Estradiol prodrugs

• US 20050288267A1
• Filed: 05/20/2005
• Published: 12/29/2005
• Est. Priority Date: 05/21/2004
• Status: Active Grant

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Ring, Sven, Hillisch, Alexander, Droescher, Peter, Elger, Walter, Schneider, Birgitt, Wyrwa, Ralf, Reddersen, Gudrun
• Granted Patent: US 7,534,780 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

The invention relates to estradiol prodrugs of general formula (I), in which group Z is bonded to the steroid, process for their production, pharmaceutical compositions that contain these compounds, as well as their use for the production of pharmaceutical agents with estrogenic action.

Claims

1. Estradiol prodrugs of general formula I

2. Compounds according to claim 1, characterized in that n is 0, 1 or 2.

3. Compounds according to claim 1, wherein R¹ represents a radical —

SO₂NH₂ or —

NHSO₂NH₂.

4. Compounds according to claim 3, wherein R¹ represents a group —

SO₂NH₂.

5. Compounds according to claim 1, wherein either R¹, R² or R³ represents a group —

SO₂NH₂.

6. Compounds according to claim 1, wherein R¹, R², R³, if the latter do not represent —

SO₂NH₂ or —

NHSO₂NH₂, as well as X and X¹, independently of one another, stand for a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group or a methoxy group.

7. Compounds according to claim 1, wherein, independently of one another,

R⁵, R⁶, R⁷ and R⁸ in each case represent a hydrogen atom,

R⁹ represents a hydrogen atom or a fluorine atom,

R¹¹ represents a hydrogen atom or a fluorine atom,

R¹⁰ represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a butciclate radical, a cyclopentylpropionate radical or a group Z,

R¹² represents a hydroxy group, a methoxy group, a trimethylsilyloxy radical, a tert.-butyldimethylsilyloxy radical, a benzoate radical, an acetate radical, a propionate radical, a valerate radical, a butciclate radical, a cyclopentylpropionate radical or a group Z,

R¹⁴ represents a hydrogen atom, and

R¹⁵ represents a hydrogen atom, a methoxy group, or an ethoxy group.

8. Compounds according to claim 1, 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate (9),

2) 3-Acetoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

3) 3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate (10),

4) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate (21),

5) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl-4′

-chloro-benzoate (3),

6) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoylbenzoate (7),

7) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate (5),

8) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate (12),

9) 3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-methoxy-5′

-sulfamoylbenzoate

10) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate (19),

11) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate (1),

12) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

13) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

14) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl4′

-chloro-benzoate,

15) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate

16) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

17) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

18) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

19) 3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate (14),

20) 17β

-(n-Pentanoyloxy)estra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate (15),

21) 17β

-Benzoyloxyestra-1,3,5(10)-trien-3-yl 3′

-sulfamoylbenzoate (16),

22) 17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 4′

-sulfamoylbenzoate (17),

23) 17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

,3′

-dichloro-5′

-sulfamoylbenzoate (24),

24) 17β

-Hydroxyestra-1,3,5(10)-trien-3-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate (23),

25) 3-Methoxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate (11),

26) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

27) 3-Benzoyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-sulfamoylbenzoate,

28) 2-Methoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3+-dimethoxy-5′

-sulfamoylbenzoate,

29) Estra-1,3,5(10)-trien-3,17β

-diyl bis(3′

-sulfamoylbenzoate) (27),

30) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

31) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

32) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoyl4′

-chloro-benzoate,

33) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,4′

-dichloro-5′

-sulfamoyl-benzoate,

34) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-fluoro-5′

-sulfamoylbenzoate,

35) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

36) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamatobenzoate,

37) 2-Ethoxy-3-hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

,3′

-dimethoxy-5′

-sulfamoylbenzoate,

38) 3-tert.-Butyldimethylsilyloxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate (28),

39) 3-Hydroxyestra-1,3,5(10)-trien-17β

-yl 2′

-chloro-4′

-sulfamoylbenzoate (29)

9. Pharmaceutical compositions that contain at least one compound according to claim 1.

10. Pharmaceutical composition according to claim 9, wherein at least one additional steroidally active compound is included.

11. Pharmaceutical composition according to claim 10, wherein an additional steroidally active compound is a gestagen, an antigestagen or a mesoprogestin.

12. Use of the compounds according to claim 1 for the production of pharmaceutical agents for hormone replacement therapy in women.

13. Use of the compounds according to claim 1 for birth control in women.

14. Uses of the compound according to claim 1 for the production of pharmaceutical agents for treating hormonally induced diseases in men and women.

15. Use according to claim 14 for the production of pharmaceutical agents for treating endometriosis, breast cancer, prostate cancer and hypogonadism.

16. Use of compounds according to claim 1 for the production of pharmaceutical agents for treating diseases that can be positively influenced by the inhibition of carboanhydrase activity.

17. Process for the production of compounds of general formula (I) according to claim 1