CN101014610B - 15beta-substituted steroids having selective estrogenic activity - Google Patents
15beta-substituted steroids having selective estrogenic activity Download PDFInfo
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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
Invention field
The present invention relates to have active 15 beta substitution of selective estrogen sterid, comprise the pharmaceutical composition of said compound; Said compound is used for treatment and relates to the purposes of medicament that said compound is used for ERs cognation treatment of diseases or prevention or is used for adjusting or the treatment or the prevention of other ERs cognation physiological situations.
Background of invention
For many years, the compound that ERs is had avidity has been widely used for treating many medical illnesss.Because the tissue distribution of ERs is extensive, so the therapeutic function of the part of ERs is extremely important.Especially, its purposes has related to contraception and prevention or treatment:
● climacterium is uncomfortable: hot flush, night sweat and emotional lability;
● because: the bone loss that osteoporosis, osteo-arthritis, hypocalcemia, hypercalcinemia, Paget, osteomalacia, osteohalisteresis, multiple myeloma cause;
● fracture;
● the urinary incontinence, urogenital tract atrophy, vagina and skin atrophy, acne, melanoma, hirsutism;
● optimum galactophore disease, mammary cancer, mamary feminism; With
● cardiovascular disorder, elevated cholesterol, high LDL level, blood coagulation disease, restenosis, vascular smooth muscle cell proliferation.
Yet,, but still have needs to new economy, effective and safe drugs therapy although can be used for alleviating the long-term utilizability of the compound of ERs cognation illness, particularly steroid.
Compound with estrogen activity is used as the medicament that (climacterium) after treatment climacteric and/or the menopause does not accommodate osteoporosis at present in the women.Yet; For women with complete uterus; Can not be with these non-selective oestrogenic hormon; For example PREMAIN, 17 beta estradiols and 17 α-ethynyl-17 beta estradiol are used for long-term treatment (＞3 months) as prescription drugs, because these compounds are induced the endometrial hyperplasia (follicular phase appearance change) of height, cause hemorrhage, endometrial hyperplasia and/or carcinoma of endometrium.General clinical practice is used in combination these non-selective oestrogenic hormon and progestogenic compounds, promptly well-known minimizing uterine endometrium stimulate and with follicular phase appearance in utero film be transformed into appearance and/or the method for atrophic endometrium luteal phase.Unfortunately; In this therapy, adding progestogenic compounds has increased the risk of mammary cancer, and this research that starts project (WHI) at nearest WomanHealth is (referring to Writing Group for the Women ' sHealth Initiative Investigators.Risks and benefits of estrogenplus progestin in healthy postmenopausal women:principalresults from The Women ' s Health Initi a t i ve r andomi zedcontrolled trial.JAMA 2002; Be confirmed 288:321-333).
After finding two kinds of distinct ERs subclass (being called ER α and ER β), existing in the possibility of finding subclass selective estrogen receptor part.Because said two kinds of subclass have different distributions in people's tissue, so these subclass alternative cpds can provide the effective therapy or the prevention of the ERs cognation illness with minimal side effect.
Summary of the invention
Have now found that the steroid derivatives of serial 15 beta substitution is the potential steroid that estrogen receptor alpha-subclass had the functionally selective of higher level.The invention provides the compound of formula I:
Wherein,
R
1Be H, C
1-5Alkyl, C
1-12Acyl group, two-(C
1-5Alkyl) aminocarboxyl, (C
1-5Alkyl) oxygen carbonyl or sulfamyl,
R
2Be H, C
1-3Alkyl, C
2-3Thiazolinyl or C
2-3Alkynyl, randomly its available separately halogen replacement,
R
3Be C
1-2Alkyl, vinyl or ethynyl, randomly its available separately halogen replace and
R
4Be H or C
1-12Acyl group.
R wherein
1And/or R
4The steroid that is not hydrogen is so-called prodrug.
