CN101014610A

CN101014610A - 15beta-substituted steroids having selective estrogenic activity

Info

Publication number: CN101014610A
Application number: CN200580030002.4A
Authority: CN
Inventors: H·J·J·鲁泽; A·G·H·埃德温; F·A·迪吉克斯
Original assignee: Organon NV
Current assignee: Organon NV
Priority date: 2004-09-08
Filing date: 2005-09-05
Publication date: 2007-08-08
Anticipated expiration: 2025-09-05
Also published as: ZA200701367B; CN101014610B

Abstract

The invention provides 15Beta-substituted steroidal compounds having selective estrogen receptor activity according to formula (I) wherein, R<1> is H, C1-5 alkyl, C1-12 acyl, di-(C1-5 alkyl)aminocarbonyl, (C1-5alkyl)oxycarbonyl or sulfamoyl, R<2> is H, C1-3alkyl, C2-3alkenyl or C2-3alkynyl, each of which may be optionally substituted with a halogen, R<3 >is C1-2alkyl, ethenyl or ethynyl, each of which may be optionally substituted with a halogen, and R<4> is H or C1-12 acyl.

Description

15 beta-substituted steroids with selective estrogenic activity

Technical Field

The present invention relates to 15 β -substituted steroid compounds having selective estrogenic activity, pharmaceutical compositions comprising said compounds, said compounds for use in therapy, and to the use of said compounds for the preparation of a medicament for the treatment or prevention of estrogen receptor associated diseases or for the modulation or treatment or prevention of other estrogen receptor associated physiological conditions.

Background

For many years, compounds having affinity for estrogen receptors have been widely used in the treatment of a number of medical conditions. Because of the wide tissue distribution of estrogen receptors, the therapeutic utility of estrogen receptor ligands is of great importance. In particular, its use has been directed to contraception and the prevention or treatment of:

● climacteric complaints: hot flashes, night sweats and mood swings;

● because: osteoporosis, osteoarthritis, hypocalcemia, hypercalcemia, paget's disease, osteomalacia, osteohalisteresis, bone loss due to multiple myeloma;

● fracture;

● urinary incontinence, urogenital atrophy, vaginal and skin atrophy, acne, melanoma, hirsutism;

● benign breast disease, breast cancer, gynecomastia; and

● cardiovascular disease, high cholesterol levels, high LDL levels, blood clotting diseases, restenosis, vascular smooth muscle cell proliferation.

However, despite the long-term availability of compounds, particularly steroids, which are useful for alleviating estrogen receptor-associated disorders, there remains a need for new economical, effective and safe drug therapies.

Compounds with estrogenic activity are currently used in women as agents for the treatment of peri-and/or post-menopausal (climacteric) complaints and osteoporosis. However, for women with an intact uterus, these non-selective estrogens, such as conjugated equine estrogens, 17 β -estradiol and 17 α -ethynyl-17 β -estradiol, cannot be prescribed for long-term treatment (> 3 months) because these compounds induce a high degree of endometrial hyperplasia (follicular like changes) leading to bleeding, endometrial hyperplasia and/or endometrial cancer. General clinical practice combines these non-selective estrogen and progestin compounds, a well-known method of reducing endometrial stimulation and converting follicular-like endometrium to luteal-like and/or atrophic endometrium. Unfortunately, The addition of progestogenic compounds to this therapy increases The risk of breast cancer, as demonstrated in recent studies of The Women's Health Initiative (WHI) (see Writing Group for The Women's Health Initiative investors, Risks and patents of estrogen protein in Health position patent, Women's clinical results from The Women's Health Initiative and clinical trial project, JAMA 2002; 288: 321-.

After the discovery of two distinct estrogen receptor subtypes (termed ER α and ER β), there exists the possibility of discovering subclass-selective estrogen receptor ligands. Because the two subtypes have different distributions in human tissues, these subtype-selective compounds may provide effective therapy or prevention of estrogen receptor-associated disorders with minimal side effects.

Disclosure of Invention

It has now been found that a series of 15 β -substituted steroid derivatives are potential steroids with a high level of functional selectivity for the estrogen receptor α -subclass. The present invention provides compounds of formula I:

wherein,

R¹is H, C_1-5Alkyl radical, C_1-12Acyl, di- (C)_1-5Alkyl) aminocarbonyl, (C)_1-5Alkyl) oxycarbonyl or sulfamoyl,

R²is H, C1_-3Alkyl radical, C_2-3Alkenyl or C_2-3Alkynyl, optionally each of which may be substituted with halogen,

R³is C_1-2Alkyl, vinyl or ethynyl, each of which may optionally be substituted with halogen, and

R⁴is H or C_1-12An acyl group.

