Steroid compound, the methods of its production and pharmaceutical composition

 

(57) Abstract:

The invention relates to a steroid compound of General formula I

< / BR>
where is = O, -HE, or SIG or R, where R represents an alkyl group having from 1 to 6 carbon atoms; R6represents H or -(CH2)mN, where m = 1 or 2; R7represents H, C1-4-alkyl, C2-4alkenyl or2-4-quinil; R11represents H, C1-4-alkyl, C2-4alkenyl,2-4-quinil; E represents, including the carbon atoms 16 and 17 of the D ring, a 4-7-membered hydrocarbon ring, where the specified ring is in the position relative to the D-ring, substituted by a group REand optionally contains one endocyclic double bond; RErepresents H, C1-5-alkyl, C2-5alkenyl,2-5-quinil,1-5-alkyliden, -(CH2)n-N3or -(CH2)n-SP, where n = 1 or 2, and where the alkyl group may be substituted by-OR, -OOCR where R is alkyl with 1-6 carbon atoms; R17is-HE-or SIG or R, where R is alkyl with 1-6 carbon atoms, where the aforementioned steroid compound may be, but not necessarily, one double bond, 5(10), 4(5), or the ring may be aromatic. Sobre compounds of the invention are highly effective when used to prevent or treat disorders, associated with peri - and postmenopause, and more preferably for the prevention or treatment of osteoporosis. In addition, steroid compounds can be used as contraceptives. 4 C. and 6 C.p. f-crystals, 1 table.

The invention relates to a new class of steroid compounds, and in particular to the steroid compounds of the formula (I)

< / BR>
where is =0, -HE; =NOR;-or, or-OOCR where R is alkyl group having from 1 to 6 carbon atoms;

R6represents H; a =CH2or -(CH2)mN, where m=1 or 2; and specified steroid compound may, but not necessarily, to have one or more double bonds, selected from the group comprising: 9(10), 5(10), 4(5); 11(12); 14(15); or any of the rings a or b may be aromatic; the presence or absence of hydrogen atoms is not specified, since it depends on whether the ring is saturated, unsaturated or aromatic, and can easily be determined by the specialist;

R7represents H; C1-4-alkyl; C2-5alkenyl or2-5-quinil, where alkyl, Alchemilla or Alchemilla group may be substituted by 1-3 halogen atoms, independently selected from fluorine atoms and chlorine;

E represents, including the carbon atoms 16 and 17 of the D ring, a 4-7-membered ring, which is in-position relative to the D-ring, substituted by a group REand optionally contains one or two endocycles double bond; and-the position of the E ring relative to the ring D is an important factor, because the corresponding steroid having the ring in position, do not possess the desired biological activity. It should be noted that based on the item, some compounds of the present invention are known in which there are 16 and/or 17-substituents. However, regardless of this, all of the compounds of the present invention, the E-ring is in General position .

RErepresents H; C1-6-alkyl; C2-6alkenyl; C2-6-quinil; C1-6-alkyliden,2-6-spiroannulated cycloalkyl; -OR; -SR; -OOCR; -other; -NRR; -NHCOR, where R (if REis-NRR, each R independently from each other represents alkyl with 1-6 carbon atoms, -NCO; -(CH2)n-N3or -(CH2)nCN, where n=0-5, and where alkylen ezavisimo selected from the group includes-OR; -SR; -OOCR; -other; -NRR; and-NHCOR, where R is defined above; the fluorine atoms and chlorine atoms;

R17is HE; -OCH2OR; -or, or-OOCR where R is alkyl with 1-6 carbon atoms. Any alkyl, Alchemilla, Alchemilla and alkylidene group in a steroid compound of the formula (I) may be branched or unbranched. If R3, R6or R11related to steroid skeleton by means of a simple connection, the substituted carbon atom of the steroid skeleton or a hydrogen atom, or participates in the formation of a double carbon-carbon linkages. If REassociated with the E-ring by means of a simple connection, the substituted carbon atom of the E-ring has a hydrogen atom.