Term C
1-5Alkyl, used in the definition suc as formula I, expression has the branched of 1-5 carbon atom or not branched alkyl.The example of these groups is methyl, ethyl, sec.-propyl, the tertiary butyl and amyl group.Similarly, term C
1-3Alkyl and C
1-2Alkyl is meant (the branched or not branched) alkyl with 1-3 and 1-2 carbon atom respectively.
Term C
2-3Thiazolinyl representes to have the branched or not branched thiazolinyl of 2-3 carbon atom and two keys.The example of these groups comprises vinyl and third-2-thiazolinyl.
Term C
2-3The alkynyl representative has 2-3 carbon atom and a triple-linked alkynyl.The example of these groups comprises ethynyl and proyl.
Term C
1-12Acyl group is represented from the acyl group of the carboxylic acid derivatives with 1-12 carbon atom.It can be branched, not branched, saturated or unsaturated hydrocarbon that acyl group can comprise.The example of these groups comprises formyl radical, ethanoyl, propionyl group, acryl, valeryl, oenanthyl, decanoyl and undecanoyl.C
1-12The definition of acyl group also comprises from dicarboxylicacid deutero-group like half maloyl, half succinyl and half glutaryl-.
Two-(C
1-5Alkyl) aminocarboxy example is the dimethylamino formyl radical.
(C
1-5Alkyl) example of oxygen carbonyl is an ethoxycarbonyl.
Halogen can be one or more halogen atoms, for example one or more chlorine or fluorine atom.
In one embodiment of the invention, R
2Be C
1-3Alkyl, C
2-3Thiazolinyl or C
2-3Alkynyl, randomly its available separately halogen replaces.
In another embodiment, R
1And R
4All be H.
In another embodiment, R
1Be H, R
2Be H, C
1-3Alkyl, C
2-3Thiazolinyl or C
2-3Alkynyl, R
3Be C
1-2Alkyl, vinyl or ethynyl, R
4Be H.
In another embodiment, R
1Be H, R
2Be H or randomly use the substituted C of halogen
1-3Alkyl, R
3Be randomly to use the substituted C of halogen
1-2Alkyl, R
4Be H.
In another embodiment, R
1Be H, R
2Be H or C
1-3Alkyl, R
3Be C
1-2Alkyl, R
4Be H.
In another embodiment, R
1Be H, R
2Be H or C
1-2Alkyl, R
3Be methyl, R
4Be H.
In another embodiment, compound is that 7 α-ethyl-15 Beta-methyls-19-removes first-17 α-pregnant-1,3,5 (10)-triolefins-20-alkynes-3,17-isoallopregnane-3.
In another embodiment, R
1Be H, C
1-5Alkyl or C
1-12Acyl group, R
2Be H or C
1-3Alkyl, R
3Be C
1-2Alkyl, R
4Be H or C
1-12Acyl group.
In another embodiment, R
1Be H, C
1-5Alkyl or C
1-12Acyl group, R
2Be C
1-3Alkyl, R
3Be methyl, R
4Be H or C
1-12Acyl group.
In another embodiment, R
1Be H, C
1-5Alkyl or C
1-12Acyl group, R
2Be C
1-3Ethyl, R
3Be methyl, R
4Be H or C
1-12Acyl group.
In another embodiment, R
1Be H or C
1-12Acyl group, R
2Be H or C
1-3Alkyl, R
3Be C
1-12Alkyl, R
4Be H or C
1-12Acyl group.
In another embodiment, R
1Be H or C
1-12Acyl group, R
2Be H or C
1-3Alkyl, R
3Be methyl, R
4Be H or C
1-12Acyl group.
In another embodiment, R
1Be H or C
1-12Acyl group, R
2Be ethyl, R
3Be methyl, R
4Be H or C
1-12Acyl group.
