Compounds effective in inducing cell differentiation and process for preparing same

• US 4,927,815 A
• Filed: 04/29/1988
• Issued: 05/22/1990
• Est. Priority Date: 04/29/1988
• 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., Kutner, Andrzej, Schnoes, Heinrich K., Perlman, Kato L.
• Primary Examiner(s): Lipovsky, Joseph A.
• Application Number:
  US07/187,680
• Time in Patent Office: 753 Days
• Field of Search: 260/397.2, 514/167
• US Class Current: 514/167
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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

This invention provides novel side chain homologs of 1α,25-dihydroxyvitamin D₃ which exhibit enhanced and highly selective activity in inducing differentiation of malignant cells. It also provides a general method of synthesis applicable to the preparation of a variety of vitamin D side chain analogs, and a method of treatment of neoplastic diseases which takes advantage of the selective differentiation activity of the new vitamin D homologs.

Claims

1. A process for the preparation of vitamin D compounds having the general structure:

##STR8## where X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, hydroxy and fluoro-substituted alkyl, hydroxy-protected hydroxy-substituted alkyl and hydroxy-protected hydroxy- and fluoro-substituted alkyl, which comprises treating a vitamin D-22-tosylate derivative, of the general structure;

##STR9## where X and Y are selected from the group consisting of hydrogen and hydroxy-protecting groups, with an alkylphenylsulfone derivative of the general structure;

space="preserve" listing-type="equation">Ph--SO.sub.2 --CH.sub.2 --R

wherein R is selected from the group consisting of alkyl, fluoro-substituted alkyl, hydroxy-substituted alkyl, and hydroxy- and fluoro-substituted alkyl, any hydroxy group present being preferably derivatized by hydroxy-protecting groups, thereby obtaining a side chain sulfone adduct, having the following general structure;

##STR10## wherein X, Y and R represent the groupings defined above, and reductively desulfonating said side chain sulfone adduct so as to obtain the corresponding vitamin D compound, and, optionally removing the hydroxy-protecting groups present.

2. The method of claim 1 where X and Y are hydroxy-protecting groups.

3. The method of claim 2 where R is 4-methyl-4-hydroxypentyl in hydroxy-protected form.

4. The method of claim 2 where R is 5-methyl-5-hydroxyhexyl in hydroxy-protected form.

5. Compounds having the structure:

##STR11## wherein X and Y, which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R is selected from the group consisting of 4-methyl-4-hydroxy-pentyl, 5-methyl-5-hydroxy-hexyl, and their corresponding hydroxy-protected forms.

6. The compounds of claim 5 where X and Y are hydrogen.

7. The compounds of claim 5 where X and Y are hydroxy-protecting groups.

8. The compounds of claim 5 where R is 4-methyl-4-hydroxypentyl.

9. The compounds of claim 5 where R is 4-methyl-4-hydroxypentyl in its hydroxy-protected form.

10. The compounds of claim 5 where R is 5-methyl-5-hydroxyhexyl.

11. The compounds of claim 5 where R is 5-methyl-5-hydroxyhexyl in its hydroxy-protected form.

12. Compounds having the structure:

##STR12## where X, Y and Z, which may be the same or different, selected from the group consisting of hydrogen and a hydroxy-protecting group, and where n is 3 or 4.

13. The compounds of claim 12 where X, Y and Z are hydroxy-protecting groups.

14. The compounds of claim 13 where X, Y and Z are alkylsilyl groups.

15. The compounds of claim 12 where X, Y and Z are hydrogen.

16. A pharmaceutical composition containing a compound as claimed in claim 12 together with a pharmaceutically acceptable excipient.

17. A pharmaceutical composition as claimed in claim 16 where the compound is 24-dihomo-1α

,25-dihydroxyvitamin D₃.

18. A pharmaceutical composition as claimed in claim 16 where the compound is 24-trihomo-1α

,25-dihydroxyvitamin D₃.

19. A method for inducing and enhancing cell differentiation in malignant cells which comprises exposing said cells to at least one of the compounds claimed in claim 12, in an amount sufficient to induce cell differentiation.

20. The method as claimed in claim 19, where the compound is 24-dihomo-1α

,25-dihydroxyvitamin D₃.

21. The method as claimed in claim 19 where the compound is 24-trihomo-1α

,25-dihydroxyvitamin D₃.

22. A method for treating neoplastic diseases which comprises administering to a subject having a neoplastic disease an effective amount of at least one of the compounds of claim 12.

23. The method of claim 22 where the compound administered is 24-dihomo-1α

,25-dihydroxyvitamin D₃.

24. The method of claim 22 where the compound administered is 24-trihomo-1α

,25-dihydroxyvitamin D₃.

25. 24-dihomo-1α

,25-dihydroxyvitamin D₃.

26. 24-trihomo-1α

,25-dihydroxyvitamin D₃.