Unexpectedly it was found that the steroid compounds of the present invention have good interest estrogenic and/or progestogenic properties. Due to these specific properties of the steroid compounds of the present invention can be used for the prevention or treatment of disorders associated with peri-menopause or post menopause, including menopausal symptoms such as hot flushes, impaired mental balance, disorders of the genitourinary tract is the absence or deficiency of estrogen, such as osteoporosis, atherosclerosis, and Alzheimer's disease. Steroid compounds of the present invention can be used for the prevention or treatment of osteoporosis due to estrogen deficiency.

In addition, steroid compounds of the present invention can be used as contraceptives.

Steroid compounds having substitution at position 16, 17 of the ring described in the literature. In Chemical Abstracts 89: R (Kamernitskii A. V. et al. ) described a steroid compound containing 16,17-annulirovano 5 - or 6-membered ring and the acetyl group in position 17. However, the compounds described in this publication differ from the compounds of the present invention in that the carbon atom in position 11 carries a hydrogen atom.

In "Chemical Abstracts 123: 285604t (Wang, J. et al.)" described steroid compounds having 10-membered E-ring with two triple bonds, hydroxyl group in position 17, and the carbon atom in position 11.

In EP 411733 (Schering AG) describes steroid compound having a 6-membered E-ring, and the carbon atom at position 17, participating in education WITH communication. However, the compounds described in EP 411733, different from the steroid compounds of the present invention which organisations are competitive antagonists in relation to progesterone.

Thus, none of the previous works are not described steroid compounds of the present invention. Steroid compounds of the present invention differ from the known compounds in that they have the substituents in positions 11, 16, and 17. More specifically steroid compounds of the present invention contain a ring E, having a 5-membered ring D total carbon atoms in position 16 and 17, and held in position with respect to the specified ring D. in Addition, the carbon atom at position 17 substituted oxygen-containing group, through communication WITH. The carbon atom in position 11 aryl group.

In addition, none of the above publications were not made assumptions about interest pharmaceutical properties, which have steroid compounds of the present invention. Therefore, compounds of the present invention constitute a new class of steroid compounds, differing in their in vitro and in vivo activity.

In particular, for the selective estrogenic activity preferably in the steroid compounds of the present invention, the E-ring was a 5-membered ring. However, from the point of view of the predominant estrogen is either mixed estrogenic/progestogen connection preferably, the E-ring was a 6-membered ring. In a preferred embodiment of the invention And the ring is aromatic and the other ring is saturated, while most preferably, R7represented-propyl. The most preferred compound denoted by the Hen 38515, characterized in that it R3and R17imagine IT, a R6, R11and RErepresent N.

The present invention also relates to pharmaceutical compositions containing the steroid compound of the present invention in a mixture with pharmaceutically acceptable additives, such as, for example, additives described in the reference, Gennaro et al., Remmington''s Pharmaceutical Sciences (18th ed., Mack publishing Company, 1990, see, in particular, Part 8: Pharmaceutical Preparations and Their Manufacture). A mixture of steroid compounds of the present invention and pharmaceutically acceptable additives can be pressed with getting a solid uniform dosage forms, such as pills and tablets or receive capsules or suppositories. With the use of pharmaceutically acceptable liquids of the compounds of the present invention can be also obtained injections in the form of a solution, suspension, emulsion or Aer the current can be used with standard additives, such as fillers, dyes, polymeric carriers, etc., Generally speaking, for the manufacture of such drugs can be used in any pharmaceutically acceptable additives provided that they do not adversely affect the function of the active compounds. Steroid compounds of the present invention can also be introduced into the implant, vaginal ring, patch, gel, and any other long-acting drugs.

Suitable media that can be introduced into the compositions of the present invention are lactose, starch, cellulose derivatives, etc. or mixtures thereof, taken in appropriate quantity.

In addition, the present invention relates to the use of steroid compounds of the present invention for the manufacture of medicinal drugs with activity aimed at the elimination or reduction of disorders associated with peri - and/or postmenopausal, and especially antiosteoporosis activity. Thus, the preparations of the present invention have read at peri - and/or post-menopausal (climacteric syndrome and osteoporosis, i.e. onidine the patient (woman) of the above compound (in a suitable pharmaceutical form).