Wherein R is¹And/or R⁴Steroids other than hydrogen are so-called prodrugs.

Term C_1-5Alkyl, as used in the definition of formula I, denotes branched or unbranched alkyl having 1 to 5 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, tert-butyl and pentyl. Similarly, the term C_1-3Alkyl and C_1-2Alkyl refers to (branched or unbranched) alkyl groups having 1-3 and 1-2 carbon atoms, respectively.

Term C_2-3Alkenyl denotes branched or unbranched alkenyl having 2 to 3 carbon atoms and one double bond. Examples of such groups include vinyl and prop-2-enyl.

Term C_2-3Alkynyl represents alkynyl having 2 to 3 carbon atoms and one triple bond. Examples of such groups include ethynyl and propynyl.

Term C_1-12Acyl represents an acyl group derived from a carboxylic acid having 1 to 12 carbon atoms. The acyl group may comprise a hydrocarbon which may be branched, unbranched, saturated or unsaturated. Examples of such groups include formyl, acetyl, propionyl, acryloyl, pivaloyl, heptanoyl, decanoyl and undecanoyl. C_1-12The definition of acyl also includes groups derived from dicarboxylic acids such as hemimaloyl, hemisuccinoyl and hemiglutaroyl.

Di- (C)_1-5Alkyl) aminocarbonyl is exemplified by dimethylcarbamoyl.

(C_1-5Alkyl) oxycarbonyl is exemplified by ethoxycarbonyl.

Halogen may be one or more halogen atoms, for example one or more chlorine or fluorine atoms.

In one embodiment of the invention, R²Is C_1-3Alkyl radical, C_2-3Alkenyl or C_2-3Alkynyl, each of which may be optionally substituted with halo.

In another embodiment, R¹And R⁴Are all H.

In another embodiment, R¹Is H, R²Is H, C_1-3Alkyl radical, C_2-3Alkenyl or C_2-3Alkynyl radical, R³Is C_1-2Alkyl, vinyl or ethynyl, R⁴Is H.

In another embodiment, R¹Is H, R²Is H or C optionally substituted with halogen_1-3Alkyl radical, R³Is C optionally substituted by halogen_1-2Alkyl radical, R⁴Is H.

In another embodiment, R¹Is H, R²Is H or C_1-3Alkyl radical, R³Is C_1-2Alkyl radical, R⁴Is H.

In another embodiment, R¹Is H, R²Is H or C_1-2Alkyl radical, R³Is methyl, R⁴Is H.

In another embodiment, the compound is 7 α -ethyl-15 β -methyl-19-nor-17 α -pregna-1, 3, 5(10) -trien-20-yne-3, 17 β -diol.

In another embodiment, R¹Is H, C_1-5Alkyl or C_1-12Acyl radical, R²Is H or C_1-3Alkyl radical, R³Is C_1-2Alkyl radical, R⁴Is H or C_1-12An acyl group.

In another embodiment, R¹Is H, C_1-5Alkyl or C_1-12Acyl radical, R²Is C_1-3Alkyl radical, R³Is methyl, R⁴Is H or C_1-12An acyl group.

In another embodiment, R¹Is H, C_1-5Alkyl or C_1-12Acyl radical, R²Is C_1-3Ethyl radical, R³Is methyl, R⁴Is H or C_1-12An acyl group.

In another embodiment, R¹Is H or C_1-12Acyl radical, R²Is H or C_1-3Alkyl radical, R³Is C_1-12Alkyl radical, R⁴Is H or C_1-12An acyl group.

In another embodiment, R¹Is H or C_1-12Acyl radical, R²Is H or C_1-3Alkyl radical, R³Is methyl, R⁴Is H or C_1-12An acyl group.

In another embodiment, R¹Is H or C_1-12Acyl radical, R²Is ethyl, R³Is methyl, R⁴Is H or C_1-12An acyl group.

