(20R) and (20S)-24-(;-toluenesulfonyloxy)-25,26,27-trinorvitamin D;analogs and their uses

• US 9,290,447 B2
• Filed: 04/19/2012
• Issued: 03/22/2016
• Est. Priority Date: 05/03/2011
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: DeLuca, Hector F., Clagett-Dame, Margaret, Plum, Lori A., Barycki, Rafal
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US13/451,317
• Publication Number:
  US 20120283227A1
• Time in Patent Office: 1,433 Days
• Field of Search: 552/653, 514/167
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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

This invention discloses (20R) and (20S)-24-(p-toluenesulfonyloxy)-25,26,27-trinorvitamin D₃ analogs, and especially (20R)-25,26,27-trinor-24-(p-methylphenylsulfonate)-vitamin D₃, its biological activities, and pharmaceutical uses therefor. This compound exhibits relatively little calcemic activity and does not promote cellular differentiation of HL-60 leukemia cells, but rather kills the cells. This cell death activity is found in small cell lung carcinoma also, but not in prostate, bone or ovarian cancer cells. This compound thus causes specific cell death in the absence of changes in calcium levels and without general toxicity in an animal. Therefore it might serve as a useful therapy for treatment of some forms of cancer, such as leukemia and lung cancer.

Claims

1. A compound of the structure:

2. The compound of claim 1 wherein X is hydrogen.

3. The compound of claim 1 wherein X is t-butyldimethylsilyl.

4. (20R)-24-(p-toluenesulfonyloxy)-25,26,27-trinorvitamin D₃.

6. A pharmaceutical composition containing an effective amount of the compound of claim 4 together with a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 6 wherein said effective amount comprises from about 1 mg to about 1 gm per grain of composition.

8. The pharmaceutical composition of claim 6 wherein said effective amount comprises from about 10 mg to about 0.5 gm per gram of composition.

9. A method of treating a disease selected from the group consisting of leukemia and lung cancer comprising administering to a subject with said disease the compound of claim 4.

10. The method of claim 9 wherein the compound is administered orally.

11. The method of claim 9 wherein the compound is administered parenterally.

12. The method of claim 9 wherein the compound is administered transdermally.

13. The method of claim 9 wherein the compound is administered rectally.

14. The method of claim 9 wherein the compound is administered nasally.

15. The method of claim 9 wherein the compound is administered sublingually.

16. The method of claim 9 wherein the compound is administered in a dosage of from about 1 mg/day to about 1 gm/day.

5. (20S)-24-(p-toluenesulfonyloxy)-25,26,27-trinorvitamin D₃.