In addition, the present invention relates to the use of steroid compounds of the present invention to obtain a drug that has the contraceptive (birth control) action. Thus, the present invention can be used for contraception, i.e., in the way of protection from pregnancy, introducing a woman or female animal of the above-described compounds (in a suitable pharmaceutical form).

Finally, the present invention relates to the use of steroid compounds to obtain a drug with selective estrogenic activity, such as a drug that can be used in HRT (hormone replacement therapy).

Synthesis of 16,17-annelated steroids carry out first by attaching appropriately functionalized WITH3- or4slice-to-C16-position of the steroid (for the formation of 5-membered or 6-membered rings, respectively). To facilitate this process, functional 17-ketogroup first turn in dimethylhydrazone, which again otscheplaut after the formation of the desired functional groups of the side chain. Ring closure can b the AK-processing italgiloti derivatives of metals of the transition series such as samarium (in the case of 5-membered rings as described in example 1), or by formation of organolithium derivatives using such reagents as tert-utility (formation of 6-membered rings described in example II). In the alternative case, the formation of the above rings may be effected by producing anions by removal of the silicon group in-cyrilovich side chains in the presence of fluoride, as described in example III.

-Acetylene can serve as substrates in the reactions of ring closure in aminopenicillanic reactions carried out with the use of elements such as sodium or lithium, as described in example IV.

A completely different method involves the formation of annelated rings by olefin exchange with the use of catalysts based on transition metals such as ruthenium, molybdenum or tungsten. To do this, as the substrates are 16,17 - dialkanolamine steroids. They can be easily obtained by alkylation steroid ketones in position C-16, followed by the introduction of alkinoos fragment using metalloorg is by example V.

Thus, in addition to obtaining the above-mentioned compounds and various applications of these compounds, the present invention also relates to methods of obtaining 16,17-annelated steroids by producing rings attached to the steroid skeleton, where the specified ring consists of carbon atoms 16 and 17 of the specified frame. These methods, which are not used in steroid chemistry, allow to obtain a wide range of 16,17-annelated steroids. For example, in the patent DE 19709870 (not previously published) describes the method, which is limited in relation to the synthesis of specific compounds. This method involves the reaction of [4+2] cycloaddition of butadiene or dimethylbutadiene with strongly activated double bond at C16-17. This means that C17should always be a strong electron-withdrawing Deputy, for example, such Deputy as-CN or-acyl, which greatly limits the possibilities of this method. In addition, this method allows to get only a 6-membered ring, and a limited number of variants of these compounds, and also requires symmetric butadiene structure, because this method is not regioselective. How nastoyashei the synthesis of a wide range of 5 - and 6-ring-16,17-annelated steroids, described above. Thus, these methods make a significant contribution to the field of steroid chemistry.

The present invention is illustrated with diagrams and examples, which should not be construed as limiting the present invention examines the specific options.

Schema:

Scheme 1: schematic illustration of (2-13) method for the synthesis of two steroid compounds (12 and 13) of the present invention described in example 1.

Scheme 2: schematic illustration of (14-21) method for the synthesis of three steroid compounds (19, 20 and 21) of the present invention described in example II.

Scheme 3: schematic illustration of (22-33) method for the synthesis of two steroid compounds (30 and 33) of the present invention described in example III.

Figure 4: schematic illustration of (34-39) method for the synthesis of steroid compounds (39) of the present invention described in example IV.

Figure 5: schematic illustration of (40-44) method for the synthesis of steroid compounds (44) of the present invention described in example V.

Figure 6: schematic illustration of (40-47) method for the synthesis of steroid compounds (47) of the present invention described in example VI.

