8β-hydrocarbyl-substituted estratrienes for use as selective estrogens

• US 7,378,404 B2
• Filed: 04/12/2001
• Issued: 05/27/2008
• Est. Priority Date: 04/12/2000
• Status: Expired due to Fees

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Kollenkirchen, Uwe, Hegele-Hartung, Christa, Thieme, Ina, Peters, Olaf, Hillisch, Alexander, Fritzemeier, Karl-Heinrich, Elger, Walter, Patchev, Vladimir
• Primary Examiner(s): Badio; Barbara P.
• Application Number:
  US10/257,288
• Publication Number:
  US 20030176405A1
• Time in Patent Office: 2,602 Days
• Field of Search: 552/617, 552/625, 552/626, 514/179, 514/182
• US Class Current: 514/179
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• 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 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/32 : Antioestrogens
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07J 1/0059 : substituted in position 17 by a keto group
• CPC Class Codes: C07J 1/0062 : substituted in position 17 alfa not substituted in position 17 beta
• CPC Class Codes: C07J 1/007 : the substituent being an OH group free esterified or etherified
• CPC Class Codes: C07J 1/0074 : Esters
• CPC Class Codes: C07J 41/0072 : the A ring of the steroid being aromatic

Abstract

This invention describes the new 8β-substituted estratrienes of general formula I in which R², R³, R⁶, R^6′, R⁷, R^7′, R⁹, R¹¹, R^11′, R¹², R¹⁴, R¹⁵, R^15′, R¹⁶, R^16′, R¹⁷ and R^17′ have the meanings that are indicated in the description, and R⁸ means a straight-chain or branched-chain, optionally partially or completely halogenated alkyl or alkenyl radical with up to 5 carbon atoms, an ethinyl- or prop-1-inyl radical, as pharmaceutical active ingredients that have in vitro a higher affinity to estrogen receptor preparations of rat prostates than to estrogen receptor preparations of rat uteri and in vivo preferably a preferential action on bone rather than the uterus and/or a pronounced action with respect to stimulation of the expression of 5HT2a-receptors and 5HT2a-transporters, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds. The invention also describes the use of these compounds for treatment of estrogen-deficiency-induced diseases and conditions as well as the use of an 8β-substituted estratriene structural part in the total structures of compounds that have a dissociation in favor of their estrogenic action on bones rather than the uterus.

Claims

1. A 8β

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

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

R² means a hydrogen or halogen atom or a hydroxy groups;

R³ means a group R¹⁸—

O—

, R¹⁹SO₂—

O—

or —

O—

C(O)R²²,

R⁶ and R⁷ each mean hydrogen atom;

R^6′

means a hydrogen atom, or a hydroxy group, a group R²²;

R^7′

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

O—

, R¹⁹SO₂—

O—

or —

R²²;

R⁸ means a branched-chain, optically partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;

R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

R¹¹ means a hydrogen atom or together with R⁹ an additional bond;

R^11′

means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or group —

X—

R^18″

, in which X is a sulfur atom, and R^18″

is an alkyl radical with 1 to 3 carbon atoms;

R¹², R¹⁴, R¹⁵ in each case mean a hydrogen atom;

R^16′

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

O—

, R¹⁹SO₂—

O—

or —

R²²;

R¹⁷ and R^17′

in each case mean a hydrogen atom, a hydrogen atom and a halogen atom;

a hydrogen atom and a benzyloxy group;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

a group R¹⁸ and a group —

C(O)R²² or —

O—

C(O)R²²;

a group R¹⁸—

O— and

a group R¹⁸—

;

a group R¹⁸—

O— and

a group —

O—

C(O)R²²;

or

R¹⁷ and R^17′

together mean a group ═

CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogenatom, or together an oxygen atom.

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

R² means a hydrogen atom or a fluorine atom or a hydroxy group,

R³ means a group R^18′

—

O—

, R¹⁹SO₂—

O—

or —

O—

C(O)R²²

R⁶ and R⁷ in each case mean a hydrogen atom;

R^6′

means a hydrogen atom or a hydroxy group,

R^7′

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

O—

, R¹⁹SO₂—

O—

or —

R²²,

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

R¹⁹ is an R²⁰R²¹N group,

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

R²² represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C₃-C₇-cycloalkyl radical, an optionally substituted C₄-C₁₅-cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical,

or R²⁰ R²¹N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;

R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

R^11′

means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C₁-C₄-alkyl group, a group —