The compounds of the invention can be synthesized according to methods well known in the general field of organic chemistry and in particular in the field of steroid chemistry. See, e.g., Fried, J. and Edwards, J.A., "Organic Reactions in Steroid Chemistry," volumes I and II, VanNostrand Reinhold Company, New York, 1972; and c.djerassi, 'Steroid Reactions,' Holden-Day, Inc., San Francisco, 1963.

A general synthetic procedure for the preparation of the compounds described in the examples below is described in scheme I. The solution can be easily modified by the person skilled in the art.

Scheme 1

Substrate a, the starting material for the synthetic method shown in scheme I, was synthesized in 4 steps. First, the conjugate addition of an organometallic species (e.g., cuprate) to a C17-protected estra-4, 6-dien-3-one provides the desired 7 α -substituted estra-4-en-3-one. The small amount of 7 β -isomer formed can be easily removed at this stage of the synthesis or occasionally at later stages by chromatography or crystallization. 7 α -substituted estrenones (estrenones) are readily aromatised by using, for example, halogenation/dehalogenation procedures to form 7 α -estrone, which after alkylation at C3 and deprotection at C17 provides the substrate A.

The α, β -unsaturated ketone C is obtained after oxidation of the silylenol ether B using, for example, palladium diacetate. The michael addition reaction of C with an organometallic species such as a dialkylcuprate then provides adduct D. Then, after deprotection of methylestrone D using, for example, boron trifluoride dimethyl sulfide complex, phenol E is provided and this material is deprotected again, for example, in the form of silyl ether F. Addition of, for example, lithium acetylide to ketone F to provide adduct G, followed by removal of the silyl ether protecting group using, for example, tetrabutylammonium fluoride, can then provide the desired product H.

Derivatives (prodrugs) of the free hydroxyl groups of compound G or H can be readily obtained from these compounds by methods well known in the art, for example, by acylation with a carboxylic acid chloride in the presence of a base or by acylation with a carboxylic acid in the presence of a coupling agent such as dicyclohexylcarbodiimide and the like, followed by removal of the silyl ether protecting group in the case of compound G.

It was found that the compounds of formula I have consistently better selectivity for the estrogen receptor alpha-subclass and have high estrogen alpha-receptor potency, i.e. equal to or higher than 1.0% (relative to having about 4 x 10)^-11EC of M₅₀17 β -estradiol, by definition, 100% potency) said compound of formula I having a group as defined in claim 1, wherein R is¹And R⁴Is hydrogen. Such compounds are agonists of the estrogen α -receptor which are at least 10-fold less active at the estrogen β -receptor and/or which are partial agonists of the estrogen β -receptor with an efficacy equal to or lower than 60% of the maximal activation induced by 17 β -estradiol. This results in a high functional selectivity for the estrogen α -receptor, i.e. selective activation of the estrogen α -receptor while not or only partial activation of the estrogen β -receptor.

Wherein R is¹And/or R⁴Steroids of formula I other than hydrogen are prodrugs, which do not necessarily satisfy the above definition. These prodrugs are converted to R by metabolic processes in vivo¹And R⁴A compound which is hydrogen, which compound satisfies the definition.

Furthermore, the selective (estrogenic) ligands of the invention surprisingly do not induce high endometrial hyperplasia (follicular like changes) and can thus be used as a medicament for the (long-term) treatment and/or prevention of peri-and/or post-menopausal (climacteric) complaints and osteoporosis without the addition of progestogenic compounds.

The activation characteristics of the selective estrogen receptors of the compounds of the present invention make them suitable for use in therapy.

The invention also relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or prevention of estrogen receptor related diseases or for the modulation or treatment or prevention of other estrogen receptor related physiological conditions.

In other aspects, the invention relates to the use of a compound of formula I for the manufacture of a medicament for hormone replacement therapy or hormone therapy. These uses are particularly suitable in women for peri-and/or post-menopausal (climacteric) discomfort and osteoporosis indications.

In other aspects, the invention relates to the use of a compound of formula I for the manufacture of a medicament for contraception. For this purpose, the compounds of the present invention may be administered as part of a treatment regimen which also includes the administration of a suitable amount of a progestagen. Such regimens are well known in the art of contraception.

