15β-substituted steroids with selective oestrogenic activity

FIELD: chemistry.

SUBSTANCE: described is a 15β-substituted oestradio derivative having selective oestrogenic activity. The preferred compound is 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17β-diol.

EFFECT: obtaining compounds which can be used in treating or preventing diseases or physiological conditions related to oestrogen receptors.

11 cl, 4 ex, 2 tbl

 

This invention relates to 15β-substituted steroid compound with selective estrogenic activity, pharmaceutical compositions of this compound, its use in the treatment, and also used in the manufacture of medicinal preparations for the treatment or prevention of diseases associated with estrogen receptors, or regulation, treatment or prevention of other physiological conditions associated with estrogen receptors.

For many years the compounds having affinity for estrogen receptors, widely used in the treatment of a wide range of conditions. Because estrogen receptors are widely present in many tissues, therapeutic value of their ligands is very high. In particular, these compounds are widely used contraceptives, as well as for prevention and treatment:

- menopausal symptoms: hot flushes, sweating, mood swings;

- bone loss as a result of osteoporosis, osteoarthritis, Hypo - and hypercalcemia, Paget's disease, osteomalacia, multiple myeloma;

- bone fractures;

- urinary incontinence, atrophy of the urinary tract, vaginal and skin atrophy, acne, melanoma, hirsutism;

- benign tumors of the breast, breast cancer, gynecomastia;

- cardiovascular disease, elevated levels of cholesterin is a, elevated levels of high-density lipoproteins, clotting disorders, restenosis, proliferation of smooth muscle cells of blood vessels.

However, although these compounds (particularly steroids) have long been available to facilitate processes related to estrogen receptors, there is still a need for an economical, effective and safe medicines.

Compounds with estrogenic activity, are currently used in women for the treatment of peri - and/or postmenopausal (menopausal) symptoms, and osteoporosis. However, for nulliparous women, such non-selective estrogens (e.g., conjugated estrogen horses, 17β-estradiol, 17α-ethinyl-17β-estradiol) may not be recommended for long-term therapy (>3 months), because it increases the level of proliferation of the endometrium (changes similar to the follicular phase of the cycle), resulting in bleeding, endometrial hyperplasia and/or cancer of the endometrium. Common clinical practice is to combine these selective estrogen with progestogenic compounds - this procedure, as it is known, allows to reduce the stimulation of the endometrium and change its state with similar follicular phase is similar to the luteal phase of the cycle and/or atrophic. Unfortunately, the introduction is their progestogenic compounds in this therapy increases the risk of breast cancer as was demonstrated in recent studies conducted by the Program in women's Health (Women's Health Initiative). (Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from The Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.)

Thanks to the discovery of two different subtypes of estrogen receptors, named α and β, at the present time, there is the possibility of developing ligands that selectively interacts with the subtypes of estrogen receptors. Because the receptor subtypes differ in their representation in various body tissues, such selective connection can provide effective treatment or prevention of conditions associated with estrogen receptors, with minimal side effects.

To date, found that the number of 15β-substituted derivatives of estradiol are effective steroids, possessing a high level of functional selectivity with respect to the α-subtype of the estrogen receptors. This invention is a compound having the General Formula 1.

where R1- H, C1-5alkyl, C1-12acyl, di(C1-5alkyl)aminocarbonyl, (C1-5alkyl)oxycarbonyl or sulfamoyl,

R2- H, C1-3alkyl, C2-3alkenyl or C2-3quinil, each of which can be amesen halogen,

R3- C1-2alkyl, ethynyl or ethinyl, each of which may be substituted with halogen, and

R4- H or C1-12acyl.

Steroids, in which R1and/or R4different from hydrogen, are so-called prodrugs of (precursors of drugs).

The term C1-5alkyl used in the Formula I denotes a branched or unbranched alkyl group having 1-5 carbon atoms. Examples: methyl, ethyl, isopropyl, tertiary butyl and pentyl. Similarly, the terms C1-3alkyl, C1-2alkyl denotes a branched or unbranched alkyl group having 1-3 or 1-2 carbon atoms, respectively.

The term C2-3alkenyl denotes a branched or unbranched alkenylphenol group having 2-3 carbon atoms. Examples of such groups include ethynyl, propen-2-yl.

The term C2-3quinil denotes alkylamino group having 2-3 carbon atoms and one triple bond. Examples of such groups include: ethinyl, PROPYNYL.

The term C1-12acyl means an acyl group derived from carboxylic acids having 1-12 carbon atoms. The acyl group may contain hydrocarbons which can be branched, unbranched, saturated or unsaturated. Examples of such groups include formyl, acetyl, propanol, propanol, pivaloyl, heptane is, decanoyl, undecanoyl. The term C1-12the also includes acyl groups derived from dicarboxylic acids, such as gemellol, hemisuccinate, hemiglutarate.

Example di(C1-5alkyl)aminocarbonyl is dimethylcarbamoyl.