Can be according to the synthetic compound of the present invention of the method for knowing in the steroid chemical field in the common organic chemistry filed and particularly.Referring to, for example, Fried, J. and Edwards, J.A., ' Organic Reactions in Steroid Chemistry, ' I and II volume, vanNostrand Reinhold Company, New York, 1972; And C.Djerassi, ' Steroid Reactions, ' Holden-Day, Inc., San Francisco, 1963.
The general compound method of the compound that the embodiment below being used for preparing describes has been described in scheme I.Those skilled in the art can easily change this scheme.
Scheme I
Synthetic substrate A, the i.e. starting material of the compound method shown in the scheme I in 4 steps.At first, organo-metallic kind (for example, cuprate) is protected female-4 to C17-, and the conjugate addition of 6-diene-3-ketone provides the female-4-alkene-3-ketone of required 7 alpha-substitution.Can should the stage or the stage after is more easily removed a small amount of 7 β-isomer of formation through chromatography or crystallization once in a while at synthetic.Through for example using, halogenation/dehalogenation method is the female ketenes (estrenones) of aromatize 7 alpha-substitution easily, forms 7 α-oestrone, and this material provides substrate A at alkanisation on the C3 with after C17 gets on protection.
After for example using Palladium Diacetate oxidation silyl enol ether B, obtain alpha, beta-unsaturated ketone C.Use then the organo-metallic kind for example the dialkyl group cuprate C is carried out Michael reaction, adducts D is provided.After for example using boron trifluoride dimethylsulphide mixture methyl oestrone D to be gone protection, phenol E is provided then, this material has been protected with the for example form of silyl ether F again.Then, will be for example the ethinylation lithium be added to ketone F so that affixture G to be provided, for example use tetrabutyl ammonium fluoride to remove the silyl ether protective group afterwards the product of wanting H can be provided.
Through the method for knowing in this area; For example through use under the situation about existing at alkali the carboxyl chloride of acid carry out acylation or through coupling agent for example under the situation of existences such as NSC 57182 the use carboxylic acid carry out acylation; Under the situation of compound G, remove silyl ether protectiveness group then, can easily obtain the verivate (prodrug) of the free hydroxyl group of compound G or H from these compounds.
The compound of discoverable type I has consistent better choice property and has high estrogen alpha-receptor usefulness estrogen receptor alpha-subclass, promptly has to be equal to or higher than 1.0% usefulness (with respect to having about 4x10
-11The EC of M
5017 beta estradiols, by definition, 100% usefulness), the compound of said formula I has in the claim 1 group of definition, wherein R
1And R
4Be hydrogen.Such compound is the agonist of estrogen receptor alpha; Its activity to the oestrogenic hormon beta-receptor is hanged down 10 times at least; And/or it is the partial agonist of oestrogenic hormon beta-receptor, has 60% the effect that is equal to or less than by 17 beta estradiol inductive maximum activation effects.This causes the high functionally selective to estrogen receptor alpha, activate optionally promptly that estrogen receptor alpha does not activate simultaneously or only part activate the oestrogenic hormon beta-receptor.
R wherein
1And/or R
4The steroid that is not the formula I of hydrogen is a prodrug, and this prodrug needn't satisfy above-mentioned definition.These prodrugs are transformed into wherein R through intravital metabolic process
1And R
4Be the compound of hydrogen, this compound satisfies said definition.
In addition; Selectivity of the present invention (estrogenic) part amazingly is not induced height endometrial hyperplasia (follicular phase appearance change), thereby can be used as the medicine that (for a long time) that (climacterium) after climacteric and/or the menopause do not accommodate osteoporosis treat and/or prevent and need not add progestogenic compounds.
The activation characteristic of the selective estrogen receptor of The compounds of this invention makes it be suitable for treatment.
The compound that the invention still further relates to use formula I is produced medicine, and said medicine is used for ERs cognation treatment of diseases or prevention or is used for adjusting or the treatment or the prevention of other ERs cognation physiological situations.
In other respects, the present invention relates to use the compound production of formula I to be used for the purposes of the medicine of hormone replacement therapy or hormonotherapy.These purposes are particularly suitable for (climacterium) after climacteric and/or the menopause and do not accommodate the indication of osteoporosis in the women.