X—

R^18″

, in which X is a sulfur atom and R^18″

means a saturated, straight-chain or branched-chain C₁-C₃-alkyl group, a chloromethyl or chloroethyl group;

R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

R^16′

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

O or —

R²²;

R¹⁷ and R^17′

in each case mean a hydrogen atom;

a hydrogen atom and a halogen atom;

a hydrogen atom and a benzyloxy group;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

a group R¹⁸ and a group —

C(O)R or —

O—

C(O)R²²;

a group R¹⁸ —

O— and

a group R¹⁸—

;

a group R¹⁸—

O— and

a group —

O—

C(O)R²²;

or

R¹⁷ and R^17′

together mean a group ═

CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.

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

R^6′

, R^7′

, R⁹, R¹¹, R¹⁴, R¹⁵, R^15′

and R¹⁶ in each case stand for a hydrogen atom or R^6′

, R^7′

, R¹⁴, R¹⁵, R^15′

and R¹⁶ in each case stand for a hydrogen atom and R⁹ and R¹¹ together stand for an additional bond, and all other substituents have the meanings that are indicated in claim 1.

5. A compound of formula I according to claim 1, which have a double bond in position 9(11), 14(15) or 15(16) or two double bonds in positions 9(11) and 14(15) or 15(16).

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

R¹⁷ and R^17′

are a group R¹⁸—

O— and

a group R¹⁸—

;

a group R¹⁸— and

a group —

O—

C(O)R²².

7. A compound of formula I according to claim 6, in which

R¹⁷ and R^17′

are a hydroxy group and a hydrogen atom, a C₁-C₄-alkyl group or C₂-C₄-alkinyl group.

8. A compound of formula I according to claim 7, in which

R¹⁷ and R^17′

are a hydroxy group and a hydrogen atom, a methyl, ethinyl, or prop-1-inyl group.

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

R^16′

stands for a group R¹⁸—

O—

or R¹⁹SO₂—

O—

, and R¹⁷ and R^17′

each stand for a hydrogen atom.

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

8β

-Vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β

-diol

3-methoxy-8β

-vinyl-estra-1,3,5(10),9(11)-tetraen-17β

-ol

8β

-(2′

,2′

-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β

-diol

8-(2′

,2′

-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β

-ol

8β

-vinyl-estra-1,3,5(10)-triene-3,17β

-diol

3-methoxy-8β

-vinyl-estra-1,3,5(10)-trien-17β

-ol

8β

-(2′

,2′

-difluorovinyl)-estra-1,3,5(10)-triene-3,17β

-diol

8β

-(2′

,2′

-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β

-ol

8β

-vinyl-estradiol-3-sulfamate

8β

-vinyl-estradiol-3,17-disulfamate

8β

-vinyl-estradiol-3-(N-acetyl)-sulfamate

8β

-vinyl-estrone-3-sulfamate

8β

-vinyl-estron-3-acetate

8β

-vinyl-estriol

8β

-vinyl-estriol-3-sulfamate

8β

-(prop-(Z)-enyl)-estradiol

8β

-ethinyl-estradiol

17α

-ethinyl-8β

-vinyl-estra-1,3,5(10)-triene-3,17β

-diol

17α

-methyl-8β

-vinyl-estra-1,3,5,(10)-triene-3,17β

-diol

8β

-vinyl-estra-1,3,5(10)-triene-3,17α

-diol

8β

-vinyl-estradiol-diacetate

8β

-vinyl-estradiol-17-valerianate or

17β

-acetoxy-8β

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

32. A pharmaceutical composition that contains at least one compound according to claims 1 and a pharmaceutically compatible vehicle.

33. A compound of formula I, according to claim 1, excluding compounds wherein R⁸ is alkyl.

35. A method for

in-vitro treatment of male infertility;

in-vivo treatment of male infertility;

in-vitro treatment of female infertility;

in-vivo treatment of female infertility;

hormone replacement therapy in a patient in need of replacement of estrogen;

therapy of osteoporosis;

treatment of arteriosclerosis;

or

treatment of benign prostate hyperplasia;

comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 32.

36. A method for the treatment of hot flashes, sleep disturbances, irritability, mood swings, incontinence, or vaginal atrophy comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 32.

37. A method according to claim 36, wherein the treatment of hot flashes, sleep disturbances, irritability, mood swings, incontinence, or vaginal atrophy is in a subject undergoing hormone replacement therapy, and wherein said subject is in need of replacement of estrogen.