The manufacture of suitable dosage forms greatly facilitates the administration of the compounds of the present invention. The invention therefore also relates to pharmaceutical compositions or dosage forms comprising a compound of the invention in admixture with a pharmaceutically acceptable excipient such as, for example, Gennaro et al, Remmington: the Science and practice of Pharmacy, 20 th edition, Lippincott, Williams and Wilkins, 2000; see especially section 5: excipients as described in pharmaceutical manufacturing. Suitable excipients are described, for example, in Handbook of pharmaceutical excipients, 2 nd edition; editors A.Wade and P.J.Weller, American pharmaceutical Association, Washington, The pharmaceutical Press, London, 1994. The mixture of the compound of the invention and pharmaceutically acceptable excipients may be compressed into solid dosage units, such as tablets, or into capsules or suppositories. The compounds can also be used as injection preparations in the form of solutions, suspensions, emulsions, or as sprays, for example nasal or oral sprays, by means of pharmaceutically suitable liquids. To prepare dosage units, e.g., tablets, the use of conventional additives such as fillers, colorants, polymeric binders, and the like is contemplated. Generally, any pharmaceutically acceptable additive may be used. The compounds of the invention may also be included in a graft, vaginal ring, patch, gel, or any other formulation for immediate and/or sustained release.

Suitable fillers for the preparation and administration of the pharmaceutical compositions include lactose, starch, cellulose and derivatives thereof and the like, or mixtures thereof used in suitable amounts.

The dosage of the present invention is within the normal orders of magnitude for estrogenic compounds, e.g., within the order of 0.01 to 100mg, more preferably 0.1 to 10mg per administration.

Detailed Description

The invention is illustrated in the following examples:

scheme 11

Example 1

Preparation of 7 α -ethyl-15 β -methyl-19-nor-17 α -pregna-1, 3, 5(10) -trien-20-yne-3, 17 β -diol (8) (see scheme II).

Preparation of 7 alpha-ethyl-3-methoxy-estra-1, 3, 5(10), 15-tetraen-17-one (3).

7 α -ethyl-3-methoxyestrone 1 was prepared in analogy to the procedure described in EP 0869132A 1 (see example I and scheme I, Compounds 1-5) from 17 β -17- (acetoxy) -estra-4, 6-dien-3-one and ethylmagnesium bromide.

LDA solution [ prepared by adding a 1.6M solution of n-butyllithium in heptane (4.7ml) to diisopropylamine (2.1ml) in THF (15ml) at-50 ℃ C. -at-60 ℃ C. ]]A solution of 7 α -ethyl-3-methoxyestrone 1(1g) in THF (3ml) was added dropwise. The mixture was stirred at-60 ℃ for half an hour and then treated with trimethylsilyl chloride (2 ml). The reaction mixture was warmed to 0 ℃ over half an hour and then 10% NH was added₄Aqueous Cl solution(100ml), the mixture was extracted with ethyl acetate. Washed and dried (Na)₂SO₄) And then concentrated to provide crude silanolate (silylenolate)2(1.1g) for the next stage without further purification.

To a solution of crude silanolate 2(1.1g) in acetonitrile (15ml) was added Pd (OAc)₂(750 mg). The mixture was heated under reflux for 15 minutes. Water and ethyl acetate were then added, the organic mixture was filtered through Celite, and the product was extracted into ethyl acetate. The separated organic material was purified by passing through a short column of silica, eluting with heptane/ethyl acetate, to give compound 3(710mg) as a colorless oil. R_f(1)0.47，R_f(2)0.80，R_f(3)0.46, eluent heptane/ethyl acetate 8/2. NMR (CDCl)₃)，δ7.58(1H)，7.21(1H)，6.74(1H)，6.66(1H)，3.79(3H，CH₃O)，1.11(s，3H，18-CH₃) 1.00(t, 3H, ethyl).

Preparation of 7 α -ethyl-15 β -methyl-3-methoxy-estra-1, 3, 5(10) -trien-17-one (4).

To solution 3 in dry THF (5ml), (300mg) was added anhydrous Cu (OAc)₂(100 mg). The mixture was stirred at-70 ℃ for 2 minutes, then methylmagnesium bromide (1M in THF, 5ml) was added dropwise. The reaction was warmed to 0 ℃ over half an hour by adding 10% aqueous NH₄The reaction was stopped with Cl solution. The product was extracted with ethyl acetate and then purified by chromatography on silica gel using heptane/ethyl acetate as eluent to afford 4(280mg) as a white solid, melting point m.p.120-122 ℃; NMR (CDCl)₃)δ 7.22(1H)，6.73(1H)，6.65(1H)，3.79(1H)，1.20(3H，s，18CH₃) 0.98, 0.96(6H, 2t, 7. alpha. -and 15. beta. -ethyl).