In other respects, the medicine that the present invention relates to use the compound production of formula I to be used to practise contraception.For this purpose, can be with using the part of compound of the present invention as regimen, this scheme also comprises the progestagen of using appropriate amount.These schemes are known in the contraception field.
The production of dosage forms helps using of The compounds of this invention widely.Therefore the present invention also relates to comprise pharmaceutical composition or formulation with the compound of the present invention of pharmaceutically acceptable mixed with excipients; Said vehicle is people such as Gennaro for example; Remmington:The Science andPractice of Pharmacy, the 20th edition, Lippincott; Williams and Wilkins, 2000; Especially referring to the 5th part: the vehicle of describing among the pharmaceutical manufacturing.Suitable vehicle is described in for example Handbook of PharmaceuticalExcipients, the 2nd edition; Editors A.Wade and P.J.Weller, AmericanPharmaceutical Association, Washington, The PharmaceuticalPress, London, 1994.Can the mixture that compound of the present invention and medicine can be accepted vehicle be pressed into solid dosage unit, tablet for example, or be pressed into capsule or suppository.Through the suitable liquid of pharmacy, said compound also can be used as the injection formulations that exists with solution, suspensoid, emulsion form, or as sprays, for example nose or oral spray.In order for example to prepare dose unit, tablet relates to the for example use of filling agent, tinting material, polymeric binder etc. of conventional additives.Usually, can use any pharmaceutically acceptable additive.Also can be or be used for discharging immediately and/or any other preparation of continuing to discharge comprises compound of the present invention at graft, pesseulum, patch, gel.
Preparation and the used suitable filling agent of drug administration compsn comprise lactose, starch, Mierocrystalline cellulose and its verivate etc. or its mixture that uses with appropriate vol.
Dosage of the present invention for example uses 0.01 to 100mg at every turn within the normal quantity level of estrogen compound, more preferably within 0.1 to 10mg the order of magnitude.
Embodiment
In the present invention of the following example illustrated:
Scheme II
Embodiment 1
7 α-ethyl-15 Beta-methyls-19-goes first-17 α-pregnant-1,3,5 (10)-triolefins-20-alkynes-3, the preparation of 17-isoallopregnane-3 (8) (referring to scheme II).
7 α-ethyl-3-methoxyl group-female-1,3,5 (10), the preparation of 15-tetraene-17-ketone (3).
To be similar to the method (referring to example I and scheme I, compound 1-5) described among the EP 0869132A1 from 17 β-17-(acetoxyl group)-female-4,6-diene-3-ketone and ethyl-magnesium-bromide prepare 7 α-ethyl-3-methoxyestrone 1.
At the solution that dropwise adds [adding n-heptane solution (4.7ml) preparation of 1.6M n-Butyl Lithium in through the Diisopropylamine (2.1ml) in THF (15ml) under-50 ℃] the 7 α-ethyl-3-methoxyestrone 1 (1g) among the THF (3ml) under-60 ℃ to LDA solution.Stir the mixture half a hour at-60 ℃, use TMS chlorine (2ml) to handle then.This reaction mixture is heated in half a hour to 0 ℃, pour 10% NH then into
4In the Cl aqueous solution (100ml), use ethyl acetate extraction.Washing, dry (Na
2SO
4), concentrate then, the rough silene alkoxide (silylenolate) 2 (1.1g) that is used for next stage and need not to be further purified is provided.