Example di(C1-5alkyl)oxycarbonyl is etoxycarbonyl.

The halogen may be one or more halogen atoms such as chlorine or fluorine.

In one of the embodiments of this invention R2- C1-3alkyl, C2-3alkenyl or2-3quinil, each of which may be substituted with halogen.

In another embodiment, incarnation, R1and R4- hydrogen atoms.

In another embodiment, incarnation, R1- N, R2- H, C1-3alkyl, C2-3alkenyl or2-3quinil, R3- C1-2alkyl, ethynyl or ethinyl and R4- N.

In another embodiment, incarnation, R1- N, R2- H, C1-3alkyl, optionally substituted with halogen, R3- C1-2alkyl, optionally substituted with halogen, and R4- N.

In another embodiment, incarnation, R1- N, R2- N or C1-3alkyl, R3- C1-2alkyl, and R4- N.

In another embodiment, incarnation, R1- N, R2- N or C1-2alkyl, R3is methyl and R4- N.

Another option structure: 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-in-3,17β-diol.

<> In another embodiment, incarnation, R1- H, C1-5alkyl or C1-12acyl, R2- N or C1-3alkyl, R3- C1-2alkyl, and R4- N or C1-12acyl.

In another embodiment, incarnation, R1- H, C1-5alkyl or C1-12acyl, R2- C1-3alkyl, R3is methyl and R4- N or C1-12acyl.

In another embodiment, incarnation, R1- H, C1-5alkyl or C1-12acyl, R2is ethyl, R3is methyl and R4- N or C1-12acyl.

In another embodiment, incarnation, R1- N or C1-12acyl, R2- N or C1-3alkyl, R3- C1-2alkyl, and R4- N or C1-12acyl.

In another embodiment, incarnation, R1- N or C1-12acyl, R2- N or C1-3alkyl, R3is methyl and R4- N or C1-12acyl.

In another embodiment, incarnation, R1- N or C1-12acyl, R2is ethyl, R3is methyl and R4- N or C1-12acyl.

This connection can be synthesized in accordance with methods well known in the art of General organic chemistry, especially the chemistry of steroids. See, for example: Fried, J. and Edwards, J.A.,'Organic Reactions in Steroid Chemistry', Volumes I and II, van Nostrand Reinhold Company, New York, 1972; and C. Djerassi,'Steroid Reactions,'Holden-Day, Inc., San Francisco, 1963. General methods of synthesis used to obtain the compounds described below in the examples and shown in the Diagram Thpecial in this field can easily make changes to this schema.

Scheme 1

.

The substrate And source material for the method of synthesis is shown in Scheme I, is synthesized in 4 steps. First, the paired adding organometallics reagents (e.g. cuprates) to R17-substituted östra-4,6-Dien-3-ONU leads to the production of 7α-substituted variety-4-EN-3-one. A small amount of 7β-isomers can be easily removed by chromatography or crystallization at this stage of the synthesis or sometimes in the later stages. 7α-substituted astronony easily aromatizers using, for example, halogenation procedures/dehalogenase in 7α-Estrany that after alkylation at position C3 and removal of the protective group at position C17 form a substrate A.

α,β-unsaturated ketone To receive as a result of oxidation similaralcohol ester using, for example, palladium diacetate. The reaction joining Michael with substance and With the use of organometallics reagents, for example dialkyl cuprate provides the adduct D. Metalectro D after removing protection from, for example, triftormetilfullerenov complex is converted into phenol E, which again introduce a protective group, receiving, for example, silyl-ether F. Adding, for example, acetonide lithium to the ketone F leads to G adduct, which is the first after the removal silyl-ester using, for example, tetrabutyltin ammonium form the desired product N.

Prodrugs of compounds G and H derivatives with free hydroxyl groups are easily derived with the use of such known technologies reactions, such as acylation using carboxylic acid anhydrides in the presence of a base or acylation using carboxylic acids in the presence of a condensing agent, such as dicyclohexylcarbodiimide etc., with the subsequent removal of the protective silyl-ether grouping in the case of compound G.

The compounds of Formula I, with a group described in the claims 1, in which R1and R4- hydrogen atoms, with consistently higher selectivity to α subtype of estrogen receptors in combination with the high efficiency of this subtype receptors, i.e. efficiency, equal to or greater than 1.0% (relative to 17β-estradiol, which has EC50approximately 4x10-11M and, by definition, 100% efficiency). This compound is an agonist of α-receptors and at least 10 times less effective against β-estrogen receptors with efficiency equal to or less 60% of the maximum activation induced by 17β-estradiol. This is reflected in the high functional selectivity for α-estrogen receptors, i.e. the village is effective activation of α-receptors in the absence or only partial activation of β-estrogen receptors.

The steroids of Formula I, where R1and R4are (is) hydrogen atoms - prodrugs not necessarily meet the above properties. These substances as a result of metabolic processes in the body are converted into compounds in which R1and R4- hydrogen atoms and which meet the above characteristics.

