9-α-substituted estratrienes as selectively active estrogens

• US 7,414,043 B2
• Filed: 06/11/2003
• Issued: 08/19/2008
• Est. Priority Date: 06/11/2002
• Status: Expired due to Fees

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Mueller, Gerd, Hillisch, Alexander, Fritzemeier, Karl-Heinrich, Kosemund, Dirk, Muhn, Peter
• Primary Examiner(s): Badio; Barbara P
• Application Number:
  US10/458,735
• Publication Number:
  US 20040087565A1
• Time in Patent Office: 1,896 Days
• Field of Search: 514/182, 556/24, 552/624
• US Class Current: 514/182
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07J 41/00 Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring

Abstract

This invention describes the new 9α-substituted estratrienes of general formula I

in which R³, R⁷, R^7′, R¹³, R¹⁶ as well as R¹⁷ and R^17′ have the meanings that are indicated in the description and R⁹ means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop-1-inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.

The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.

Claims

1. A 9α

-Substituted estra-1,3,5(10)-triene compound of formula I

2. A compound of formula I according to claim 1, in which R³ is a hydrogen atom.

3. A compound of formula I according to claim 1, in which

R⁷ is a hydrogen atom or an α

-position fluorine atom,

R⁹ is a vinyl, ethinyl or prop-1-inyl group,

R¹⁶ is a hydroxy group, and

R¹⁷ is a hydrogen atom or an α

-position fluorine atom.

4. A compound of formula I according to claim 1, in which R¹⁶ is R¹⁸—

O—

or R²⁰SO₂—

O—

.

5. A compound of formula I according to claim 1, which is

9α

-Vinyl-estra-1,3,5(10)-triene-3,16α

-diol

9α

-Allyl-estra-1,3,5(10)-triene-3,16α

-diol

18a-Homo-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol

18a-Homo-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diol

3-Methoxy-9α

-vinyl-estra-1,3,5(10)-trien-16α

-ol

9α

-Allyl-3-methoxy-estra-1,3,5(10)-trien-16α

-ol

18a-Homo-3-methoxy-9α

-vinyl-estra-1,3,5(10)-trien-16α

-ol

18a-Homo-9α

-allyl-3-methoxy-estra-1,3,5(10)-trien-16α

-ol

9α

-(2′

,2′

-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α

-diol

9α

-(2′

,2′

-Difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16α

-ol

16α

-Hydroxy-9α

-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate

9α

-Allyl-16α

-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate

18a-Homo-16α

-hydroxy-9α

-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate

18a-Homo-9α

-allyl-16α

-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate

9α

-Vinyl-estra-1,3,5(10)-triene-3,16α

-diyl-disulfamate

9α

-Allyl-estra-1,3,5(10)-triene-3,16α

-diyl-disulfamate

18a-Homo-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diyl-disulfamate

18a-Homo-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diyl-disulfamate

16α

-Hydroxy-9α

-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate

9α

-Allyl-16α

-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate

18a-Homo-16α

-hydroxy-9α

-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate

18a-Homo-9α

-allyl-16α

-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate

9α

-(Prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α

-diol

9α

-(n-Propyl)-estra-1,3,5(10)-triene-3,16α

-diol

9α

-Ethinyl-estra-1,3,5(10)-triene-3,16α

-diol

9α

-Vinyl-estra-1,3,5(10)-triene-3,16α

-diol-diacetate

18a-Homo-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol-diacetate

16α

-Valeroyloxy-9α

-vinyl-estra-1,3,5(10)-trien-3-ol

16α

-Acetoxy-9α

-vinyl-estra-1,3,5(10)-trien-3-ol

18a-Homo-16α

-acetoxy-9α

-vinyl-estra-1,3,5(10)-trien-3-ol

7α

-Fluoro-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol

7α

-Fluoro-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diol

17β

-Fluoro-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol

17β

-Fluoro-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diol

18a-Homo-7α

-fluoro-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol

18a-Homo-7α

-fluoro-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diol

18a-Homo-17β

-fluoro-9α

-vinyl-estra-1,3,5(10)-triene-3,16α

-diol or

18a-Homo-17β

-fluoro-9α

-allyl-estra-1,3,5(10)-triene-3,16α

-diol.

6. A compound of formula I according to claim 5, which is 17β

-Fluoro-9α

-vinyl-estra- 1,3,5(10)-triene-3,16α

-diol.

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

8. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically compatible vehicle.

9. A method for in vitro treatment of female infertility comprising administering to a female in need thereof an effective amount of a pharmaceutical composition according to claim 7.

10. A method for in vivo treatment of female infertility comprising administering to a female in need thereof an effective amount of a pharmaceutical composition according to claim 7.

11. A method for hormone replacement therapy comprising administering to a patient in need of replacement of estrogen, an effective amount of a pharmaceutical composition according to claim 7.

12. A method according to claim 11 further comprising administering to said patient a selective estrogen receptor modulator or raloxifene.

13. A method for therapy of prostate hyperplasia comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 7, an antiestrogen and a selective estrogen receptor modulator.

14. A method for treating rheumatoid arthritis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 6.

15. A method for treating multiple sclerosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 7.

16. A method for treatment of prostate hyperplasia comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 7.

17. A method for treatment of a perimenopausal or postmenopausal symptom selected from hot flashes, sleep disturbances, irritability, mood swings, incontinence and vaginal atrophy, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 7.

18. A method according to claim 17, wherein hot flashes are treated.

19. A method according to claim 17, wherein sleep disturbances are treated.

20. A method according to claim 17, wherein irritability is treated.

21. A method according to claim 17, wherein mood swings are treated.

22. A method according to claim 17, wherein incontinence is treated.

23. A method according to claim 17, wherein vaginal atrophy is treated.

24. A method for treatment of prostate hyperplasia comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 8.

25. A method for in vitro treatment of female infertility or for in vivo treatment of female infertility or for hormone replacement therapy comprising administering to a female in need thereof an effective amount of a pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically compatible vehicle.

26. A method for treatment of prostate hyperplasia;

rheumatoid arthritis;

multiple sclerosis;

a perimenospausal or postmenopausal symptom selected from hot flashes, sleep disturbances, irritability, mood swings, incontinence, and vaginal atrophy, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically compatible vehicle.