VITAMIN D ANALOG - RAK, METHODS AND USES THEREOF

Abstract

Compounds of formula IA or IB are provided where X1, X2 and X3 are independently selected from H or hydroxy protecting groups and R1 is 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; 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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-5 illustrate various biological activities of (20R,25R)-2-Methylene-19,26-dinor-1α,25-dihydroxyvitamin D3 (referred to as “RAK” in the Figures) compared with those of the native hormone 1α,25-dihydroxyvitamin D₃ (referred to as “1,25(OH)₂D₃” in the Figures).

FIG. 1 is a graph comparing the relative activity of RAK and 1,25(OH)₂D₃ to compete for binding with [³H]-1,25-(OH)₂-D₃ to the full-length recombinant rat vitamin D receptor.

FIG. 2 is a bar graph comparing the bone calcium mobilization activity of RAK with that of 1,25(OH)₂D₃.

FIG. 3 is a bar graph comparing the intestinal calcium transport activity of RAK with that of 1,25(OH)₂D₃.

FIG. 4 is a graph comparing the percent HL-60 cell differentiation as a function of the concentration of RAK with that of 1,25(OH)₂D₃.

FIG. 5 is a graph comparing the in vitro transcription activity of RAK with that of 1,25(OH)₂D₃.

Claims

1. A compound having the formula IA or IB

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 t-butyldimethylsilyl groups.

4. The compound of claim 1, wherein X1, X2 and X3 are H and R1 is CH3 and the compound has the formula IIA or IIB

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 μg 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 μg to about 500 μg 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 psoriasis; leukemia; colon cancer; breast cancer; prostate 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; 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, 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, 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 μg per day to 1 mg per day.

17. The use of the compound of claim 1 in the preparation of a medicament for the treatment of a biological condition selected from psoriasis; leukemia; colon cancer; breast cancer; prostate 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; or osteoporosis.

18. The compound having the formula IIA

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

20. The use of the compound of claim 19 in the preparation of a medicament for the treatment of a biological condition selected from psoriasis; leukemia; colon cancer; breast cancer; prostate 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; or osteoporosis.