40. A method according to claim 36, wherein mood swings are treated.

41. A method according to claim 36, wherein incontinence is treated.

11. A method for

in-vitro treatment of male infertility;

in-vivo treatment of male infertility;

in-vitro treatment of female infertility;

in-vivo treatment of female infertility;

hormone replacement therapy in a patient in need of replacement of estrogen;

therapy of osteoporosis;

treatment of arteriosclerosis;

or treatment of benign prostate hyperplasia;

comprising administering to a subject in need thereof an effective amount of an 8β

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

12. A method according to claim 11, in which

R² means a hydrogen or halogen atom or a hydroxy group;

R³ means a group R^18′

—

O—

, R¹⁹SO₂—

O—

or —

O—

C(O)R²²;

R⁶ and R⁷ each mean a hydrogen atom;

R^6′

means a hydrogen atom, a hydroxy group, or a group R²²;

R^7′

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

O—

, R¹⁹SO₂—

O—

or —

R²²;

R⁸ means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms, or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or prop-1-inyl radical;

R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

R¹¹ means a hydrogen atom or together with R⁹ an additional bond;

R^11′

means a hydrogen atom, a halogen atom, a saturated or unsaturated, optionally partially or completely halogenated (F, Cl) hydrocarbon radical, which has a maximum linear chain length of 4 carbon atoms, or a group —

X—

R^18″

, in which X is a sulfur atom, and R^18″

is an alkyl radical with 1 to 3 carbon atoms;

R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

R^16′

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

O—

, R¹⁹SO₂—

O—

or —

R²²;

R¹⁷ and R^17′

in each case mean a hydrogen atom;

a hydrogen atom and a halogen atom;

a hydrogen atom and a benzyloxy group;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

a group R¹⁸ and a group —

C(O)R²² or —

O—

C(O)R²²;

a group R¹⁸—

O— and

a group R¹⁸—

;

a group R¹⁸—

O— and

a group —

O—

C(O)R²²;

or

R¹⁷ and R^17′

together mean a group ═

CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.

13. A method according to claim 11, in which

R² means a hydrogne atom or a fluorine atom or a hydroxy group,

R³ means a group R^18′

—

O—

, R¹⁹SO₂—

O—

or —

O—

C(O)R²²,;

R⁶ and R⁷ in each case mean a hydrogen atom;

R^6′

means a hydrogen atom or a hydroxy group,

R^7′

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

O—

, R¹⁹SO₂—

O—

or —

R²²;

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

R¹⁹ is an R²⁰R²¹N group,

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

R²² represents an optionally substituted, straight-chain or branched-chain, saturated or unsaturated in up to three places, an optionally partially or completely halogenated hydrocarbon radical with up to 10 carbon atoms, an optionally substituted C₃C₇-cycloalkyl radical, an optionally substituted C₄-C₁₅-cycloalkylalkyl radical or an optionally substituted aryl, heteraryl or aralkyl radical,

or R²⁰R²¹N means a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical;

R⁸ means a branched-chain, optionally partially or completely halogenated alkyl radical with up to 5 carbon atoms or a straight chain or branched chain, optionally partially or completely halogenated alkenyl radical with up to 5 carbon atoms, an ethinyl or pro-1-inyl radical;

R⁹ means a hydrogen atom or together with R¹¹ an additional bond;

R^11′

means a hydrogen atom, a fluorine or chlorine atom, a saturated, straight-chain or branched-chain C₁-C₄-alkyl group, a group —

X—

R^18″

, in which X is a sulfur atom and R^18″

means a saturated, straight-chain or branched-chain C₁-C₃alkyl group, a chloromethyl or chloroethyl group;

R¹², R¹⁴, R¹⁵ and R¹⁶ in each case mean a hydrogen atom;

R^16′

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

O or —

R²²;

R¹⁷ and R^17′

in each case mean a hydrogen atom;

a hydrogen atom and a halogen atom;

a hydrogen atom and a benzyloxy group;

a hydrogen atom and a group R¹⁹SO₂—

O—

;

a group R¹⁸ and a group —

OC(O)R²² or —

O—

C(O)R²²;

a group R¹⁸—

O— and

a group R¹⁸—

;

a group R¹⁸—

O— and

a group —

O—

C(O)R²², in all above cases with R¹⁸, R¹⁹ and R²² in each case in the meaning that is indicated under R² in claim 11;

or

R¹⁷ and R^17′

together mean a group ═

CR²³R²⁴, in which R²³ and R²⁴, independently of one another, represent a hydrogen atom and a halogen atom, or together an oxygen atom.