Rough silene alkoxide 2 in acetonitrile (15ml) (1.1g) adds Pd (OAc) in the solution
2(750mg).Mixture was heated 15 minutes under situation about refluxing.Add entry and ETHYLE ACETATE then, this organic mixture is filtered through Celite, product is extracted in the ETHYLE ACETATE.The isolating organic substance of institute through short silica column, is used heptane/ETHYLE ACETATE to carry out wash-out and comes purifying, produce the compound 3 (710mg) of colorless oil.R
f(1) 0.47, R
f(2) 0.80, R
f(3) 0.46, eluent heptane/ETHYLE ACETATE 8/2.NMR (CDCl
3), δ 7.58 (1H), 7.21 (1H), 6.74 (1H), 6.66 (1H), 3.79 (3H, CH
3O), 1.11 (s, 3H, 18-CH
3), 1.00 (t, 3H, ethyls).
7 α-ethyl-15 Beta-methyls-3-methoxyl group-female-1,3, the preparation of 5 (10)-triolefins-17-ketone (4).
Solution 3 in doing THF (5ml), (300mg) the middle anhydrous Cu (OAc) that adds
2(100mg).Under-70 ℃, stirred the mixture 2 minutes, (1M is in THF, 5ml) dropwise to add methylmagnesium-bromide then.In half a hour, reactant is heated to 0 ℃, through adding 10% moisture NH
4Cl solution termination reaction.Use the ethyl acetate extraction product, use heptane/ETHYLE ACETATE then, come purified product, so that 4 (280mg) of white solid, fusing point m.p.120-122 ℃ to be provided through chromatography on the silicon gel as eluent; NMR (CDCl
3) δ 7.22 (1H), 6.73 (1H), 6.65 (1H), 3.79 (1H), 1.20 (3H, s, 18CH
3), 0.98,0.96 (6H, 2t, 7 α-and 15 β-ethyl).
7 α-ethyl-15 Beta-methyls-3-[(trimethyl silyl) oxygen]-female-1,3, the preparation of 5 (10)-triolefins-17-ketone
(6)
The solution of 4 (270mg) in methylene dichloride (1ml) adds BF
3DMS mixture (800 μ l).Stirred the mixture 1.5 hours, and poured into then in the frozen water, use ethyl acetate extraction.The residue that grinds gained with ether/heptane (1/1) is to provide 5 of light rosy amorphous solid shape, (250mg); R
f(0.27 heptane/ETHYLE ACETATE 8/2).Said substance dissolves in DMF (3ml), is added imidazoles (300mg), add the tert-butyldimethylsilyl chloride thing then.After at room temperature stirring 2 hours, accomplish silylanizing.Through adding the frozen water termination reaction, use the ethyl acetate extraction product then.Chromatography purification on short silica column (heptane/ETHYLE ACETATE 9/1) has produced 6 (220mg) of thick colorless oil; R
f(0.60 heptane/ETHYLE ACETATE 8/2).NMR (CDCl
3) δ 7.12 (1H), 6.62 (1H), 6.18 (1H), 1.03 (s, 3H, 18-CH
3), 0.98 (s, 9H, tertiary butyl silyl), 0.97,0.95 (2t, 6H, 7 α-and 15 β-ethyl), 0.20 (s, 6H, CH
3-silyl ether).
7 α-ethyl-15 Beta-methyls-19-goes first-17 α-pregnant-1,3,5 (10)-triolefins-20-alkynes 3, the preparation of 17-isoallopregnane-3 (8).
Through under-60 ℃ in doing THF (6ml) 1, (1.6M 5ml) produces ethinylation lithium solution in hexane dropwise to add n-Butyl Lithium in the 2-sym-dibromoethane (300 μ l).After stirring 20 minutes, add the solution of 6 (220mg) among the THF (2ml), remove cooling apparatus, 0 ℃ of following stirring reaction 1 hour.Add 5%NH then
4Cl (50ml) extracts with ETHYLE ACETATE then.With raw product through short silica column (with heptane/ETHYLE ACETATE 8/2 wash-out) after, the compound 7 (180mg) of the white foam shape that acquisition exists with pure basically form; R
f(0.28 heptane/ETHYLE 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
3With tertiary butyl silyl), 0.95 and 0.86 (2xt, 3H, ethyl), 0.20 (s, 6H, dimetylsilyl).