Moreover, selective estrogen ligands of the present invention, surprisingly, do not cause a higher level of proliferation of the endometrium (changes similar to the follicular phase of the cycle) and, thus, can be used to (long-term) treatment and/or prevention of peri - and/or postmenopausal (climacteric) States and osteoporosis without adding progestogenic component.

Selective activation of estrogen receptors presented in this invention the compounds makes their profile suitable for use in therapy.

Further, the present invention considers the use of the compounds corresponding to the Formula I for the production of drugs used for the treatment and prevention of diseases associated with estrogen receptors, or regulation, treat, cure or prevent development of other physiological conditions associated with estrogen receptors.

Another aspect of the invention concerns the use of compounds is s, corresponding to the Formula I for the production of medicinal products for hormone replacement therapy or hormonal treatment. Such use is particularly suitable for women with signs of peri - and/or postmenopausal (menopausal) symptoms and osteoporosis.

Another aspect of the invention concerns the use of compounds corresponding to the Formula I for the manufacture of drugs for contraception. These compounds may be used for similar purposes as part of the medical course, which also includes the appropriate amount of progestin. Such schemes are well known in the field of contraception.

The use of compounds of the invention, the most successfully reaches the goal when receiving dosage forms appropriate dosage. This invention also relates to a pharmaceutical composition or dosage form combining a compound according to the invention is mixed with (a) a pharmaceutically acceptable(and) filler(s), such as described in Gennaro et al., Remmington: The Science and Practice of Pharmacy 20thEdition, Lippincott, Williams and Wilkins, 2000, see especially part 5: pharmaceutical manufacturing. Suitable fillers are described, for example, in the Handbook of Pharmaceutical Excipients, 2ndEdition, Editors A. Wade and P.J. Weller, American Pharmaceutical Association, Washington. The mixture of compounds suitable for the invention, and (the) pharmaceutically acceptable excipients may be deposited in solid form, such as tablets or capsules, or suppositories. When using pharmaceutically acceptable liquids this connection can be used in the form of injection solutions, suspensions, emulsions, or as a spray, for example as a spray to the nasal or oral cavity. For the production of dosage forms such as tablets, suitable use of additives, fillers, dyes, polymeric binder, etc. may generally be used in any pharmaceutically acceptable additive. Compounds according to the invention can be incorporated into implants, vaginal rings, patches, gels or any other means with immediate and/or delayed release.

Suitable fillers used in the production or use of pharmaceutical compositions, include lactose, starch, cellulose and the like, derivatives thereof, and mixtures of the above ingredients in appropriate quantities.

Dosages of this compound are insignificant for the estrogen compounds, i.e. in the range from 0.01 to 100 mg, in particular from 0.1 to 10 mg a single administration.

The invention is illustrated by the following examples:

Scheme II

Example 1

Obtain 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-ine-3,17β-diol (8) (see Scheme 2).

Obtain 7α-ethyl-3-methoxy-e the tra-1,3,5(10),15-tetraen-17-she (3).

7α-Ethyl-3-meloxican1was obtained from 17β-17-(atomic charges)-östra-4,6-Dien-3-one and ethyl magnesium bromide by the method similar to that described in EP 0869132 A1 (see Example 1 and Scheme 1, compounds 1-5).

A solution of 7α-ethyl-3-methoxyacetone1(1 g) in tetrahydrofuran (THF) (3) was added at -60°C dropwise to a solution of LDA (diisopropylamide lithium) [obtained by adding 1.6 M solution of n-BuLi in heptane (4,7 ml) at -50°C to Diisopropylamine (2.1 ml) in THF (15 ml)]. The mixture was stirred for ½ hour at -60°C, after which was added trimethylsilyl chloride (2 ml). The reaction mixture was heated to 0°C. for ½ hour, then poured into 10% aqueous solution of NH4Cl (100 ml) and was extracted with ethyl acetate. Rinsing, drying (Na2SO4) and subsequent concentration produces crude selenolate2(1.1 g)which was used in further steps without further purification.

To a solution of the crude sildenafila2(1.1 g) in acetonitrile (15 ml) was added Pd(OAc)2(750 ml). The mixture was heated under reflux for 15 minutes. Then added water and ethyl acetate, the organic mixture was filtered through Celite and the product was extracted into ethyl acetate. Separated thus the organic material was purified on a short silica column was suirable a mixture of heptane/ethyl acetate to obtain compound 3 in the form of a demon who Vatan oil. Rf(1) of 0.47, Rf(2) 0,80, Rf(3) 0,46, the composition additionally separated by: heptane/ethyl acetate : 8/2. NMR (CDCI3), δ 7,58 (1H), 7,21 (1H), 6,74 (1H), 6,66 (1H), with 3.79 (3H, CH3O)a 1.11 (s,3H, 18-CH3), and 1.00 (t,3H, ethyl).

