Vitamin D derivatives

• US 6,043,385 A
• Filed: 12/01/1998
• Issued: 03/28/2000
• Est. Priority Date: 12/16/1997
• Status: Expired due to Term

• Current Assignee: Basilea Pharmaceutica Ag
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Mohr, Peter, Muller, Marc, Bauer, Franz, Barbier, Pierre, Pirson, Wolfgang
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): Qazi, Sabiha N.
• Application Number:
  US09/203,088
• Time in Patent Office: 483 Days
• Field of Search: 552/653, 514/167
• US Class Current: 552/653
• 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

The present invention relates to vitamin D derivatives of the formula I ##STR1## wherein X is C═CH₂ or CH₂ ;

Y is hydrogen, fluorine or hydroxy

Z is hydroxy

n is 1 or 2

R¹ is lower alkyl,

R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents, or is a phenyl group which is unsubstituted or substituted with a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents;

and the dotted carbon-carbon bond in ring D is --C--C-- or --C═C--; or a pharmaceutically usable salt thereof.

Claims

1. A compound of the formula I ##STR52## wherein X is C═

CH₂ or CH₂ ;

Y is hydrogen, fluorine or hydroxy

Z is hydroxy

n is 1 or2

R¹ is lower alkyl,

R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents, or is a phenyl group which is unsubstituted or substituted with a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents;

and the dotted carbon-carbon bond in ring D is --C--C-- or --C═

C--;

or a pharmaceutically usable salt thereof.

2. A compound according to claim 1, wherein Y is hydrogen or hydroxy.

3. A compound according to claim 2, wherein Y is hydroxy.

4. A compound according to claim 3, wherein n is 2.

5. A compound according to claim 4, wherein the dotted carbon--carbon bond in ring D is --C--C--.

6. A compound according to claim 5, wherein R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents.

7. A compound according to claim 6, wherein R² is 2-hydroxy-2-methylpropyl, 2-hydroxy-2-trifluoromethylpropyl and 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl.

8. A compound according to claim 6, wherein the compound is (E)--(R)--N--[(1R,3R,20S)-1,3-Dihydroxy-17a,20a-dihomo-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

9. A compound according to claim 6, wherein the compound is (E)--(S)--N--[(1R,3R,20S)-1,3-Dihydroxy-17a,20a-dihomo-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

10. A compound according to claim 6, wherein the compound is (E)--N--[(1R,3R,20S)-1,3-Dihydroxy-17a,20a-dihomo-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-trifluoromethyl-3-hydroxy-butyramide.

11. A compound according to claim 4, wherein the dotted carbon--carbon bond in ring D is --C═

C--.

12. A compound according to claim 11, wherein R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents.

13. A compound according to claim 11, wherein R² is 2-hydroxy-2-methylpropyl, 2-hydroxy-2-trifluoromethylpropyl and 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl.

14. A compound according to claim 2, wherein n is 1 and the dotted carbon--carbon double bond in ring D is --C--C--.

15. A compound according to claim 14, wherein R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents.

16. A compound according to claim 15, wherein R² is 2-hydroxy-2-methylpropyl, 2-hydroxy-2-trifluoromethylpropyl and 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropyl.

17. A compound according to claim 15, wherein the compound is (E)--(1R,3R,20S)--N-(1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyramide.

18. A compound according to claim 14, wherein the compound is (E)--(1R,3R,20S)--N-(1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl)-3-(1-hydroxy-1-methyl-ethyl)-benzamide.

19. A compound according to claim 15, wherein the compound is (E)--(1R,3R,20S)--N-(1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl)-2,2-dimethyl-propionamide.

20. A compound according to claim 15, wherein the compound is (E)--(1R,3R,20S)--N-(1,3-Dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl)-2-hydroxy-2-methyl-propionamide.

21. A compound according to claim 15, wherein the compound is E--(R)--N--[(1R,3R,20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

22. A composition comprising a 1:

1 mixture of (R) and (S) stereoisomers of a compound of the formula I ##STR53## wherein X is C═

CH 2 or CH2;

Y is hydrogen, fluorine or hydroxy

Z is hydroxy

n is 1 or2

R1 is lower alkyl,

R2 is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents, or is a phenyl group which is unsubstituted or substituted with a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents;

and the dotted carbon--carbon bond in ring D is --C--C-- or --C═

C--;

or

a pharmaceutically usable salt thereof.

23. A composition according to claim 22, wherein Y is hydrogen or hydroxy.

24. A composition according to claim 22, wherein n is 1 and the dotted carbon--carbon double bond is --C--C--.

25. A composition according to claim 23, wherein R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents.

26. A composition according to claim 24, wherein the mixture is a 1:

1 mixture of[5E,7E)--(R) and --(S)-4,4,4-trifluoro-3-hydroxy-N--[(1S,3R,20S)-1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]-3-methyl-butyramide.

27. A composition according to claim 24, wherein the mixture is a 1:

1 mixture of [E]--(R) and --(S)--N--[(1R,3R,20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

28. A composition according to claim 24, wherein the mixture is a 1:

1 mixture of (5Z,7E)--(R)-- and --(S)--N--[(3S,20S)-3-hydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

29. A composition according to claim 22, wherein n is 2 and the dotted carbon--carbon bond in ring D is --C═

C--.

30. A composition according to claim 29, wherein R² is a branched alkyl having 3 to 8 carbon atoms which is unsubstituted or substituted with one or more halogen or OH substituents.

31. A composition according to claim 24, wherein the mixture is a 1:

1 mixture of (5Z,7E)--(R)-- and (S)--N--[(1S,3R,20S)-1,3-dihydroxy-17a,20a -dihomo-9,10-seco-pregna-5,7,10(19),17-tetraen-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

32. A composition according to claim 30, wherein the mixture is a 1:

1 mixture of(E)--(R)-- and (S)--N--(1R,3R,20S)-1,3-dihydroxy-17a,20a-dihomo-19-nor-9,10-seco-pregna-(5,7,7-trien-21-yl)-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

33. A composition according to claim 25, wherein the mixture is a 1:

1 mixture of (5Z,7E)--(R)-- and (S)--N--[(1S,3R,20S)-1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

34. A composition according to claim 25, wherein the mixture is a 1:

1 mixture of (E)--(R)-- and (S)--N--(1R,3R,20S)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

35. A composition according to claim 25, wherein the mixture is a 1:

1 mixture of (E)--(S)-- and (R)--N--(1R,3R,20R)-1,3-dihydroxy-20-methyl-19-nor-9,10-seco-pregna-5,7-dien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

36. A composition according to claim 25, wherein the mixture is a 1:

1 mixture of (5Z,7E)--(R)-- and (S)--N--[(3S,20R)-3-hydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.

37. A composition according to claim 25, wherein the mixture is a 1:

1 mixture of (5Z,7E)--(R)-- and (S)--N--[(1S,3R,20R)-1,3-dihydroxy-20-methyl-9,10-seco-pregna-5,7,10(19)-trien-21-yl]-4,4,4-trifluoro-3-hydroxy-3-methyl-butyramide.