14. A method according to claim 11, in which

R^6′

, R^7′

, R⁹, R¹¹, R¹⁴, R¹⁵, R^15′

and R¹⁶ in each case stand for a hydrogen atom or R^6′

, R^7′

, R¹⁴, R¹⁵, R^15′

and R¹⁶ in each case stand for a hydrogen atom and R⁹ and R¹¹ together stand for an additional bond.

15. A method according to claim 11, wherein the estratrienes have a double bond in position 9(11), 14(15) or 15(16) or two double bonds in positions 9(11) and 14(15) or 15(16).

16. A method according to claim 11, in which R¹⁷ and R^17′

are a group R¹⁸—

O— and

a group R¹⁸—

;

a group R¹⁸— and

a group —

O—

C(O)R²².

17. A method according to claim 16, in which R¹⁷ and R^17′

are a hydroxy group and a hydrogen atom, a C₁-C₄-alkyl group or a C₂-C₄-alkinyl group.

18. A method according to claim 17, in which R¹⁷ and R^17′

are a hydroxy group and a hydrogen atom, a methyl, ethinyl or prop-1-inyl group.

19. A method according to claim 11, in which R^16′

stands for a group R¹⁸—

O—

or R¹⁹SO₂—

O—

.

20. A method according to claim 11, wherein the estratriene is

8β

-vinyl-estra-1,3,5(10),9(11)-tetraene-3,17β

-diol

3-methoxy-8β

-vinyl-estra-1,3,5(10),9(11)-tetraen-17β

-ol

8β

-(2′

,2′

-difluorovinyl)-estra-1,3,5(10),9(11)-tetraene-3,17β

-diol

8β

-(2′

,2′

-difluorovinyl)-3-methoxy-estra-1,3,5(10),9(11)-tetraen-17β

-ol

8β

-vinyl-estra-1,3,5(10)-triene-3,17β

-diol

3-methoxy-8β

-vinyl-estra-1,3,5(10)-trien-17β

-ol

8β

-(2′

,2′

-difluorovinyl)-estra-1,3,5(10)-triene-3,17β

-diol

8β

-(2′

,2′

-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-17β

-ol

8β

-vinyl-estradiol-3-sulfamate

8β

-vinyl-estradiol-3,17-disulfamate

8β

-vinyl-estradiol-3-(N-acetyl)-sulfamate

8β

-vinyl-estrone-3-sulfamate

8β

-vinyl-estron-3-acetate

8β

-vinyl-estriol

8β

-vinyl-estriol-3-sulfamate

8β

-(prop-(Z)-enyl)-estradiol

8β

-ethinyl-estradiol

17α

-ethinyl-8β

-vinyl-estra-1,3,5(10)-triene-3,17β

-diol

17α

-methyl-8β

-vinyl-estra-1,3,5,(10)-triene-3,17β

-diol

8β

-vinyl-estra-1,3,5(10)-triene-3,17α

-diol

8β

-vinyl-estradiol-diacetate

8β

-vinyl-estradiol-17-valerianate or

17β

-acetoxy-8β

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

22. A method according to claim 11, which is for the in-vitro treatment of male infertility.

23. A method according to claim 11, which is for the in-vivo treatment of male infertility.

24. A method according to claim 11, which is for the in-vitro treatment of female infertility.

25. A method according to claim 11, which is for the in-vivo treatment of female infertility.

26. A method according to claim 11, which is for the hormone replacement therapy in a patient in need of replacement of estrogen.

27. A method according to claim 11, which is for the therapy of osteoporosis.

28. A method according to claim 11, which is for the treatment of arteriosclerosis.

29. A method according to claim 11, which is for the treatment of benign prostate hyperplasia.

21. A method according for the treatment of hot flashes, sleep disturbances, irritability mood swings, incontinence, or vaginal atrophy comprising administering to a subject in need thereof an effective amount of an 8β

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

34. A method according to claim 21, wherein the treatment of hot flashes, sleep disturbances, irritability, mood swings, incontinence, or vaginal atrophy is in a subject undergoing hormone replacement therapy, and wherein said subject is in need of replacement of estrogen.

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

39. A method according to claim 21, wherein incontinence is treated.

30. A compound having partial formula II or II′

31. A method of achieving estrogenic action on bone, and not on uterine tissue, comprising administering a compound according to claim 30.