Obtain 7α-ethyl-15β-methyl-3-methoxy-östra-1,3,5(10)-triene-17-it (4)

To a solution of the substance3in dry THF (5 ml) was added anhydrous Cu(SLA)2(100 mg). The mixture was stirred for 2 minutes at -70°C. and then was added dropwise Metalmania chloride (1M in THF, 5 ml). The reaction mixture was heated to 0°C. for ½ hour and was suppressed by the addition of 10% aqueous solution of NH4Cl. The product was extracted with ethyl acetate and then purified by chromatography on silica gel using a mixture of heptane/ethyl acetate as eluant for connection4in the form of a white solid (280 mg), TPL120-122°C, NMR (CDCI3) δ 7,22 (1H), 6.73 x (1H), 6,65 (1H), with 3.79 (1H), 1,20 (3H,s,18CH3), 0,98, of 0.96 (6H, 2T,7α-and 15β-ethyl).

Obtain 7α-ethyl-15β-methyl-3-[(trimethylsilyl)oxy]-östra-1,3,5(10)-triene-17-it (6)

To a solution of compound4(270 mg) in dichloromethane (1 ml) was added BF3LCA complex (800 μl). The mixture was stirred for 1.5 hours and then poured into ice-cold water, and then extraction was performed with ethyl acetate. Thus obtained residue triturated with a mixture of ether/heptane (1/1) to obtain compound5(250 mg) as a pale pink am hego solids; Rf0,27 (heptane/ethyl acetate 8/2). The substance was dissolved in DMF (3 ml), then sequentially added imidazole (300 mg) and tert-butyldimethylsilyl chloride. The reaction was suppressed by the addition of ice water, and then carried out the extraction of the product with ethyl acetate. After chromatographic separation carried out on a short silica columns (heptane/ethyl acetate 9/1), received the connection6(220 mg) as a thick colorless oil; Rf0,60 (heptane/ethyl acetate 8/2). NMR (CDCI3) δ for 7.12(1H), 6,62 (1H), 6,18 (1H), of 1.03 (s, 3H, 18-CH3), and 0.98 (s, 9H, tert-butisol), 0,97, of 0.95 (2T, 6H, 7α-and 15β-ethyl), of 0.20 (s, 6H, CH3-similair).

Obtain 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-ine-3,17β-diol (8)

A solution of Li-acetylide was obtained by adding dropwise n-butyl lithium (1.6 M in hexane, 5 ml) to 1,2-dibromethane (300 ml) in dry THF (6 ml) at -60°C. After stirring for 20 minutes, the solution was added compound6(220 mg) in THF (2 ml), the cooling unit was removed and the reaction mixture was stirred for 1 hour at 0°C. Then was added 5% NH4Cl (50 ml), and then extraction was performed with ethyl acetate. By passing through a short silica column (suirable a mixture of heptane/ethyl acetate 8/2) received connection7in the form of a white foam is essentially pure; Rf0,28 (heptane/ethyl acetate 8/2), Rfthe source material of 0.48. NMR (CDCI3) δ 7,14 (H), 6,62 (1H), to 6.57 (1H, 2,60, acetylene), 0,99 (s, 12H, 18-CH3and tert-butisol), 0.95 and 0,86 (HT, 3H, ethyl), of 0.20 (s, 6H, dimethylallyl).

To a solution of compound7(180 mg) in THF (1 ml) was added TBAF (1M in THF, 0.7 ml). The mixture was stirred for 15 minutes and then was poured into 10% aqueous solution of NH4Cl (20 ml). The product was extracted with ethyl acetate and passed through a short silica column using as eluent a mixture of heptane/ethyl acetate 7/3 for connection8(120 mg) as an amorphous substance. NMR (DMSO-D6) δ 8,89 (s, phenolic OH), was 7.08 (1H), and 6.5 (1H), gold 6.43 (1H), of 5.34 (s,1H, 17-OH), is 0.84 (s, 3H, 18-CH3), to 0.80 and 0.90 (HT, 6H, 15β and 7α - ethyl).

Example 2

Obtaining 3-pivaloyloxy-7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-ine-17β-ol (9a)

Connection8(300 mg) was dissolved in pyridine (10 ml). Pivaloate (1.5 equivalent) was added dropwise. After 2 hours the reaction was suppressed by the addition of water. The reaction mixture was concentrated, re-dissolved in ethyl acetate and was extracted with water raster sodium bicarbonate and water. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica columns (heptane-ethyl acetate (1:0 -> 4:1) to obtain pure substances 9a (347 mg). NMR (CDCI3) δ is 1.35 (s, 9H, pivaloyl), a 1.08 (d, 3H, 15β-Me), of 1.02 (s, 3H, 18-Me), were 0.94 (t, 3H, 7-ethyl).

