18 Norsteroids as selectively active estrogens

• US 6,958,327 B1
• Filed: 11/02/2000
• Issued: 10/25/2005
• Est. Priority Date: 11/02/1999
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Hegele-Hartung, Christa, Sauer, Gerhard, Boidol, Werner, Hillisch, Alexander, Schwede, Wolfgang, Fritzemeier, Karl-Heinrich, Esperling, Peter, Kollenkirchen, Uwe
• Primary Examiner(s): Badio, Barbara P.
• Application Number:
  US10/111,933
• Time in Patent Office: 1,818 Days
• Field of Search: 514/182, 552/628, 552/613, 552/625, 552/629, 552/630
• 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 novel 18-norsteroids (gonatrienes) of general formula (I), wherein R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹¹, R^11′, R¹⁴, R¹⁵, R^15′, R¹⁶, R¹⁷ and R^17′ have the meaning cited in the description, and to the use of said compounds as pharmaceutical active ingredients. Said compounds exhibit a high affinity in vitro for estrogen receptor preparations of rat prostate and in an estrogen receptor preparation of rat uterus. Said compounds exhibit in vivo preferential activity on bones as compared to the uterus and/or significant activity with regard to stimulating the expression of 5HT2a-receptors and transporter molecules. The invention also relates to the production of said compounds, therapeutic use and galenic form of said compounds contained in the novel compounds of invention. The invention also relates to utilization of steroids based on the gonatriene molecular skeleton in order to treat estrogen deficiency-induced diseases and disorders, in addition to the use of said gonatriene structural component in the total structure of compounds which dissociate to produce enhanced estrogen activity in bone as compared to the uterus

Claims

1. A gona-1,3,5(10)-triene compound of formula I

in which

R¹ means a halogen atom, or R¹⁸—

O—

,

R¹⁸ means a hydrogen atom or a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms,

R² means a hydrogen atom

R¹⁹ is an R²⁰R²¹N group,

R²⁰ and R²¹, independently of one another, represent a hydrogen atom, a C₁-C₅ alkyl radical, a group C(O)R²²,

R²² can contain a straight-chain or branched-chain hydrocarbon radical with up to 12 carbon atoms, which in addition can contain up to three double bonds and/or triple bonds, a C₃-C₇ cycloalkyl radical, an aryl radical or a combination of these structural features, or, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;

R³ means a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

O—

C(O)R²², or an —

O-aryl —

O-heteroaryl or —

O-aralkyl radical;

R⁶ is hydrogen,

R⁷ is a hydrogen atom, a halogen atom, a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

R²², a straight-chain or branched-chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,

R⁸ and R⁹ are hydrogen,

R¹¹ means a hydrogen atom, a halogen atom, a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

R²², a group —

X—

R¹⁸, a nitrooxy group, a straight-chain or branched-chain, saturated or unsaturated, partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,

X is an oxygen or sulfur atom,

R^11′

, R¹⁴, R¹⁵, R^15′

and R¹⁶ each mean a hydrogen atom, and

R¹⁷ and R^17′

mean a hydrogen atom and a halogen atom;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

hydrogen and a group —

O—

C(O)R²²;

or hydrogen and —

R¹⁸—

O—

.

2. A compound according to claim 1, in which

R¹ is a hydroxy group.

3. A compound according to claim 1, in which

R⁷ is a hydrogen atom, a fluorine or chlorine atom, a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

R²², a straight-chain or branched-chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical.

4. A compound according to claim 1, in which

X is an sulfur atom,

R¹¹ is a hydrogen atom, a halogen atom, a group —

R²², a group —

X—

R¹⁸, a straight-chain or branched-chain, saturated or unsaturated, partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms or an optionally substituted aryl or heteroaryl radical.

5. A compound according to claim 1, in which

X is an sulfur atom,

R¹⁸ is a saturated, straight-chain or branched-chain C₁-C₆ alkyl group,

R¹¹ is a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C₁-C₆ alkyl group, a group —

X—

R¹⁸, a chloromethyl or chloroethyl group or an optionally substituted aryl or heteroaryl radical.

6. A compound according to claim 1, in which

R¹ means a hydroxy group,

R⁷ means a hydrogen atom, a fluorine or chlorine atom, a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

R²², a straight-chain or branched-chain, saturated or unsaturated, partially or completely halogenated alkyl group with up to 10 carbon atoms or an optionally substituted aryl, heteroaryl or aralkyl radical,

R¹¹ means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C₁-C₆ alkyl group, a group —

X—

R¹⁸, a chloromethyl or chloroethyl group or an optionally substituted aryl or heteroaryl radical,

X is a sulfur atom, and

R¹⁸ means a saturated, straight-chain or branched-chain C₁-C₆ alkyl group.