The solution of 7 (180mg) in THF (1ml) adds TBAF, and (1M is in THF, 0.7ml).Stirred the mixture 15 minutes, and poured 10% moisture NH then into
4Among the Cl (20ml).With the ethyl acetate extraction product and use heptane/ETHYLE ACETATE 7/3, it through short silica column, is produced amorphous material 8 (120mg) as eluent.NMR (DMSO D6) δ 8.89 (s, the OH of phenol), 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 β-and 7 α-ethyl).
Embodiment 2
3-pivalyl oxygen-7 α-ethyl-15 Beta-methyls-19-goes first-17 α-pregnant-1,3, the preparation of 5 (10)-triolefins-20-alkynes 17 β-alcohol (9a)
Compound 8 (300mg) is dissolved in the pyrimidine (10ml).Dropwise add pivalyl chloride (1.5 equivalent).After 2 hours, water termination reaction mixture.Concentrated reaction mixture is dissolved in ETHYLE ACETATE again, extracts with aqueous carbonic acid hydrogen sodium and water.Dry (Na
2SO
4) and concentrated organic layer.((1: purifying residue 0-＞4: 1) produces pure 9a (347mg) to heptane-ETHYLE ACETATE through on the silicon gel, carrying out chromatography.NMR (CDCl
3) δ 1.35 (s, 9H, valeryl), 1.08 (d, 3H, 15 β-Me), 1.02 (s, 3H, 18-Me), 0.94 (t, 3H, 7-ethyl).
In a similar manner, but use N respectively, N-dimethylaminoethyl chloride and ethoxy carbonyl chloride prepare compound 9b (289mg; NMR (CDCl
3) δ 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 (283mg; NMR (CDCl
3) δ 4.32 (q, 2H, OCH
2CH
3), 1.38 (d, 3H, OCH
2CH
3), 1.08 (d, 3H, 15 β-Me), 1.02 (s, 3H, 18-Me), 0.93 (t, 3H, 7-ethyl)).
Embodiment 3
With the agonist activity of reorganization Chinese hamster ovary (CHO) raji cell assay Raji compound to ERs, said Chinese hamster ovary cell is that personnel selection estrogen receptor alpha-(hER α-) or β-(hER β-), rat pitocin promote the factor (RO) and luciferase reporter gene (LUC) cell of cotransfection stably in vitro bioassay.Test-compound stimulate through ERs hER α-or the commentaries on classics of the luciferase of hER β-mediation live, promptly the exciting usefulness of changeing alive of oestrogenic hormon is expressed as the EC with respect to oestrogenic hormon 17 beta estradiols of standard
50Per-cent (the %) (usefulness of the test-compound=(EC of 17 beta estradiols
50The EC of/test-compound
50) * 100%).Effect; The i.e. amount of the maximum activation effect through compound inductive acceptor is expressed as with respect to the per-cent (%) (effect of test-compound=(the maximum activation effects of the maximum activation effect of test-compound/17 beta estradiols) * 100%) by the oestrogenic hormon 17 beta estradiol inductive maximum activation effects of standard.Can be at De Gooyer M.E., Deckers G.H., SchoonenW.G.E.J., Verheul H.A.M. and Kloosterboer H.J., Steroids, the 68th volume, 2003, find this methodological more detailed description among the pp.21-30.
The selectivity definition of ER α/ER β is the ratio of ER α-usefulness/ER β-usefulness.Compound of the present invention has agonism to estrogen receptor alpha; Usefulness is equal to or higher than 1.0% (with respect to 17 beta estradiols); Its to low at least 10 times of activity of oestrogenic hormon beta-receptor (ER α-/ER β-selectivity be equal to or higher than 10) and/or its be the partial agonist of oestrogenic hormon beta-receptor, effect is equal to or less than by 60% of 17 beta estradiol inductive maximum activation effects.