Compound 9b (289 mg; NMR (CDCI3) δ 3.0 and a 3.0 (HS, 6H, NMe2) a 1.08 (d, 3H, 15β-Me), of 1.02 (s, 3H, 18-Me), of 0.93 (t, 3H, 7-ethyl)) and 9c (283 mg; NMR (CDCI3) δ 4,32 (q, 2H, OCH2CH3), to 1.38 (d, 3H, OCH2CH3), a 1.08 (d, 3H, 15β-Me), of 1.02 (s, 3H, 18-Me), of 0.93 (t, 3H, 7-ethyl)) was obtained in a similar manner, but using N,N-dimethylammoniumchloride and ethoxycarbonylphenyl respectively.

Example 3

To characterize compounds as agonists of estrogen receptors were heldin vitroa biological sample on a cell line of Chinese hamster ovary (CHO)carrying the gene for the estrogen receptor of human subtype α (hERα) or β (hERβ) the promoter of the rat oxytocin (RO) and the reporter gene luciferase (LUC). The activity of test compounds is mediated by the estrogen receptors of type α or β TRANS-activation of synthesis of the enzyme luciferase, i.e. TRANS-activation of the estrogen agonists is expressed as the ratio (in percent) for EC50standard estrogen 17β-estradiol (activity test connection = (EC5017β-estradiol/ EC50the test compound) x 100%). The efficiency, i.e. the value of the maximal activation of the receptor compound, expressed as the ratio (in percent) to the maximum activation caused by the standard estrogen 17β-estradiol (efficiency test connection = (maximum activation test connection/ maximum activation 17β-estradiol) x 100%)for a more detailed description of the methodology see in De Gooyer M.E., Deckers GH, Schoonen W.G.E.J., Verheul H.A.M. and H.J. Kloosterboer,SteroidsVol. 68, 2003, pp.21-30.

The selective Erα/Erβ is defined as the ratio of Erα activity to Erβ activity. Compounds according to the invention are agonists α-estrogen receptor activity equal to or greater than 1% (relative to 17β-estradiol), and 10 times less active against β-estrogen receptors (Erα/Erβ selectivity equal to or greater than 10) and/or are partial agonists of β-estrogen receptors with efficiency equal to or less 60% of the maximum activation caused by 17β-estradiol.

Histopathological examination was performed on tissues of the uterus cynomolgus macaque after 8 weeks of oral administration of test compounds (4 animals in each test group). The substance of the comparison X was administered 40 mg/kg/day, the substance of the comparison in the 200 μg and connection840 and 200 mcg/kg Were investigated following morphological characteristics, using procrasti with hematoxylin/eosin, on the basis of data on the condition of the uterus cynomolgus macaque in certain phases of the menstrual cycle.

A. Changes similar to those, follicular phase:

- free stroma of the endometrium

- direct endometrial cancer

- hypertrophy of the epithelium of the endometrium

- hypertrophy of the myometrium

early angiogenesis (sprouting or early proliferation)

- basal secretion

B. Changes similar to those, luteal phase:

- pseudocereals increased stromal cells

- the tortuous glands of the endometrium

- late angiogenesis (the formation of spiral arteries)

secretion into the uterine cavity

- luminally secretion

Century Endometrium ovariectomised animals or restimulating (atrophic) endometrium

- compact stroma of the endometrium

- atrophy of the epithelium of the endometrium

- atrophy of the endometrial glands

- atrophy of the epithelium of the myometrium

The severity of the above symptoms was assessed by the following classification scale:

- level 0: no signs

- level 1: minimal, very small amount, very small size

- level 2: a small, small amount, small size

- grade 3: medium, medium, medium

- level 4: noticeable, much larger

- grade 5: massive, very large number, a very large size.

This assessment was conducted for all animals. Then, for each trait was calculated the average value for the test group. In the end, the average value for each category, such atrophy, follicular or luteal phases was calculated from the average for each characteristic. From the point of view of safety of the endometrium of the investigated compounds is their has more favorable characteristics in relation to induction fewer changes characteristic of the follicular phase, and more changes characteristic of the luteal phase and/or atrophic endometrium.

Data for Compounds8for States compare X (17α-ethinyl-17β-estradiol, the Formula I, where R1-R4- hydrogen atoms) and (17β-estradiol) are shown in Table 1 (in vitro data obtained in cell culture) and in Table 2 (in vivo data).

Table 1
ConnectionERα activity (%)ERβ activity (%)ERβ-efficiency (%)ERα/Erβ-selectivity (activity)
823,451,544015,2
X102,820,701045,0
100,0100,01001,0

The results in Table 1 demonstrate that the patented compounds of the invention are stable most of selectionist what to estrogen receptors subtype α, and also have a high activity, mediated by estrogen receptor subtype α, i.e. selectively activate the α-estrogen receptors without activating or only partially activating β-estrogen receptors. Connection8has estrogen α receptor activity equal 23,45%, and 15.2 times greater selectivity for the estrogen α-receptors than to estrogen β-receptors, and is a partial agonist of the estrogen β-receptors with efficiency equal to 40%. Closely related compound 17α-ethinyl-17β-estradiol (Compound X) and 17β-estradiol (Connection) show equal affinity (preference) to both subtypes of estrogen receptors and are full agonists of the estrogen β receptor.

