Estriol and estetrol prodrugs

• US 20050277625A1
• Filed: 05/23/2005
• Published: 12/15/2005
• Est. Priority Date: 05/21/2004
• Status: Abandoned Application

• 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
• Application Number:
  US11/134,618
• Publication Number:
  US 20050277625A1
• 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

This invention provides estriol and estetrol prodrugs of general formula (I), in which group Y 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. Estriol and estetrol 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, fluorine or chlorine atom, or a hydroxy or methoxy group.

7. Compounds according to claim 1, wherein R⁴, R¹⁶ and R¹⁷ in each case and independently of one another represent a hydroxy, trimethylsilyloxy, tert.-butyldimethylsilyloxy, benzoate, acetate, propionate, valerate, butciclate, or cyclopentylpropionate group or a group Y, and R¹⁵ represents a hydrogen atom.

8. Compounds according to claim 1, wherein STEROID stands for a steroidal ABCD-ring system of general partial formulas II B and II C.

9. Compounds according to claim 1, namely 3,16α

-Dihydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate (7),

2) 3,16α

-Dihydroxyestra-1,3,5(10)trien-17β

-yl 4′

-sulfamoylbenzoate (1),

3) 3-tert.-butyldimethylsilyloxy-16α

-hydroxyestra-1,3,5(10)-trien-17β

-yl 3′

sulfamoylbenzoate,

4) 3-tert.-butyldimethylsilyloxy-16α

-hydroxyestra-1,3,5(10)-trien-17β

-yl 4-sulfamoylbenzoate,

5) 3,17β

-Dihydroxyestra-1,3,5(10)-trien-16α

-yl 3′

-sulfamoylbenzoate (10),

6) 3,17β

-Dihydroxyestra-1,3,5(10)-trien-16α

-yl 4′

-sulfamoylbenzoate (4),

7) 3-tert.-butyldimethylsilyloxy-17β

-hydroxyestra-1,3,5(10)-trien-16α

-yl 3′

-sulfamoylbenzoate,

8) 3-tert.-butyldimethylsilyloxy-17β

-hydroxyestra-1,3,5(10)-trien-16α

-yl 4′

-sulfamoylbenzoate,

9) 3,16α

-Dihydroxyestra-1,3,5(10)trien-17β

-yl 2′

-chloro-5′

-sulfamoylbenzoate,

10) 16α

, 17β

-Dihydroxyestra-1,3,5(10)-trien-3-yl 4′

-sulfamoylbenzoate (13),

11) 3,15α

, 16α

-Trihydroxyestra-1,3,5(10)-trien-17β

-yl 3′

-sulfamoylbenzoate,

12) 3,15α

, 16α

-Trihydroxyestra-1,3,5(10)-trien-17β

-yl 4′

-sulfamoylbenzoate,

13) 3,15α

, 17β

-Trihydroxyestra-1,3,5(10)-trien-16α

-yl 3′

-sulfamoylbenzoate,

14) 3,15α

, 17β

-Trihydroxyestra-1,3,5(10)-trien-16α

-yl 4′

-sulfamoylbenzoate,

15) 3,16α

, 17β

-Trihydroxyestra-1,3,5(10)-trien-15α

-yl 3′

-sulfamoylbenzoate,

16) 3,16α

, 17β

-Trihydroxyestra-1,3,5(10)-trien-15α

-yl 4′

-sulfamoylbenzoate,

17) 15α

, 16α

, 17β

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

-sulfamoylbenzoate,

18) 15α

, 16α

, 17β

-Trihydroxyestra-1,3,5(10)-trien-3yl 4′

-sulfamoylbenzoate.

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

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

12. Pharmaceutical composition according to claim 11, wherein the additional steroidally active compound is a gestagen.

13. Pharmaceutical composition according to claim 12, wherein the gestagen is selected from the following group:

progesterone, norethisterone, dienogest, cyproterone acetate, chlormadinone acetate, drospirenone, medroxy progesterone acetate, levonorgestrel, and gestodene.

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

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

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

17. Use according to claim 16 for the production of pharmaceutical agents for treatment of endometriosis, breast cancer, prostate cancer and hypogonadism.

18. Use of the 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.

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