In 4 animals of every treatment group, carry out 8 all oral treatments with test-compound after, carry out the histopathology evaluation of stump-tailed macaque uterine cancer cell by the pathologist.Use comparative compound X with the dosage of 40 μ g/kg once a day, use comparative compound Y and with the dosage administered compound 8 of 40 and 200 μ g/kg with the dosage of 200 μ g/kg.Based on the uterus phase of the normal menstrual cycle in the stump-tailed macaque, the following morphological feature of inspection in the painted section of H&E.
A. follicular phase, appearance changed:
. loose endometrial stroma
. straight endometrial gland
. the hypertrophy of endometrial epithelium
. MF
. myometrial hypertrophy
. (sprouting or early stage hyperplasia) takes place in early stage blood vessel
. basal secretion
B. luteal phase, appearance changed
. the stroma cell of false demoulding increase
. curling of endometrial gland
. late period, (helicine artery formation) took place in blood vessel
. the cavity of endometrial epithelial cell forms
. luminal sectetion
C. (atrophic) uterine endometrium of OO or non-stimulation
. fine and close endometrial stroma
. the atrophy of endometrial epithelium
. the atrophy of endometrial gland
. myometrial atrophy
Use following step scale to give each severity of the finding scoring in these above-mentioned discoveries:
.0 level: find not exist
.1 the level: minimum, considerably less, very little
.2 level: slight, minority is little
.3 the level: moderate, medium number, middle size
.4 level: significantly many, extensive
.5 level: a large amount of, quantity is very many, and size is very big
Each animal is carried out this classification.Then with regard to the average score of each each treatment group of feature calculation.At last, calculate every kind according to average personal feature, atrophy, ovarian follicle or luteal phase appearance average score.The favourable uterine endometrium security feature spectrum of compound is characterised in that less compound inductive appearance follicular phase active and more luteal phase of appearance characteristic and/or atrophic endometrium.
Table 1 (cell in vitro data) and table 2 (data in the body) provide compound 8 and comparative compound X (17 α-ethynyl-17 beta estradiol, wherein R
1-R
4All be the formula I of H) and the data of Y (17 beta estradiol).
Table 1
| Compound | ER α usefulness (%) | ER β usefulness (%) | ER β effect (%) | The selectivity (usefulness) of ER α/ER β |
| 8 | 23.45 | 1.54 | 40 | ?15.2 |
| X | 102.8 | 20.70 | 104 | ?5.0 |
| Y | 100.0 | 100.0 | 100 | ?1.0 |
Result shown in the table 1 proves that compound of the present invention has consistent better functionally selective and high estrogen alpha-receptor usefulness for estrogen receptor alpha-subclass, promptly optionally activates estrogen receptor alpha and or does not only partly activate the oestrogenic hormon beta-receptor.Compound 8 shows 23.45% estrogen receptor alpha usefulness, and its selectivity for estrogen receptor alpha surpasses 15.2 times to the oestrogenic hormon beta-receptor, and it is the partial agonist of oestrogenic hormon beta-receptor, and effect is 40%.Closely-related compound 17 α-ethynyl-17 beta estradiol (compounds X) shows identical selectivity with 17 beta estradiols (compound Y) for two kinds of ERs subclass and is the full agonist of oestrogenic hormon beta-receptor.
Table 2
The favourable uterine endometrium security feature spectrum of The compounds of this invention is wondrous; Because closely-related compound 17 α-ethynyl-17 beta estradiol and 17 beta estradiols all stimulate uterine endometrium; As active clearly sign showed through appearance follicular phase active and few corpus luteum appearance in the table 2, thereby there is not atrophic endometrium.
Embodiment 4
The sexual behaviour of female rats is a hormonal dependent.In estrogen-primed female rats, progesterone strengthens female sexual behaviour or lordosis behavior significantly.Yet, do not accept estrogenic OO female in, progesterone can not induce effectively lordosis (also referring to, J.B.Becker, S.M.Breedlove and D.Crews (Eds.), BehavioralEndocrinology, 1992, pp.82-84).