Table 2
ConnectionThe state of the endometrium cynomolgus macaque (points)
FollicularLuteinAtrophic
8: 40 ug/kg0,00,03,0
8: 200 ug/kg0,50,2 2,3
X: 40 ug/kg2,80,40
Y: 200 ug/kg3,60,20

Favourable state of conservation of the endometrium for patentable compounds of the invention is unexpected because both closely related compound 17α-ethinyl-17β-estradiol and 17β-estradiol stimulate the endometrium, which can be seen from Table 2, which shows clear characteristics of induction of changes relevant to the follicular phase, with minimal changes relevant to the luteal phase, and, accordingly, without atrophy of the endometrium.

Example 4

Sexual behavior of female rats is hormone dependent. The estrogen-stimulated female rats, progesterone significantly increases sexual behavior or reactions of lordosis. However, progesterone inactive, including in relation to the reactions of lordosis, ovariectomised and not receiving estrogen in females (see also J.B. Becker, S.M. Breedlove and D. Crews (Eds.) Behavioral Endocrinology, 1992, pp. 82-84).

The ability of test compounds to stimulate the progesterone-induced reactions of lordosis in ovariectomized female rats was used to demonstrate estrogenic activity data is soedinenii in vivo when administered orally. Within three days female rats received the test compound, then on the fourth day they were given a progestogen. Sexual behavior of female rats was investigated through four hours after receipt of progesterone in the presence of male rats by recording the number of reactions lordosis within 10 minutes.

For all prodrugs Connection type8where R1is pivaloyl (Connection9a), dimethylcarbamoyl (Connection9bor etoxycarbonyl (Connection9c), it was demonstrated that they are active estrogen compounds in oral dose of 1 mg/kg

1. 15β-substituted steroid compound of the formula I

where
R1-H (8), C1-12acyl (9a), di-(C1-5alkyl)aminocarbonyl (9b), (C1-5alkyl) oxycarbonyl (9),
R2- H1-3alkyl (8),
R3- C1-2alkyl, and
R4- H.

2. Compounds according to claim 1, wherein R1is a hydrogen atom, and R2- ethyl.

3. Compounds according to claim 1, wherein R1- C1-12acyl, di(C1-5alkyl)aminocarbonyl, (C1-5alkyl)oxycarbonyl.

4. The compound according to claim 1, characterized in that it is a 7α-ethyl-15β-methyl-19-nor-17α-pregna-1,3,5(10)-triene-20-in-3,17β-diol.

5. Pharmaceutical composition having selective estrogenic activity, including compounds is their any one of claims 1 to 4, and pharmaceutically acceptable carrier.

6. The compound according to any one of claims 1 to 4 for use in the treatment or prevention of diseases or physiological conditions associated with estrogen receptors.

7. The use of compounds according to any one of claims 1 to 4 to obtain drugs for treatment or prevention of diseases associated with estrogen receptors, or regulation, treatment or prevention of physiological processes associated with estrogen receptors.

8. The use according to claim 7 for the production of medicinal products for hormone replacement therapy.

9. The use of claim 8, wherein the hormonal therapy is used for menopausal syndromes.

10. The use of claim 8, wherein the hormonal therapy is used in osteoporosis.

11. The use of claim 8 for the production of drugs for contraception.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to new 3.15-substituted estrone derivatives that are inhibitors of 17β-hydroxysteroid-dehydrogenase type 1 (17β-HSD1), to their salts, pharmaceutical compositions, containing specified compounds and to methods of such compound producing. Besides the invention refers to application in medicine of specified new 3,15-substituted estrone derivatives firstly to their application for treatment or prevention of steroid-dependent diseases or disorder such as steroid-dependent diseases or disorders treatment of which requires inhibition of 17β-hydroxysteroid dehydrogenase type 1 and/or reducing of endogenous 17β-estradiol concentration. The invention also relates to general application of selective inhibitors of 17β-hydroxysteroid-dehydrogenase type 1 that do not bind with estrogen receptor or display antipathic affinity to estrogen receptor.

EFFECT: possibility of application for treatment and prevention of benign gynaecologic diseases.

49 cl, 836 ex, 42 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of [18F]fluororganic compounds ensured by reaction of [18F]fluoride and relevant halogenide or sulphonate with alcoholic vehicle of formula 1 where R1, R2 and R3 represent hydrogen atom or C1-C18 alkyl.

EFFECT: possibility for mild process with low reaction time and high yield.

21 cl, 2 tbl, 27 ex

FIELD: technological processes.