Preparation of 7 alpha-ethyl-15 beta-methyl-3- [ (trimethylsilyl) oxy ] -estra-1, 3, 5(10) -trien-17-one

(6)

To a solution of 4(270mg) in dichloromethane (1ml) was added BF₃DMS compoundingSubstance (800. mu.l). The mixture was stirred for 1.5 hours, then poured into ice water and extracted with ethyl acetate. Triturating the resulting residue with ether/heptane (1/1) to give 5 as an amorphous solid which is rose bengal, (250 mg); r_f0.27 (heptane/ethyl acetate 8/2). The material was dissolved in DMF (3ml), imidazole (300mg) was added, followed by tert-butyldimethylsilyl chloride. After stirring at room temperature for 2 hours, the silylation was completed. The reaction was terminated by adding ice water, and the product was extracted with ethyl acetate. Chromatographic purification on a short silica column (heptane/ethyl acetate 9/1) yielded 6 as a thick colorless oil (220 mg); r_f0.60 (heptane/ethyl acetate 8/2). NMR (CDCl)₃)δ7.12(1H)，6.62(1H)，6.18(1H)，1.03(s，3H，18-CH₃) 0.98(s, 9H, tert-butylsilyl), 0.97, 0.95(2 t, 6H, 7. alpha. -and 15. beta. -ethyl), 0.20(s, 6H, CH)₃-silyl ethers).

Preparation of 7 α -ethyl-15 β -methyl-19-nor-17 α -pregna-1, 3, 5(10) -trien-20-yne 3, 17 β -diol (8).

A lithium acetylide solution was generated by dropwise addition of n-butyllithium (1.6M in hexanes, 5ml) to 1, 2-dibromoethylene (300. mu.l) in dry THF (6ml) at-60 ℃. After stirring for 20 min, a solution of 6(220mg) in THF (2ml) was added, the cooling device removed and the reaction stirred at 0 deg.C for 1 h. Then 5% NH was added₄Cl (50ml) and then extracted with ethyl acetate. After passing the crude product through a short column of silica (eluting with heptane/ethyl acetate 8/2), compound 7 was obtained as a white foam in essentially pure form (180 mg); r_f0.28 (heptane/ethyl acetate 8/2), R_fRaw material, 0.48. NMR (CDCl)₃) Δ 7.14(1H), 6.62(1H), 6.57(1H, 2.60, acetylene), 0.99(s, 12H, 18-CH)₃And t-butylsilyl), 0.95 and 0.86(2xt, 3H, ethyl), 0.20(s, 6H, dimethylsilyl).

To a solution of 7(180mg) in THF (1ml) was added TBAF (1M in THF, 0.7 ml). The mixture was stirred for 15 minutes and then poured into 10% aqueous NH₄Cl (20 ml). Extracting the product with ethyl acetate and reactingIt was passed through a short column of silica using heptane/ethyl acetate 7/3 as eluent to yield amorphous material 8(120 mg). NMR (DMSO D6) delta 8.89(s, phenolic OH), 7.08(1H), 6.5(1H), 6.43(1H), 5.34(s, 1H, 17-OH), 0.84(s, 3H, 18-CH)₃) 0.80 and 0.90(2xt, 6H, 15. beta. -and 7. alpha. -ethyl).

Example 2

Preparation of 3-pivaloyloxy-7 alpha-ethyl-15 beta-methyl-19-nor-17 alpha-pregna-1, 3, 5(10) -trien-20-yne 17 beta-ol (9a)

Compound 8(300mg) was dissolved in pyrimidine (10 ml). Pivaloyl chloride (1.5 eq) was added dropwise. After 2 hours, the reaction mixture was quenched with water. The reaction mixture was concentrated, redissolved in ethyl acetate and extracted with aqueous sodium bicarbonate and water. Drying (Na)₂SO₄) And concentrating the organic layer. The residue was purified by chromatography on silica gel (heptane-ethyl acetate (1: 0- > 4: 1) to give pure 9a (347 mg). NMR (CDCl)₃) δ 1.35(s, 9H, pivaloyl), 1.08(d, 3H, 15 β -Me), 1.02(s, 3H, 18-Me), 0.94(t, 3H, 7-ethyl).

