1a-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin D compounds and methods of making and treatment thereof

• US 8,058,265 B2
• Filed: 04/05/2007
• Issued: 11/15/2011
• Est. Priority Date: 04/05/2006
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Glebocka, Agnieszka, Plum, Lori A., Clagett-Dame, Margaret, Sicinski, Rafal R., Deluca, Hector F.
• Primary Examiner(s): QAZI, SABIHA NAIM
• Application Number:
  US11/732,924
• Publication Number:
  US 20070244072A1
• Time in Patent Office: 1,685 Days
• Field of Search: 514/167, 552/653
• US Class Current: 514/167
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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
• CPC Class Codes: C07C 45/29 of hydroxy groups
• CPC Class Codes: C07C 49/443 the condensed ring system containing eight or nine carbon atoms

Abstract

Disclosed are 1α-hydroxy-2-(3′-hydroxypropylidene)-19-nor-vitamin D compounds, pharmaceutical compositions, and methods of making and treatment thereof. The compounds are generally directed to biologically active 2-alkylidene-19-nor-vitamin D compounds and analogs thereof characterized by the presence of a 3′-hydroxypropylidene moiety at C-2 and the presence of an abbreviated alkyl side-chain free of any hydroxyl moiety.

Claims

1. A compound of the formula:

2. The compound of claim 1 wherein X is a member selected from the group consisting of hydrogen, deuterium, C_1-10 branched or straight alkyl, C_1-10 branched or straight alkyl substituted with one or more hydroxy groups, C_1-10 branched or straight alkyl substituted with one or more C_1-10 branched or straight alkoxy groups, C_1-10 branched or straight alkyl substituted with one or more aryloxy groups, carbonyl substituted with one or more C_1-10 branched or straight alkoxy groups, C_1-6 branched or straight alkanoyl, C_1-6 branched or straight carboxyalkanoyl, aromatic acyl, silyl substituted with one or more C_1-10 branched or straight alkyl groups, silyl substituted with one or more C_1-10 branched or straight alkyl groups and silyl substituted with one or more aryl groups.

3. The compound of claim 2, wherein the carbonyl substituted with a C_1-10 branched or straight alkoxy groups is a member selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propoxycarhonyl, iso-propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and allyloxycarbonyl.

4. The compound of claim 2, wherein the C_1-6 branched or straight carboxyalkanoyl is a member selected from the group consisting of oxalyl, malonyl, succinyl and glutaryl and wherein the aromatic acyl is a member selected from the group consisting of benzoyl, halo-substituted benzoyl, nitro-substituted benzoyl and C_1-10 straight or branched alkyl substituted benzoyl.

5. The compound of claim 2, wherein the C_1-10 branched or straight alkyl substituted with one or more C_1-10 branched or straight alkoxy groups is a member selected from the group consisting of methoxymethyl, ethoxymethyl, methoxyethoxymethyl, tetrahydrofuranyl and tetrahydropyranyl.

6. The compound of claim 2, wherein the silyl substituted with one or more C_1-10 branched or straight alkyl groups is a member selected from the group consisting of trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and dibutylmethylsilyl and wherein the silyl substituted with one or more aryl groups is a member selected from the group consisting of diphenymethylsilyl, phenyldimethylsilyl and diphenyl-t-butylsilyl.

7. The compound of claim 2, wherein the C_1-10 branched or straight alkyl substituted with one or more aryloxy groups is a member selected from the group consisting of phenyl-substituted phenyl, C_1-10 straight or branched alkyl-substituted phenyl, nitro-substituted phenyl and halo-substituted phenyl.

8. The compound of claim 1, wherein the compound is an E-geometrical isomer.

9. The compound of claim 1, wherein the compound is a Z-geometrical isomer.

10. The compound of claim 6, wherein X is t-butyldimethylsilyl.

11. The compound of claim 10. wherein Y₁ is t-butyldimethylsilyl.

12. The compound of claim 11, wherein Y² is t-butyldimethylsilyl.

13. The compound of claim 1, wherein X is hydrogen.

14. The compound of claim 13, wherein Y¹ is hydrogen.

15. The compound of claim 14, wherein Y² is hydrogen.

16. The compound of claim 1, wherein n is 1, wherein R¹ and R² are methyl, and wherein R³ is hydrogen.

21. A method of making a hydrindanone intermediate compound for use in making the compound of claim 1, wherein n is 1, wherein R¹, R², and R³ are each hydrogen and wherein is , comprising:

providing a starting compound of the formula;

22. A method of making the compound of claim 1, wherein n is 1, wherein R¹, R², and R³ are each hydrogen and wherein is , comprising:

coupling a hydrindanone intermediate compound having the formula,

23. A method of making a hydrindanone intermediate compound for use in making the compound of claim 1, wherein n is 1, wherein R¹, R², and R³ are each hydrogen and wherein is , comprising:

providing a starting compound of the formula;

24. A method of making the compound of claim 1, wherein n is 1, wherein R¹, R², and R³ are each hydrogen and wherein is comprising:

coupling a hydrindanone intermediate compound having the formula,

25. A method of making the compound of claim 1, wherein at least one of R¹, R² or R³ is a methyl and wherein is , comprising:

providing a starting compound of the formula;

26. The method of claim 25, wherein n is 1, wherein Z is Br, wherein R¹ and R² are methyl, and wherein R³ is hydrogen.

27. A method of making the compound of claim 1, wherein at least one of R¹, R² or R³ is a methyl and wherein is , comprising:

providing a starting compound of the formula;

28. The method of claim 27, wherein n is 1, wherein Z is Br, wherein R¹ and R² are methyl, and wherein R³ is hydrogen.

17. An E-isomer of (20R)-1α

-hydroxy-2-(3′

-hydroxypropylidene)-19,24,25,26,27-penta-nor-vitamin D₃.

18. An E-isomer of (20S)-1α

-hydroxy-2-(3′

-hydroxypropylidene)-19,24,25,26,27-penta-nor-vitamin D₃.

19. An E-isomer of (20R)-1α

-hydroxy-2-(3′

-hydroxypropylidene)-19,23,24-tri-nor-vitamin D₃.

20. An E-isomer of (20S)-1α

-hydroxy-2-(3′

-hydroxypropylidene)-19,23,24-tri-nor-vitamin D₃.