SUBSTANCE: invention is related to automation of technological processes and may be used in automation of process of production of loose form of powdery choline chloride from its aqueous solution. In method that provides for use of crushed and fractionated dry sugar beet pulp as active adsorbent, its mixing with previously heated aqueous solution of choline chloride, and then drying in vibration dryer by superheated steam of atmospheric pressure, separation of spent superheated steam flow into the main one, sent to vibration dryer with creation of recirculation circuit, and additional one sent for reheating of choline chloride prior to its supply for mixing, the novelty is the fact that superheating of atmospheric pressure steam is done with heating steam, at that heating steam is produced by means of steam generator with electric heating elements, feed pump and safety valve, heating steam condensate produced in this process after superheating and condensate produced during heating of aqueous solution of choline chloride is taken to condensate collector, and then in mode of closed circuit is supplied in steam generator, at that flow rate of crushed and fractionated dry pulp is measured, as well as aqueous solution of choline chloride coming for mixing, flow rate and temperature of superheated steam upstream vibration dryer, choline chloride temperature before and after its heating, pressure of choline chloride after heating, temperature and humidity of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, amplitude and frequency of oscillations in gas-distributing grid of vibration dryer, flow rate and humidity of powdery choline chloride after drying, level of condensate in steam generator and pressure of heating steam, at that flow arte of dry sugar beet pulp after fractionation is used to set flow rate of heated choline chloride coming for mixing, and flow rate and humidity of prepared mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride prior to supply for drying, flow rate and humidity of powdery choline chloride after drying are used to determine amount of evaporated moisture in vibration dryer, which is used to establish flow rate of superheated steam in the main circuit of recirculation, and its temperature is established by current value of temperature of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride by setting of specified capacity of steam generator affecting power of electric heating elements, at that in case condensate level in steam generator falls below specified value, condensate is supplied from condensate collector, and when pressure of steam in steam generator reaches upper limit value, steam pressure is released through safety valve, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates prior to supply for drying to the side of increase from specified value, at first frequency is increased, and then amplitude of oscillations in gas-distributing grid of vibration dryer, if flow rate of mixture of crushed and fractionated dry pulp and aqueous solution of choline chloride deviates to the side of reduction from specified value, at first frequency is reduced, and then amplitude of oscillations in gas-distributing grid of vibration dryer, current values of temperature and flow rate of choline chloride prior to heating are used to set flow rate of spent superheated steam in additional recirculation circuit, at that temperature of choline chloride after heating is used to set specified pressure of choline chloride at the inlet to mixer.

EFFECT: provides for increased quality of finished product, accuracy and reliability of control, increased yield of finished product, reduced specific heat and power inputs and prime cost of finished product.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of formula I: , where M is macrolide subunit of substructure II: , L is chain of substructure III: -X1-(CH2)m-Q-(CH2)n-X2-, D is steroid or non-steroid subunit derived from steroid or non-steroid NSAID medicines (nonsteroid anti-inflammatory drug) with anti-inflammatory effect; pharmaceutically acceptable salts and solvates of claimed compounds; methods and intermediary compounds for obtainment of claimed compounds.

EFFECT: improved therapeutic effect, application in inflammatory disease and state treatment for humans and animals.

37 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula [I], where X represents halogen, trifluoromethyl, C1-C7alkyl, substituted with phenyl, C2-C9alkenyl, optionally substituted with C1-C7alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C1-C7alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, phenyl or benzoyl, where C1-6alkyl is optionally substituted with one or more halogens, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or C1-6alkoxy; Q1 represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q2 represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

FIELD: veterinary.

SUBSTANCE: claimed is method, which allows to separate from pregnant horse urine by hard-phase extraction mixture of conjugated estrogens, depleted of phenol urine components and non-conjugated lipophilic compounds from group including non-conjugated flavonoids, non-conjugated isoflavonoides, non-conjugated norisoprenoids, non-conjugated steroids, first of all, androstane and preganane steroids, and comparable with them non-conjugates compounds.

EFFECT: improved method of obtaining extract, containing natural mixture of conjugated horse estrogens.

16 cl, 3 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved methods of obtaining eplerenone pharmaceutical compound: (9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarbonic acid, γ-lactone, methyl ether) involving new intermediary products. Methods are implemented by Δ4,6-3-ketosteroid or its ketal transformation into respective Δ4-3-ketosteroid-7α-carbonic acid through a number of stages including oxidation, methylation, epoxydation stages.

EFFECT: reduced process stage number, high yield of product.

11 cl, 38 ex, 15 dwg

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns ethonogestrel new esters of formula 1 , 2 , 3 , applied for male and female contraception. Compositions are characterised by improved disposition profile.

EFFECT: production of composition with improved disposition profile.

3 cl, 2 dwg, 1 ex

FIELD: organic chemistry, natural compounds, medicine.

SUBSTANCE: invention describes a glycoside derivative of 4-methylergost-7-ene-3-ol of the formula (I): , method for its preparing and composition for correction of hyperglycemia. The composition represents extract from plant of Liliaceae family, preferably, from Aloe vera. Also, invention describes a medicinal agent used for correction of hyperglycemia, foodstuffs and beverages.

EFFECT: valuable medicinal and nutrient properties of derivative and composition.