In a similar manner, but using N, N-dimethylcarbamoyl chloride and ethoxycarbonyl chloride respectively, Compound 9b (289 mg; NMR (CDCl)₃) Delta.3.0 and 3.08(2xs, 6H, NMe)₂)1.08(d, 3H, 15 β -Me), 1.02(s, 3H, 18-Me), 0.93(t, 3H, 7-ethyl)) and 9c (283 mg; NMR (CDCl)₃)δ4.32(q，2H，OCH₂CH₃)，1.38(d，3H，OCH₂CH₃)1.08(d, 3H, 15. beta. -Me), 1.02(s, 3H, 18-Me), 0.93(t, 3H, 7-ethyl)).

Example 3

Agonist activity of compounds at the estrogen receptor was determined in an in vitro bioassay using recombinant Chinese Hamster Ovary (CHO) cells stably co-transfected with human estrogen receptor α - (hER α -) or β - (hER β -), rat oxytocin-promoting factor (RO) and luciferase reporter gene (LUC). Test compounds stimulate receptor hER alpha-or hER beta-mediated stimulation via estrogen receptorsThe efficiency of transduction of luciferase, i.e. estrogen agonism, is expressed as EC relative to the standard estrogen 17 β -estradiol₅₀Percent (%) of (c) (potency of test compound ═ EC of 17 β -estradiol)₅₀EC of test Compound₅₀) X 100%). The efficacy, i.e. the amount of maximum activation of the receptor induced by the compound, is expressed as a percentage (%) relative to the maximum activation induced by the standard estrogen 17 β -estradiol (efficacy of the test compound ═ maximum activation of test compound/maximum activation of 17 β -estradiol x 100%). A more detailed description of this methodology can be found in De Gooyer m.e., Deckers g.h., schoonen w.g.e.j., Verheul h.a.m., and Kloosterboer h.j., Steroids, volume 68, 2003, pp.21-30.

The selectivity of ER α/ER β is defined as the ratio ER α -potency/ER β -potency. The compounds of the invention have an agonistic effect on the estrogen α -receptor with a potency equal to or higher than 1.0% (with respect to 17 β -estradiol), are at least 10-fold less active on the estrogen β -receptor (selectivity ER α/ER β -equal to or higher than 10) and/or are partial agonists of the estrogen β -receptor with an efficacy equal to or lower than 60% of the maximal activation induced by 17 β -estradiol.

Histopathological evaluation of the tissues of the cynomolgus monkey uterus was performed by a pathologist after 8 weeks of oral treatment with the test compound in 4 animals per treatment group. Comparative compound X was administered once daily at a dose of 40 μ g/kg, comparative compound Y at a dose of 200 μ g/kg and compound 8 at doses of 40 and 200 μ g/kg. Based on the uterine phase of the normal menstrual cycle in cynomolgus monkeys, the following morphological features were examined in H & E stained sections.

A. Follicular phase-like changes:

● Loose endometrium matrix

● straight endometrial gland

● hypertrophy of endometrial epithelium

● mitosis image

● hypertrophy of myometrium

● early angiogenesis (sprouting or early hyperplasia)

● basic secretion

B. Luteal phase-like changes

● pseudodecidually enlarged stromal cells

● curling of endometrial glands

● late angiogenesis (spiral artery formation)

● vacuole formation of endometrial epithelial cells

● secretion in cavity

C. Ovariectomized or non-stimulated (atrophic) endometrium

● dense endometrial matrix

● atrophy of endometrial epithelium

● atrophy of endometrial glands

● atrophy of myometrium

The severity of each of these above findings was scored using the following scale:

● 0 level: found to be absent

● 1 level 1: minimum, very few, very small

● 2 level 2: slight, small

● 3 level 3: medium, medium number, medium size

● 4 level 4: remarkably, many, large-scale

● 5 level: large, very large in number and size

This ranking was performed for each animal. The average score for each treatment group was then calculated for each feature. Finally, the average score for each category, atrophy, follicle or luteal phase-like, was calculated from the average individual characteristics. The favorable endometrial safety profile of the compounds is characterized by less compound-induced follicular phase-like activity and more luteal phase-like characteristics and/or atrophic endometrium.

Table 1 (in vitro cell data) and table 2 (in vivo data) provide compound 8 and comparative compound X (17 α -ethynyl-17 β -estradiol, wherein R is¹-R⁴Formula I) and Y (17. beta. -estradiol), both H.