A number pointed to by the Example 1

Although the desired substrate 1 can be easily synthesized by dehydrogenation of steroids in6WITH7the methods described in the literature (for example, using chloranil or DDQ), however, a new method was developed, allowing the use of various 17-alpha ethinyl,17-beta-hydroxysteroid, as well as substrates, in order to obtain the corresponding 17-ketosteroids. These compounds can be definilion by treatment with carbonate of copper, precipitated celite. Although a similar conversion using silver carbonate has been described in the literature, however, the method of the present invention, has the advantage that it is much cheaper reagent. Party ISSS3on celite was prepared as follows. 100 g of celite was purified by stirring in a mixture of 500 ml methanol and 100 ml of 6 N. Hcl for 15 minutes the mixture was filtered and repeatedly washed with water until, until it became neutral. Thus obtained product is suspended in a solution of 60 g of cu(NO3)23H20 in 400 ml of water. To this solution dropwise with vigorous stirring solution was added 30 g of Na2CO3H2O in 200 ml of water. After premesis is drying the resulting material suspended in acetone and filtered, and then washed with pentane). Final drying was performed in vacuum at 80oWith during the night and got 160 g of reagent.

4 g (17)-17-Hydroxypregn-4,6-Dien-20-in-3-one and 20 g ISSS3-Celica suspended in 100 ml of toluene. The resulting mixture was heated under reflux for approximately 6 h using traps Dean-stark removal of residual amounts of water. Over the course of the reaction was monitored using thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was filtered through celite. Then the filtrate was concentrated, and the residue was treated with isopropyl ether/hexane and was obtained 2.4 g of pregna-4,6-Dien-20-in-3,17-dione, so pl. 182-184oC. the compound Obtained was subjected to reaction recovery with sodium borohydride and received the necessary 17--alcohol, which, after acetylation reaction with acetic anhydride gave the desired substrate 1.

(7-alpha,17-beta)-17-(atomic charges)-7-propylether-4-EN-3-one (2)

The solution propylaia (from 1.4 g of lithium and 9 ml of propyl bromide in 60 ml of ether at -20oC) was added at -40oWith 7.6 g CuI in 60 ml of anhydrous THF. After stirring for 0.5 h to a solution dropwise at -40oC was added a solution of 5.2 g (17-b the resulting mixture was poured into 300 ml of a saturated solution of NH4C1, and then was extracted with ethyl acetate. Organic matter allocated after washing, drying and evaporation of the solvent, was dissolved in 30 ml of THF, and stirred in the presence of 3 ml of 6 N. H2SO4for isomerization of a particular 5,6-isomer 4.5-isomer. After one hour the mixture was neutralized with a saturated solution Panso3and then was extracted with ethyl acetate. After chromatography of the crude product on silica gel (heptane/ethyl acetate = 8/2) was obtained 2.1 g of compound 2, so pl. 97-100oC.

(7-alpha,17-beta)-7-propylether-1,3,5(10)-triene-3,17-diol-17-acetate (3)

To a solution of 15 g of compound 2 in 300 ml of acetonitrile was added 12 g Siug2. The resulting mixture was stirred for 20 h and the reaction course was monitored by TLC (TLC-plates were purchased from Merck A. G., Germany). Then the reaction mixture was poured into water and was extracted with ethyl acetate. The crude product was chromatographically on a short column of silica gel (eluent: heptane/ethyl acetate = 4/1) was obtained 13.5 g of compound 3 as a white amorphous substance. Rf0,57 (heptane/ethyl acetate = 7/3).

(7-alpha, 17-beta)-3-methoxy-7-propylether-1,3,5(10)-triene-17-olacetat (4)

To a solution of 13.5 g of compound 3 in 60 ml of DMF portions were added 2.4 g NaH (60% dispersion in ml min under the conditions. After stirring for one hour at room temperature the reaction mixture was poured into 300 ml of water and the product was extracted with ethyl acetate. The residue resulting from evaporation of volatile substances was dissolved in 20 ml of THF, and then injected with a solution of 4 g of NaOH in 80 ml of CH3HE. After stirring for one hour the reaction of saponification was complete. The reaction mixture was neutralized by adding 1N. sulfuric acid, and the product was extracted with ethyl acetate to obtain the 11.5 g of compound 4, Rf0,34 (heptane/ethyl acetate = 7/3).