14 cl, 2 tbl, 4 dwg, 8 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: proposed are human growth hormone conjugates, obtained by removing a hydrogen atom from -NH2 in the Gln side chain which is formed from the human growth hormone or a human growth hormone compound.

EFFECT: design of an efficient method of producing human growth hormone conjugates.

6 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to agonists of neuropeptide-2 receptor with formula (I): Y-R1-R2-X-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-NH2(l), as well as their pharmaceutically acceptable salts, derivatives and fragments, in which substitutes assume values given in the description.

EFFECT: compounds and pharmaceutical compositions containing said compounds can be used to treat diseases which are modulated by neuropeptide-2 receptors, mainly obesity.

13 cl, 10 dwg, 1 tbl, 74 ex

FIELD: medicine.

SUBSTANCE: extraction of young immature fruits with diametre not more than 3 mm is carried out. Fresh raw material is preliminarily grinded, covered with 60% alcohol with ratio 1:2 and extraction with addition of propylene glycol in amount 1% at temperature 50° during 5 hours is carried out, extract is poured out. Second stage of extraction is performed at room temperature during 15 hours with ratio raw material extractant 1:2. Raw material is squeezed, extracts are poured together, recovered material is filtered.

EFFECT: increasing yield of active substances.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: for treatment patients with hypogonadism with obstructive sleep apnea syndrome before substitutive therapy with androgens CPAP- therapy is carried out. After that CPAP- therapy is realised simultaneously with therapy with testosterone medications until its normal level is recovered.

EFFECT: method allows to carry out substitutive therapy of hypogonadism in patients with syndrome of obstructive sleep apnea, who have relative contraindications to administering androgens.

3 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula (I), where: A represents O, CH2, S, SO or SO2; X and Y are chosen from Br, Cl and -CN3; R1 is chosen from the group consisting of -(CH2)nCOOH, -NHC(=O)COOH, -NHCH2COOH, ;

Z represents H or -C=H; R2 is lower alkyl; R3 - H or lower alkyl; n means 1, 2 or 3; p means 1 or 2; or to their pharmaceutically acceptable salts or esters. Besides the invention covers a pharmaceutical composition based on said compounds expressing an agonist activity in relation to thyroid hormone receptor.

EFFECT: said compounds and pharmaceutical compositions containing thereof there can be effective for treatment of such diseases as obesity, hyperlipidemia, hypercholesterolemia and diabetes, and the other similar conditions and diseases, and can be used for treatment of the other diseases, such as NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and the other similar conditions and diseases.

25 cl, 1 tbl, 27 ex

FIELD: medicine.

SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.

EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.

9 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula I , its pharmaceutically acceptable salt or stereoisomer, where X is -CH- or -N-; n equals 0, 1, 2 or 3; m equals 0, 1 or 2; R1 and R4 are each independently selected from hydrogen, halogen, cyano, perfluoroC1-6alkyl, C1-10alkyl, C2-10alkenyl, C3-8cycloalkylC0-10alkyl, R5 is hydrogen; R2 and R3 are each independently selected from hydrogen, hydroxyC0-10alkyl, perfluoroC3-6alkyl, C1-10alkyl, C3-8cycloalkylC0-10alkyl, (C0-10alkyl)1-2aminocarbonyloxyC0-10alkyl, C3-8heterocyclylcarbonyloxyC0-10alkyl, to their use in making a medicinal agent with activity which his mediated with androgen receptor modulation (SARM), as well as to a pharmaceutical composition and preparation method thereof.

EFFECT: novel compounds which can be used as androgen receptor modulators (SARM) are obtained and described.

15 cl, 5 ex, 4 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to medicine and can be used as an effective remedy for precise delivery of DNA complexes with molecular conjugates to certain organs and tissues in mammals. The technical effect is ensured by introduction of modified nuclear localisation signal (NLS) that shall allow for conjugates to form complexes with plasmid DNA containing a suicidal gene, and also shall provide higher conjugate concentration in tumour cell nuclei that leads to intensification of cytotoxic properties of doxorubicine.

EFFECT: higher effectiveness of tumour cell exposure.

3 cl, 5 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and concerns hypertension treatments in women in combination with hormone replacement therapy. That is ensured by introduction of Drospirenone (DRSP) in amount 0.5-3 mg/day and 17β-estradiol in amount 1-3 mg/day.

EFFECT: invention provides maximally effective arterial pressure reduction with minimum by-effects in given category of patients.

17 cl, 3 ex, 1 tbl, 8 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns normalisation of thromboplastin formation in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated static and dynamic physical exercises, and also introduction of pioglitazone in a dose 30 mg once in the morning and a lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: complex of specific medical agents and physical activity combined with empirically specified duration of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is produced β-glycyrrhetinic acid by hydrolysis of licorice extract in air-tightness in aqueous medium or aqueous solution of mineral acids at temperature 190-270°C followed with recovery of an end product.

EFFECT: invention allows for said process without using organic solvents with simplifying thereof.

5 cl, 9 ex

Up!