TABLE 1

Compound (I)	ER α potency (%)	ER β potency (%)	ER β efficacy (%)	Selectivity (potency) of ER α/ER β
Compound (I)	ER α potency (%)	ER β potency (%)	ER β efficacy (%)	Selectivity (potency) of ER α/ER β	8	23.45	1.54	40	15.2
X	102.8	20.70	104	5.0	8	23.45	1.54	40	15.2
X	102.8	20.70	104	5.0	Y	100.0	100.0	100	1.0

The results shown in table 1 demonstrate that the compounds of the present invention have consistently better functional selectivity for the estrogen receptor alpha-subclass and high estrogen alpha-receptor potency, i.e. selectively activate the estrogen alpha-receptor and not or only partially activate the estrogen beta-receptor. Compound 8 showed an estrogen α -receptor potency of 23.45% which was more than 15.2-fold selective for the estrogen α -receptor than for the estrogen β -receptor, which is a partial agonist of the estrogen β -receptor with an efficacy of 40%. The closely related compounds 17 α -ethynyl-17 β -estradiol (compound X) and 17 β -estradiol (compound Y) show the same selectivity for both estrogen receptor subtypes and are full agonists of the estrogen β -receptor.

TABLE 2

Compound (I)	Endometrial profile of monkey (score)
	Endometrial profile of monkey (score)			Follicle and follicle	Corpus luteum	Atrophy (atrophy)
	8：40μg/kg	0.0	0.0	Follicle and follicle	Corpus luteum	Atrophy (atrophy)	3.0
8：200μg/kg	8：40μg/kg	0.0	0.0	0.5	0.2	2.3	3.0
8：200μg/kg	X：40μg/kg	2.8	0.4	0.5	0.2	2.3	0
Y：200μg/kg	X：40μg/kg	2.8	0.4	3.6	0.2	0	0

The advantageous profile of endometrial safety features of the compounds of the present invention is surprising, since both the closely related compounds 17 α -ethynyl-17 β -estradiol and 17 β -estradiol stimulate the endometrium, as shown in table 2 by the clear indications of follicular-like activity and minimal luteal-like activity, and thus no atrophic endometrium.

Example 4

The sexual behaviour of female rats is hormone dependent. In female rats induced by estrogen, progesterone significantly enhances female sexual or lordotic behavior. However, progesterone is not effective in inducing lordosis in ovariectomized females not receiving estrogen (see also, j.b. becker, s.m. breeledlove and d.cress (Eds.), behavioral endocrinology, 1992, pp.82-84).

The ability of test compounds to promote progesterone-induced lordotic behavior in ovariectomized female rats is commonly used to demonstrate in vivo estrogenic activity following oral administration of these compounds. Females were pretreated with test compound for 3 days and then treated with progestogen on day 4. The sexual behaviour of female rats was measured by counting the number of lordotic reactions within 10 minutes in the presence of male rats 4 hours after progestagen treatment.

Wherein R is¹Is pivaloyl (compound 9a), R¹Is dimethylcarbamoyl (compound 9b) or R¹Prodrugs of compound 8, which is ethoxycarbonyl (compound 9c), all proved to be active estrogenic compounds after oral administration at a dose of 1mg/kg. days.

Claims

1. A 15 β -substituted steroid compound of formula I:

wherein,

R²is H, C_1-3Alkyl radical, C_2-3Alkenyl or C_2-3Alkynyl, each of which may be optionally substituted by halogen,

R³is C_1-2Alkyl, vinyl or ethynyl, each of which may optionally be substituted by halogen, and

R⁴is H or C_1-12An acyl group.

2. A compound according to claim 1, characterized in that R²Is C_1-3Alkyl radical, C_2-3Alkenyl or C_2-3Alkynyl, optionally each of which may be substituted with halo.

3. A compound according to claim 1 or 2, characterized in that R¹And R⁴Are all H.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

5. A compound according to any one of claims 1 to 3 for use in therapy.

6. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prophylaxis of estrogen receptor related diseases or modulation or treatment or prophylaxis of other estrogen receptor related physiological conditions.

7. Use according to claim 6 for the manufacture of a medicament for hormone therapy.

8. Use according to claim 7, characterized in that the hormone therapy is for climacteric complaints.

9. Use according to claim 7, characterized in that the hormone therapy is for osteoporosis.

10. Use according to claim 6, for the manufacture of a medicament for contraception.