Prodrugs of ERbeta-selective substances, processes for their preparation and pharmaceutical compositions comprising these compounds

• US 20070123500A1
• Filed: 11/28/2006
• Published: 05/31/2007
• 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: Mueller, Gerd, Kosemund, Dirk, Wyrwa, Ralf
• Application Number:
  US11/604,891
• Publication Number:
  US 20070123500A1
• 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 present invention makes available prodrugs of 9α-substituted oestratrienes of the general formula (I) in which the group Z is bonded to the steroid, processes for their preparation, pharmaceutical compositions which comprise these compounds and use thereof. The compounds of the general formula I according to the invention do not bind to the oestrogen receptor a and/or β. They bind to carboanhydrases and inhibit these enzymes.

Claims

1. Sulphamoyl compounds of 9α

-substituted oestra-trienes of the general formula (I)

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

3. Compounds according to claim 1, characterized in that in each case one radical R¹, R² or R³ is a group —

SO₂NH₂.

4. Compounds according to claim 1, characterized in that R¹ is a group —

SO₂NH₂ or —

NHSO₂NH₂.

5. Compounds according to claim 4, characterized in that R¹ is a group —

SO₂NH₂.

6. Compounds according to claim 1, characterized in that if one of the radicals R¹, R², R³ is not —

SO₂NH₂ or —

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

7. Compounds according to claim 1, characterized in that R⁶ is a methyl, ethyl, vinyl or difluorovinyl radical.

8. Compounds according to claim 1, 3-hydroxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

2) 3-hydroxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

3) 3-hydroxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

4) 3-hydroxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

5) 3-acetoxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

6) 3-acetoxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

7) 3-acetoxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

8) 3-acetoxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 3′

-sulphamoylbenzoate,

9) 3-hydroxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5 ′

-sulphamoylbenzoate,

10) 3-hydroxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

11) 3-hydroxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

12) 3-hydroxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

13) 3-acetoxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

14) 3-acetoxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

15) 3-acetoxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

16) 3-acetoxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 2′

-chloro-5′

-sulphamoylbenzoate,

17) 3-hydroxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

18) 3-hydroxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

19) 3-hydroxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

20) 3-hydroxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

21) 3-acetoxy-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

22) 3-acetoxy-17β

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

23) 3-acetoxy-7α

-methyl-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate,

24) 3-acetoxy-7α

-fluoro-9α

-vinyloestra-1,3,5(10)-trien-16α

-yl 4′

-sulphamoylbenzoate.

9. Pharmaceutical compositions comprising at least one compound according to claim 1, and a pharmaceutically tolerable carrier.

10. Pharmaceutical composition according to claim 9, characterized in that at least one further steroidal compound is present.

11. Pharmaceutical composition according to claim 10, characterized in that the further steroidal compound is a gestagen, antigestagen or mesoprogestin.

12. Pharmaceutical composition according to claim 11, where the gestagen is drospirenone, dienogest, norethisterone or levonorgestrel, and the anti-gestagen is onapristone or mifepristone or the mesoprogestin is asoprisnil.

13. Use of the compounds according to the invention as set forth in claim 1 for the production of a medicament.

14. Use according to claim 13 for the treatment of diseases and conditions in women and in men which are caused by an oestrogen deficit.

15. Use according to claim 13 for the treatment of peri- and postandropausal 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-related symptoms in ovarian dysfunction caused surgically, medicinally or in another way.

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

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

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

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

25. Use according to claim 23 in combination with the natural vitamin D3 or with calcitriol analogues for osteogenesis or as a supportive therapy for therapies which cause a loss of bone mass (for example a therapy using glucocorticoids, aromatase inhibitors, GnRH agonists or antagonists, chemotherapy).

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

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

28. Use according to claim 27 for the treatment of rheumatoid arthritis.

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

30. Use according to claim 13 for the prevention and treatment of benign prostate hyperplasia (BPH).

31. Use according to claim 30 in combination with anti-oestrogens and selective oestrogen receptor modulators for the prevention and treatment of benign prostate hyperplasia (BPH).

32. Use according to claim 31, where the anti-oestrogen used is 7α

-[9-[(4,4,5,5,5-pentafluoro-pentyl)sulphinyl]nonyl]oestra-1,3,5(10)-triene-3,17β

-diol (fulvestrant) and the SERM used is raloxifen, tamoxifen or 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl)pentyl}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol.

33. Use according to claim 13 for the treatment of arthritic symptoms, in particular after therapies which lead to oestrogen deprivation, for example after treatment with aromatase inhibitors or GnRH antagonists or agonists.

34. Use of compounds according to claim 1 for production of medicaments for the treatment of diseases which can be positively influenced by the inhibition of the carboanhydrase activity.

35. Use of compounds according to claim 1 for production of medicaments for the treatment of alopecia.

36. Use of 3-hydroxy-9α

-vinyloestra-1,3,5(10)-trien-16β

-yl 3′

-sulphamoylbenzoate, 3-acetoxy-9α

-vinyl-oestra-1,3,5(10)-trien-16β

-yl 3′

-sulphamoyl-benzoate as set forth in claim 13.

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