent Office: 2,181 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• 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 3/04 Anorexiants; Antiobesity agents
• 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 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: 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, II or III are provided where X₁, X₂ and X₃ are independently selected from H and hydroxy protecting groups and R₁ and R₂ are independently selected from H or straight or branched chain alkyl groups having from 1 to 8 carbon atoms, straight or branched chain alkenyl groups having from 2 to 8 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 1 to 8 carbon atoms, or straight and branched chain hydroxy-substituted alkenyl groups having from 2 to 8 carbon atoms; and R₃ is independently selected from straight or branched chain alkyl groups having from 1 to 8 carbon atoms, straight or branched chain alkenyl groups having from 2 to 8 carbon atoms, straight or branched chain hydroxy-substituted alkyl groups having from 1 to 8 carbon atoms, or straight and branched chain hydroxy-substituted alkenyl groups having from 2 to 8 carbon atoms. 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. A pharmaceutical composition, comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 wherein the effective amount comprises from about 0.01 μ

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

6. The pharmaceutical composition of claim 4 wherein the effective amount comprises from about 0.1 μ

g to about 500 μ

g of the compound per gram of the composition.

7. 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 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.

8. The method of claim 7, wherein the biological condition is renal osteodystrophy, vitamin D-resistant rickets, osteoporosis or psoriatic arthritis.

9. The method of claim 7, wherein the biological condition is selected from leukemia, colon cancer, breast cancer, skin cancer, lung cancer or prostate cancer.

10. The method of claim 7, wherein the biological condition is selected from multiple sclerosis, lupus, diabetes mellitus, host versus graft reaction, or rejection of organ transplants.

11. The method of claim 7, wherein the biological condition is selected from rheumatoid arthritis, asthma, or inflammatory bowel diseases selected from celiac disease, ulcerative colitis and Crohn'"'"'s disease.

12. The method of claim 7, wherein the biological condition is selected from wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration, or insufficient sebum secretion.

13. The method of claim 7, wherein the compound is administered orally, parenterally, transdermally, nasally, rectally, sublingually or topically to the subject.

14. The method of claim 7, wherein the compound is administered intraperitoneally.

15. The method of claim 7, wherein the compound is administered in a dosage of from 0.01 μ

g per day to 1 mg per day.

16. A compound having the formula IA:

17. A pharmaceutical composition, comprising an effective amount of the compound of claim 16 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, wherein the effective amount comprises from about 0.01 μ

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

19. The pharmaceutical composition of claim 17, wherein the effective amount comprises from about 0.1 μ

g to about 500 μ

g of the compound per gram of the composition.

20. A method of treating 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 I:

21. The method of claim 20, wherein the compound is administered orally, parenterally, nasally, rectally, sublingually, transdermally or topically to the animal.

22. The method of claim 20, wherein the compound is administered in a dosage of from 0.01 μ

g per day to 1 mg per day.

23. The method of claim 20, wherein the compound is 2-methylene-1α

,25-dihydroxy-19,26,27-trinorvitamin D₃ having the formula;

24. The method of claim 20, wherein the animal is a human.

25. The method of claim 20, wherein the animal is a domestic animal.

26. The method of claim 20, wherein the animal is an agricultural animal.