NEW 2-SUBSTITUTED D-HOMO-ESTRA-1,3,5(10)-TRIENES AS INHIBITORS OF 17BETA-HYDROXY STEROID DEHYDROGENASE TYPE 1

• US 20080306164A1
• Filed: 08/15/2008
• Published: 12/11/2008
• Est. Priority Date: 07/02/2004
• Status: Active Grant

• Current Assignee: Alexander Hillisch, Birgitt Schneider, Christian Gege, Dominga Deluca, Gabriele Moeller, Jerzy Adamski, Olaf Peters, Walter Elger, Wilko Regenhardt
• Original Assignee: Alexander Hillisch, Birgitt Schneider, Christian Gege, Dominga Deluca, Gabriele Moeller, Jerzy Adamski, Olaf Peters, Walter Elger, Wilko Regenhardt
• Inventors: Peters, Olaf, Gege, Christian, Hillisch, Alexander, Elger, Walter, Schneider, Birgitt, Deluca, Dominga, Regenhardt, Wilko, Adamski, Jerzy, Moeller, Gabriele
• Granted Patent: US 7,732,493 B2
• Time in Patent Office: Days
• US Class Current: 514/680
• CPC Class Codes: C07J 63/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

Abstract

The invention relates to new 2-substituted D-homo-estra-1,3,5(10)-trienes of general formula I

in which

• • R² means a C₁-C₈-alkyl group, a C₁-C₈-alkyloxy group or a halogen atom,
  • R¹³ means a hydrogen atom or a methyl group,
  • R¹⁷ means a hydrogen atom or a fluorine atom,
    as well as their pharmaceutically acceptable salts,
    their manufacture and use as medicaments for prophylaxis and therapy of estrogen-dependent diseases that can be influenced by inhibition of 17β-hydroxy steroid dehydro-genase type 1.

Claims

1-14. -14. (canceled)

15. A 2-substituted D-homo-estratriene compound of formula I

16. A 2-substituted D-homo-estratriene compound according to claim 15, wherein R¹³ is a hydrogen atom.

17. A 2-substituted D-homo-estratriene compound according to claim 15, which is:

1) 2-Methoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

2) 2-Ethoxy-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

3) 2-Chloro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

4) 2-Bromo-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

5) 2-Iodo-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

6) 2-Chloro-17α

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

7) 2-Chloro-17β

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

8) 2-Bromo-17α

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

9) 2-Bromo-17β

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

10) 2-Allyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

11) 2-Allyl-17α

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

12) 2-Allyl-17β

-Fluoro-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

13) 2-Chloro-17a-oxo-17a-homoestra-1,3,5(10),16-tetraen-3-ol;

14) 2-Bromo-17a-oxo-17a-homoestra-1,3,5(10),16-tetraen-3-ol;

15) 2-Allyl-17a-oxo-17a-homoestra-1,3,5(10),16-tetraen-3-ol;

16) 2-Propyl-17a-oxo-17a-homoestra-1,3,5(10)-trien-3-ol;

17) 2-Methoxy-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

18) 2-Ethoxy-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

19) 2-Chloro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

20) 2-Bromo-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

21) 2-Iodo-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

22) 2-Chloro-17α

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

23) 2-Chloro-17β

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

24) 2-Bromo-17α

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

25) 2-Bromo-17β

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

26) 2-Allyl-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

27) 2-Allyl-17α

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

28) 2-Allyl-17β

-Fluoro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10)-trien-3-ol;

29) 2-Chloro-17a-oxo-17a-homo-18a-homoestra-1,3,5(10),16-tetraen-3-ol;

30) 2-Bromo-17a-oxo-17a-homo-18a-homoestra-1,3,5(10),16-tetraen-3-ol;

or

31) 2-Allyl-17a-oxo-17a-homo-18a-homoestra-1,3,5(10),16-tetraen-3-ol.

18. A pharmaceutical composition that comprises at least one compound of formula I according to claim 15 and a pharmaceutically compatible adjuvant and/or vehicle.

19. The pharmaceutical composition of claim 18, wherein the composition further comprises at least one additional active ingredient.

20. The pharmaceutical composition of claim 19, wherein the at least one additional active ingredient is an antiandrogen, antigestagen, aromatase inhibitor or an antiestrogen.

21. The pharmaceutical composition of claim 18, wherein the composition is provided in a daily dose form containing 5 μ

g to 50 mg, per kg body weight of the intended patient, of the at least one compound of formula I.

22. A method for preparing a medicament which comprises at least one compound of formula I according to claim 15, wherein the method comprises formulating at least one compound of formula I into a suitable medicament form.

23. A method for treating an estrogen-dependent disease that can be positively influenced by the inhibition of the 17β

-hydroxy steroid dehydrogenase wherein the disease is selected from breast cancer, prostate cancer and endometriosis, which comprises administering to a patient in need thereof a 17β

-hydroxy steroid dehydrogenase inhibiting effective amount of a 2-substituted D-homoestra-1,3,5(10)-triene compound according to claim 15.

24. The method of claim 23, wherein the at least one compound of formula I is administered in a daily dose of 5 μ

g to 50 mg per kg of body weight of the patient.

25. The method of claim 23, wherein the at least one compound of formula I is administered in a daily dose of 10 μ

g to 30 mg per kg of body weight of the patient.

26. The method of claim 23, which further comprises administering to the patient at least one additional active ingredient.

27. The method of claim 26, wherein the at least one additional active ingredient is an antiandrogen, antigestagen, aromatase inhibitor or an antiestrogen.