(7-alpha-3-methoxy-7-propylether-1,3,5(10)-triene-17-one (5)

To a solution of 10.4 g of 3-O-methyl-7-profileschedule 4 in 50 ml of methylene chloride was sequentially added 15 g of powdered sodium acetate, 30 g of silica gel, and 32 g Harrogate pyridinium. After stirring for one hour the oxidation reaction was completed. The excess reagent was decomposed by adding 1 ml of isopropanol and, after 10 minutes 150 ml of hexane. All precipitation was filtered through celite and the filtrate was concentrated to dryness. Thus was obtained 9.6 g mostly pure ketone 5; Rf0,54 (heptane/ethyl acetate = 7/3)

(7-alpha-3-methoxy-7-propylether-1,3,5(10)-triene-17-she dimethylhydrazone (6)
3and the organic layer is repeatedly washed with water and dried with sodium sulfate. After concentration the residue was chromatographically and received 11.4 g of hydrazone 6 in the form of an oily product; Rf0,30 (heptane/ethyl acetate = 7/3).

[7-alpha, 16-alpha(S)]3-16-[3-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-2-methylpropyl] -3-methoxy-7-propylether-1,3,5(10)-triene-17-she dimethylhydrazone (7)

To a solution of 2.6 g of compound 6 in 30 ml of dry THF was added at -40oWith 5.6 ml of BuLi (1,5-called solution in hexane). After stirring for half an hour at this temperature was added 2.7 g (2R)-2-methyl-3-iodopropane-O-tert-butyldimethylsilyl ether (TBDMS) in 5 ml of THF. After stirring for a further one hour at -20oTo the reaction mixture was poured into water and was extracted. In the chromatography was obtained 4.6 g of compound 7; f0,50 (heptane/ethyl acetate =7/3).

[7-alpha, 16-alpha(S)] -16-(3-hydroxy-2-methylpropyl)-3-methoxy-7-propylether-1,3,5(10)-triene-17-she dimethylhydrazone (8)

A solution of 4.6 g of compound 7 in 5 ml of THF was treated with 15 ml of 1M TBAF in THF for one who their product through a short column with silica gel was obtained 3.1 g of compound 8 in the form of an oily product, Rf0,18 (heptane/ethyl acetate = 7/3).

[7-alpha,16-alpha(S)]-16-[2-methyl-3-[[(4-were)sulfonyl] oxy]propyl] -7-propylether-1,3,5(10)-triene-17-one(10)a Solution of 2.8 g of compound (9) in 1 ml of pyridine at 0oWith treated mozillateam (2.6 g). After stirring for 2 h, the excess reagent was dissolved under stirring with ice within half an hour. The product was extracted with ethyl acetate and purified by chromatography, which was obtained 3.2 g of compound 10 as a colorless oily substance; Rf0,35 (heptane/ethyl acetate = 7/3).

[7-alpha, 16-alpha(S)] -16-(3-hydroxy-2-methylpropyl)-3-methoxy-7-propylether-1,3,5(10)-triene-17-one (9)

A mixture of 3.1 g of compound 8 in 30 ml of acetone and 3 ml of water was treated with 3 g of the acid resin Amberlist 15 (Fluka A. G.) for 2 h at 55oC. Then the reaction mixture was filtered, concentrated and obtained 2.8 g of compound (9) in the form of oily substance; Rf0,75 (heptane/acetone = 1/1).

[7-alpha,16-alpha(S)]-16-(3-iodine-2-methylpropyl)-7-propylether-1,3,5(10)-triene-17-one (11)

A mixture of 3.2 g of compound 10 and 10 g of sodium iodide in 30 ml of acetone was heated for 1 h at 65oC. Then the reaction mixture was poured into ice water, extracted with ethyl acetate and obtained 2.9 g of iodide 11; Rfis-cyclopent[16,17]östra-1,3,5(10)-trien-17-ol (12)

The solution SmI2was obtained from 3 g of metallic samarium and 4.7 g of 1,2-diiodoethane in 70 ml anhydrous THF. To this solution was added at 0oWith 20 mg of Tris(dibenzyl-metadata)iron, and then a solution of 2.8 g of compound (11) in 10 ml of THF. After stirring for 1 h the mixture was poured into water, acidified 2 N. N2S04and was extracted with ether.

Thus obtained crude product was chromatographically to remove 16,17-beta-isomer was obtained 1.6 g of compound 12; Rf0,32 (heptane/ethyl acetate = 7/3).

Related beta-isomer has Rf=0,37.

