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

• US 20070244072A1
• Filed: 04/05/2007
• Published: 10/18/2007
• 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: Plum, Lori, Clagett-Dame, Margaret, Glebocka, Agnieszka, Sicinski, Rafal, Deluca, Hector
• Granted Patent: US 8,058,265 B2
• Time in Patent Office: Days
• US Class Current: 514/63
• 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 comprising:

wherein the solid line to C(1′

) provides that the compound is an E- or Z-geometrical isomer respecting the 2-propylidene segment,

wherein the C(20) is the stereochemical center,

wherein the provides an R or S configuration,

wherein n is an integer from 1 to 3,

wherein Y¹ is a member selected from the group consisting of hydrogen, deuterium and a first hydroxy-protecting group,

wherein Y² is a member selected from the group consisting of hydrogen, deuterium and a second hydroxy-protecting group,

wherein X is a third hydroxy-protecting group,

wherein R¹ is a member selected from the group consisting of hydrogen, deuterium and methyl,

wherein R² is a member selected from the group consisting of hydrogen, deuterium and methyl,

wherein R³ is a member selected from the group consisting of hydrogen, deuterium and methyl, and,

wherein is a member selected from the group consisting of and

and esters thereof.

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, propoxycarbonyl, 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 diphenylmethylsilyl, 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;

reacting the starting compound with a ylide reactant to produce an alkene-containing product,

hydrogenating the alkene-containing product to produce an oily ester product,

hydrolysing the oily ester product to produce an alcohol product, and,

oxidizing the alcohol product to produce the hydrindanone intermediate compound having 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 the hydrindanone intermediate compound of claim 21 with lithium phosphinoxy carbanion to produce a coupled product having the protecting groups, and,

hydrolyzing the protecting groups.

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;

reacting the starting compound with a ylide reactant to produce an alkene-containing product,

hydrogenating the alkene-containing product to produce an oily ester product,

hydrolysing the oily ester product to produce an alcohol product, and,

oxidizing the alcohol product to produce the hydrindanone intermediate compound having 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 the hydrindanone intermediate compound of claim 21 with lithium phosphinoxy carbanion to produce a coupled product having the protecting groups, and, hydrolyzing the protecting groups.

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;

wherein is a member selected from the group consisting of and

converting the starting compound into a nitrile compound,

alkylating the nitrile compound with a first reactant of the formula;

wherein n is an integer from 1 to 3, wherein Z is a member selected from the group consisting of Br, Cl and I, and, wherein at least one of R¹, R² or R³ is a methyl to produce an alkylated nitrile product,

hydrolysing the alkylated nitrile product to produce a hydroxy nitrile product,

reductively decyanating the hydroxy nitrile product to produce a mixture of epimeric alcohol products,

oxidizing the mixture of epimeric alcohol products to produce a mixture of a 20S-ketone product and a 20R-ketone product,

separating the 20S-ketone and 20R-ketone products,

coupling the 20R-ketone product with lithium phosphinoxy carbanion to produce a coupled 20R product having the protecting groups, and,

hydrolysing the protecting groups.

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;

wherein is a member selected from the group consisting of and

converting the starting compound into a nitrile compound,

alkylating the nitrile compound with a first reactant of the formula;

wherein n is an integer from 1 to 3, wherein Z is a member selected from the group consisting of Br, Cl and I, and, wherein at least one of R¹, R² or R³ is a methyl, to produce an alkylated nitrile product,

hydrolysing the alkylated nitrile product to produce a hydroxy nitrile product,

reductively decyanating the hydroxy nitrile product to produce a mixture of epimeric alcohol products,

oxidizing the mixture of epimeric alcohol products to produce a mixture of a 20S-ketone product and a 20R-ketone product,

separating the 20S-ketone and 20R-ketone products,

coupling the 20S-ketone product with lithium phosphinoxy carbanion to produce a coupled 20S product having the protecting groups, and,

hydrolysing the protecting groups,

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. A compound comprising an E-isomer of (20R)-1α

-hydroxy-2-(3′

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

18. A compound comprising an E-isomer of (20S)-1α

-hydroxy-2-(3′

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

19. A compound comprising an E-isomer of (20R)-1α

-hydroxy-2-(3′

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

20. A compound comprising an E-isomer of (20S)-1α

-hydroxy-2-(3′

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