Test-compound promotes the ability of the lordosis behavior of progesterone induced to be generally used for proving that the body inner estrogen behind Orally administered these compounds is active in ovariectomized female rats.With the test-compound pre-treatment female 3 days, handled with progestagen at the 4th day then.After progestagen was handled 4 hours, under the situation that male rat exists, the sexual behaviour of measuring female rats through the number of times of counting lordosis reaction in 10 minutes.
R wherein
1Be valeryl (compound 9a), R
1Be dimethylamino formyl radical (compound 9b) or R
1Be the prodrug of the compound 8 of ethoxycarbonyl (compound 9c), after with 1mg/kg. days oral dose, all prove the active estrogen compound.
Claims (7)
1. the sterid of 15 beta substitution of formula I:
Wherein,
R
1Be H, R
2Be C
1-3Alkyl, R
3Be C
1-2Alkyl, and R
4Be H.
2. the compound of claim 1 is characterized in that said compound is selected from:
7 α-ethyl-15 Beta-methyls-19-removes first-17 α-pregnant-1,3,5 (10)-triolefins-20-alkynes-3,17-isoallopregnane-3.
3. comprise each compound and the pharmaceutical composition of pharmaceutically acceptable vehicle among the claim 1-2.
4. the purposes that each compound is used to produce medicine among the claim 1-2, said medicine is as oestrogenic hormon α receptor stimulant.
5. each compound production is used for the purposes of the medicine of hormonotherapy among the claim 1-2, it is characterized in that said hormonotherapy is used for the climacterium discomfort.
6. each compound production is used for the purposes of the medicine of hormonotherapy among the claim 1-2, it is characterized in that said hormonotherapy is used for osteoporosis.
7. claim 1 or 2 the compound purposes that is used to produce contraceptive.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60850104P | 2004-09-08 | 2004-09-08 | |
| US60/608,501 | 2004-09-08 | ||
| EP04104334.0 | 2004-09-08 | ||
| EP04104334 | 2004-09-08 | ||
| PCT/EP2005/054368 WO2006027347A1 (en) | 2004-09-08 | 2005-09-05 | 15β-SUBSTITUTED STEROIDS HAVING SELECTIVE ESTROGENIC ACTIVITY |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101014610A CN101014610A (en) | 2007-08-08 |
| CN101014610B true CN101014610B (en) | 2012-08-22 |
Family
ID=38701502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800300024A Expired - Fee Related CN101014610B (en) | 2004-09-08 | 2005-09-05 | 15beta-substituted steroids having selective estrogenic activity |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101014610B (en) |
| ZA (1) | ZA200701367B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686437A (en) * | 1988-10-31 | 1997-11-11 | Endorecherche Inc. | Estrogen nucleus derivatives for use in the inhibition of sex steroid activity |
| CN1444596A (en) * | 2000-07-28 | 2003-09-24 | 阿克佐诺贝尔公司 | 16 alpha-methyl or ethyl substituted estrogens |
| US6677324B1 (en) * | 1998-02-19 | 2004-01-13 | Schering Aktiengesellschaft | Combination preparation of estrogen and anti-estrogen |
-
2005
- 2005-09-05 CN CN2005800300024A patent/CN101014610B/en not_active Expired - Fee Related
-
2007
- 2007-02-15 ZA ZA200701367A patent/ZA200701367B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686437A (en) * | 1988-10-31 | 1997-11-11 | Endorecherche Inc. | Estrogen nucleus derivatives for use in the inhibition of sex steroid activity |
| US6677324B1 (en) * | 1998-02-19 | 2004-01-13 | Schering Aktiengesellschaft | Combination preparation of estrogen and anti-estrogen |
| CN1444596A (en) * | 2000-07-28 | 2003-09-24 | 阿克佐诺贝尔公司 | 16 alpha-methyl or ethyl substituted estrogens |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200701367B (en) | 2008-08-27 |
| CN101014610A (en) | 2007-08-08 |
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