7. A compound according to claim 1, in which

R¹⁷ and R^17′

are hydrogen and —

R¹⁸—

O—

;

or hydrogen and a group —

O—

C(O)R²².

8. A compound according to claim 1, in which

R³ means a group R¹⁹SO₂—

O—

or —

O—

C(O)R²², or an —

O-aryl —

O-heteroaryl or —

O-aralkyl radical.

9. A compound according to claim 1, in which

R¹⁷ and R^17′

mean a hydrogen atom and a halogen atom;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

or hydrogen and a group —

O—

C(O)R²².

11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically compatible vehicle.

12. A method for treating an estrogen-deficiency-induced disease or condition in a woman or man, comprising administering to the woman or man a compound according to claim 1.

14. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a perimenopausal and postmenopausal symptom.

15. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a peri- and post-male-menopausal symptom.

16. A method according to claim 14, wherein the estrogen-deficiency-induced disease or condition is hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy or a hormone-deficiency-induced emotional disease.

17. A method according to claim 16, wherein the disease is in the urogenital tract.

18. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a disease of stomach or intestine.

19. A method according to claim 18, wherein the estrogen-deficiency-induced disease or condition is an ulcer or a hemorrhagic diatheses in the gastrointestinal tract.

20. A method according to claim 19, wherein the estrogen-deficiency-induced disease or condition is neoplasia.

21. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is male infertility, which is treated in-vitro.

22. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is male infertility, which is treated in-vivo.

23. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is female infertility, which is treated in-vitro.

24. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is female infertility, which is treated in-vivo.

25. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a disease treated with hormone replacement therapy (HRT).

26. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is hormone-deficiency-induced bone mass loss.

27. A method according to claim 26, wherein the estrogen-deficiency-induced disease or condition is osteoporosis.

28. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a cardiovascular disease.

29. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a vascular disease.

30. A method according to claim 29, wherein the estrogen-deficiency-induced disease or condition is arteriosclerosis.

31. A method according to claim 29, wherein the estrogen-deficiency-induced disease or condition is neointimal hyperplasia.

32. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a hormone-deficiency-induced neurodegenerative disease.

33. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is a hormone-deficiency-induced impairment of memory and learning capacity, wherein Alzheimer'"'"'s disease is optionally also treated.

34. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is an inflammatory disease or a disease of the immune system.

35. A method according to claim 12, wherein the estrogen-deficiency-induced disease or condition is benign prostate hyperplasia (BPH).

10. A compound which is

11β

-Fluoro-gona-1,3,5(10)-triene-3,17-diol

11β

-chloro-gona-1,3,5(10)-triene-3,17-diol

11β

-methyl-gona-1,3,5(10)-triene-3,17-diol

11β

-ethyl-gona-1,3,5(10)-triene-3,17-diol

11β

-phenyl-gona-1,3,5(10)-triene-3,17-diol

7α

-fluoro-gona-1,3,5(10)-triene-3,17-diol

7α

-methyl-gona-1,3,5(10)-triene-3,17β

-diol

7α

-phenyl-gona-1,3,5(10)-triene-3,17β

-diol

7α

-methyl-gona-1,3,5(10)-triene-3,17-diol

7β

-fluoro-gona-1,3,5(10)-triene-3,17-diol

7β

-methyl-gona-1,3,5(10)-triene-3,17β

-diol

7β

phenyl-gona-1,3,5(10)-triene-3,17β

-diol

7β

-methyl-gona-1,3,5(10)-triene-3,17-diol

11β

-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

11β

-chloro-gona-1,3,5(10)-triene-1,3,17-triol

11β

-methyl-gona-1,3,5(10)-triene-1,3,17-triol

11β

-ethyl-gona-1,3,5(10)-triene-1,3,17-triol

11β

-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7α

-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

7α

-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7α

-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7α

-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7β

-fluoro-gona-1,3,5(10)-triene-1,3,17-triol

7β

-methyl-gona-1,3,5(10)-triene-1,3,17-triol

7β

-phenyl-gona-1,3,5(10)-triene-1,3,17-triol

7β

-methyl-gona-1,3,5(10)-triene-1,3,17-triol or

13α

-H-18-nor-estradiol.

13. A method for treating an estrogen-deficiency-induced disease or condition in a woman or man, comprising administering to the woman or man a compound according to claim 10.