Prodrugs of ERbeta-selective substances, process for their production, and pharmaceutical compositions that contain these compounds

• US 20070197488A1
• Filed: 11/29/2006
• Published: 08/23/2007
• Est. Priority Date: 11/29/2005
• Status: Abandoned Application

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer Schering Pharma AG (Bayer AG)
• Inventors: Peters, Olaf, Prelle, Katja, Hillisch, Alexander, Droescher, Peter, Elger, Walter, Reddersen, Gudrun, Wyrwa, Ralf
• Application Number:
  US11/605,472
• Publication Number:
  US 20070197488A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: C07J 41/0044 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group

Abstract

This invention provides prodrugs of 8β-substituted estratrienes of general formula (I), in which the group Z is bonded to the steroid, process for their production, pharmaceutical compositions that contain these compounds as well as use thereof. The compounds of general formula I according to the invention do not bind to the estrogen receptor α and/or β. They bind to carbonic anhydrases and inhibit these enzymes.

Claims

1. Sulfamoyl compounds of 8β

-substituted estratrienes 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 in each case a radical

R¹, R² or R³ represents a group —

SO₂NH₂.

4. Compounds according to claim 1, wherein R¹ represents a group

—

SO₂NH₂ or —

NHSO₂NH₂.

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

SO₂NH₂.

6. Compounds according to claim 1, wherein if one of the radicals R¹, R², and R³ does not mean —

SO₂NH₂ or —

NHSO₂NH₂, the other two radicals R¹, R², and R³ in each case, as well as X and X¹, independently of one another, stand for a hydrogen, fluorine or chlorine atom, a hydroxy group or a methoxy group.

7. Compounds according to claim 1, wherein R⁸ is a methyl, ethyl, vinyl or difluorovinyl radical.

8. Compounds according to claim 1, (3′

-Hydroxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate

2) (3′

-Hydroxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

3) (3′

-Hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

4) (3′

-Hydroxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

5) (3′

-Hydroxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

6) (3′

-Hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate

7) (3′

-Acetoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

8) (3′

-Acetoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

9) (3′

-Acetoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

10) (3′

-Acetoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

11) (3′

-Acetoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

12) (3′

-Acetoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

13) (3′

-Benzoyloxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

14) (3′

-Benzoyloxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

15) (3′

-Benzoyloxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

16) (3′

-Benzoyloxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

17) (3′

-Benzoyloxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

18) (3′

-Benzoyloxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

19) (3′

-Hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)2-chloro-5-sulfamoyl benzoate,

20) (3′

-Hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl-4-chloro-benzoate,

21) (3′

-Hydroxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)2-chloro-5-sulfamoyl benzoate,

22) (3′

-Hydroxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl-4-chlorobenzoate,

23) (3′

-Hydroxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)2-chloro-5-sulfamoyl benzoate,

24) (3′

-Hydroxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl-4-chloro-benzoate,

25) (17′

β

-(n-Pentanoyloxy)-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

26) (17′

β

-(n-Pentanoyloxy)-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

27) (17′

β

-(n-Pentanoyloxy)-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

28) (17′

β

-Benzoyloxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

29) (17′

β

-Benzoyloxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

30) (17′

β

-Benzoyloxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

31) (17′

β

-(n-Pentanoyloxy)-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

32) (17′

β

-(n-Pentanoyloxy)-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

33) (17′

β

-(n-Pentanoyloxy)-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

34) (17′

β

-Benzoyloxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

35) (17′

β

-Benzoyloxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

36) (17′

β

-Benzoyloxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

37) (17′

β

-Acetoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

38) (17′

β

-Acetoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

39) (17′

β

-Acetoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)3-sulfamoyl benzoate,

40) (17′

β

-Acetoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate

41) (17′

β

-Acetoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

42) (17′

β

-Acetoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-3′

-yl)4-sulfamoyl benzoate,

43) (3′

-Methoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

44) (3′

-Methoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

45) (3′

-Methoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate,

46) (3′

-Methoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

47) (3′

-Methoxy-8′

β

-ethyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate,

48) (3′

-Methoxy-8′

β

-methyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate.

9. Pharmaceutical compositions that contain at least one compound according to claim 1 as well as a pharmaceutically compatible vehicle.

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

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

12. Pharmaceutical composition according to claim 11, wherein the gestagen is drospirenone, dienogest, norethisterone or levonorgestrel, the antigestagen is onapristone or mifepristone or the mesoprogestin is asoprisnil.

13. Use of the compounds according to the invention according to claim 1 for the production of a pharmaceutical agent.

14. Use according to claim 13 for treating diseases and conditions in women and in men that are caused by an estrogen deficiency.

15. Use according to claim 13 for treating perimenopausal and postmenopausal symptoms.

16. Use according to claim 13 for the in-vitro treatment of male infertility.

17. Use according to claim 13 for the in-vivo treatment of male infertility.

18. Use according to claim 13 for the in-vitro treatment of female infertility.

19. Use according to claim 13 for the in-vivo treatment of female infertility.

20. Use according to claim 13 for the therapy of hormone-deficiency-induced symptoms in ovarian dysfunction that is caused by surgery, medication, etc.

21. Use according to claim 13 for hormone replacement therapy (HRT).

22. Use according to claim 20 in combination with a selective estrogen receptor modulator (SERM), for example raloxifene.

23. Use according to claim 13 for prophylaxis and therapy of a hormone-deficiency-induced bone mass loss.

24. Use according to claim 13 for prophylaxis and therapy of osteoporosis.

25. Use according to claim 23 in combination with the natural vitamin D3 or with calcitriol analogs for bone building or as supporting therapies to therapies that cause a bone mass loss (for example, a therapy with glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, or chemotherapy).

26. Use according to claim 13 for prevention against and therapy of cardiovascular diseases.

27. Use according to claim 13 for treating inflammatory diseases and diseases of the immune system.

28. Use according to claim 27 for treating rheumatoid arthritis.

29. Use according to claim 27 for treating multiple sclerosis, Crohn'"'"'s disease or endometriosis.

30. Use according to claim 13 for preventing and treating benign prostate hyperplasia (BPH).

31. Use according to claim 30 in combination with antiestrogens and selective estrogen receptor modulators for preventing and treating benign prostate hyperplasia (BPH).

32. Use according to claim 31, whereby 7alpha-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β

-diol (fulvestrant) is used as antiestrogen or raloxifene, tamoxifen, or 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulfinyl]-pentyl}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol is used as SERM.

33. Use according to claim 13 for treating arthritic symptoms, in particular after therapies that result in estrogen deprivation, for example after treatment with aromatase inhibitors or GnRH antagonists or agonists.

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

35. Use of compounds according to claim 1 for the production of pharmaceutical agents for treating alopecia.

36. Use of 3′

-hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate, (3′

-hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate, 3′

-hydroxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl-4-chlorobenzoate, (3′

-methoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)3-sulfamoyl benzoate and (3′

-methoxy-8′

β

-vinyl-estra-1′

,3′

,5′

(10′

)-trien-17′

β

-yl)4-sulfamoyl benzoate according to claim 13.

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