Novel estrogenic compounds

• US 20030207855A1
• Filed: 05/15/2003
• Published: 11/06/2003
• Est. Priority Date: 03/10/2000
• Status: Active Grant

• Current Assignee: Duramed Pharmaceuticals Incorporated
• Original Assignee: Barr Laboratories Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Hill, Edward N., Whittle, Robert R., Sancilio, Frederick D.
• Granted Patent: US 6,844,334 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: C07J 1/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Abstract

Novel estrogenic compounds of Formula I are provided.

wherein the bond represented by the wavy line may be a single or double bond such that when the wavy line is a single bond, R₁ is selected from the group consisting of hydrogen, sulfate and glucoronate or other esters, and when the wavy line is a double bond, R₁ does not exist; R₂ is lower alkyl; R₃ may be selected from the group consisting of hydrogen, sulfate, or glucuronide or other esters; and R₄ through R₁₃ may independently be selected from the group consisting of hydrogen, hydroxy, ketone, lower alkyl, lower alkoxy, halogen, and carbonyl groups and R₁₄ is selected from the group consisting of hydrogen, sulfate and glucoronide and other esters. When R₁ is hydroxy, the hydroxy or ester substituent may have either an α or a β orientation. Compositions of matter including compounds of the present invention are also provided as are methods of treating mammals in need of treatment using compounds of the present invention.

Claims

1. A compound represented by Formula I:

2. The compound according to claim 1, wherein said compound is of Formula II:

3. The compound according to claim 1, wherein said compound is of Formula III:

4. The compound according to claim 1, wherein said compound is greater than about 95% pure.

5. The compound according to claim 1, wherein R₂ is C₁ to C₄ alkyl, R₄-R₁₂ are hydrogen and R₁₃ is hydrogen or ethynyl.

6. The compound according to claim 1, wherein when R₁ is hydroxy, the compound has a β

orientation.

7. The compound according to claim 1 in conjugated form.

8. The compound according to claim 1 having the following physicochemical properties:

molecular formula of C₁₈H₁₉O₆S;

¹H-NMR spectrum as shown in FIG. 6; and

¹³C-NMR spectrum as shown in FIG. 12.

9. The compound according to claim 1 having the following physicochemical properties:

molecular formula of C₁₈H₁₇O₆S;

¹H-NMR spectrum as shown in FIG. 27; and

¹³C-NMR spectrum as shown in FIG. 33.

10. A pharmaceutical composition incorporating a compound represented by Formula I:

11. The pharmaceutical composition according to claim 10, wherein said compound is of Formula II:

12. The pharmaceutical composition according to claim 10, wherein said compound is of Formula III:

13. The pharmaceutical composition according to claim 10, wherein said compound is greater than about 95% pure.

14. The pharmaceutical composition according to claim 10, wherein R₂ is C₁ to C₄ alkyl, R₄-R₁₂ are hydrogen and R₁₃ is hydrogen or ethynyl.

15. The pharmaceutical composition according to claim 10, wherein when R₁ is hydroxy, the compound has a B orientation.

16. The pharmaceutical composition according to claim 10, wherein said compound is in conjugated form.

17. The pharmaceutical composition according to claim 10, wherein the composition further comprises at least one additional pharmaceutically active ingredient.

18. The pharmaceutical composition according to claim 17, wherein the at least one additional pharmaceutically active ingredient is selected from the group consisting of estrogenic compounds, androgenic compounds, progestin compounds, vasodilation agents, calcium salts, and vitamin D and its derivatives, and mixtures and combinations thereof.

19. The pharmaceutical composition according to claim 10, wherein said compound has the following physicochemical properties:

molecular formula of C₁₈H₁₉O₆S;

¹H-NMR spectrum as shown in FIG. 6; and

¹³C-NMR spectrum as shown in FIG. 12.

20. The pharmaceutical composition according to claim 10, wherein said compound has the following physicochemical properties:

molecular formula of C₁₈H₁₇O₆S;

¹H-NMR spectrum as shown in FIG. 27; and

¹³C-N spectrum as shown in FIG. 33.

21. A method of treating mammals in need of treatment, said method comprising administering an effective amount of a compound represented by Formula I:

22. The method according to claim 21, wherein said compound is of Formula II:

23. The method according to claim 21, wherein said compound is of Formula III:

24. The method according to claim 21, wherein said compound is greater than about 95% pure.

25. The method according to claim 21, wherein R₂ is C₁ to C₄ alkyl, R₄-R₁₂ are hydrogen and R₁₃ is hydrogen or ethynyl.

26. The method according to claim 21, wherein when R₁ is hydroxy, the compound has a β

orientation.

27. The method according to claim 21, wherein said compound is in conjugated form.

28. The method according to claim 21, wherein said compound is administered as part of a pharmaceutical composition, said composition further comprising at least one additional pharmaceutically active ingredient.

29. The method according to claim 28, wherein the at least one additional pharmaceutically active ingredient is selected from the group consisting of estrogenic compounds, androgenic compounds, progestin compounds, vasodilation agents, calcium salts, and vitamin D and its derivatives, and mixtures and combinations thereof.

30. The method according to claim 21, wherein said compound has the following physicochemical properties:

molecular formula of C₁₈H₁₉O₆S;

¹H-NMR spectrum as shown in FIG. 6; and

¹³C-NMR spectrum as shown in FIG. 12.

31. The method according to claim 21, wherein said compound has the following physicochemical properties:

molecular formula of C₁₈H₁₇O₆S;

¹H-NMR spectrum as shown in FIG. 27; and

¹³C-NMR spectrum as shown in FIG. 33.