(4'S, 7-alpha, 16 beta, 17-beta)-3', 4',5',16-tetrahydro-4'-methyl-7-propyl-17H-cyclopent[16,17]östra-1,3,5 (10)-triene-3,17-diol (13)

To a solution of 700 mg of compound 12 in 5 ml of toluene was added 15 ml of DIBAL (1M in toluene). The mixture was heated under reflux for 3 h for cleavage of the ether. The excess reagent was decomposed by addition of water followed by dilution with 40 ml of 2 N. Hcl. The product was extracted with ethyl acetate. After drying and concentrating, the residue is triturated with diisopropyl ether and received 460 mg of crystalline compound 13; so pl. 166-168oC; Rf0,36 (heptane/ethyl acetate = 7/3).

Example 11

[7-alpha, 16-alpha)->To a solution of 3.9 g of the hydrazone 6 in 45 ml of anhydrous THF was added at -60oWith 8.5 ml of a 1.5 n solution of utility in hexane. After stirring for 0.5 h was added dropwise a solution of 4.2 g of 4-iodobutane-DS-ester in 5 ml THF. The resulting mixture was stirred for 1 h at -20oWith, and then poured into water (200 ml) and was extracted with ethyl acetate.

In the purification using chromatography on silica gel was obtained 6.2 g of compound 14 in the form of oily substance; f0,52 (heptane/ethyl acetate = 7/3).

(7-alpha, 16-alpha)-16-(4-hydroxybutyl)-3-methoxy-7-propylether-1,3,5(10)-triene-17-she dimethylhydrazone (15)

A solution of 6 g of compound 14 in 5 ml of THF was treated with 20 ml of 1M tetrabutylammonium fluoride in THF for 2 h, the Reaction mixture was poured into water and was extracted with ethyl acetate. After chromatography was obtained 4.1 g of compound 15 in the form of an oily product; Rf0,17 (heptane/ethyl acetate = 7/3).

(7-alpha, 16-alpha)-16-(4-hydroxybutyl)-3-methoxy-7-propylether-1,3,5(10)-triene-17-one (16)

A mixture containing 4 g of compound 15, 40 ml of acetone, 4 ml of water and 4 g of acid resin Amberlist 15, was stirred for 2 hours at a temperature of 50oC. the resulting mixture was filtered, concentrated, dissolved in 40 ml of toluene, Susan/acetone = 1/1); for the original product Rf=0,65.

(7-alpha, 16-alpha)-16-[4-[[4-were)sulfonyl] oxy]butyl]-7-propylether-1,3,5(10)-triene-17-one (17)

A mixture of 3.7 g of the product 16 and 3.2 g of tosylchloramide in 10 ml of anhydrous pyridine was stirred at 0-5oC for 3 hours After dilution with water the product was extracted with ethyl acetate. After chromatographic purification was obtained 4.6 g tosilata 17; Rf0,45 (heptane/ethyl acetate = 7/3).

(7-alpha, 17-alpha)-16-(4-iodobutyl)-3-methoxy-7-propyl-östra-1,3,5(10)-triene-17-one (18)

A mixture of 4.6 g of compound 17 and 20 g of sodium iodide in 50 ml of acetone was heated at 60oC for 1.5 h, the Reaction mixture was concentrated, diluted with water and extracted with toluene. After drying and concentration was obtained 4.4 g is basically pure iodide 18; Rf0,50 (heptane/ethyl acetate = 7/3).

(7-alpha, 16-alpha, 17-alpha)-3-methoxy-7-propyl-16,24-cyclo-19,21-Generala-1,3,5(10)-trien-17-ol (19)

A solution of 3.8 g of iodide 18 in 20 ml of dry THF was treated at -60oWith 9 ml of 1.7 M solution of tert-utility in heptane. After stirring for 15 min at -60oC, the mixture was poured into water and was extracted with ethyl acetate. The crude product obtained after removal of volatiles, triturated with heptane, and received 1.9 grams in OS-alpha)-17-hydroxy-7-propyl-16,24-cyclo-19,21-General-4-EN-3-one (21)

To a solution of 1 g of lithium in 90 ml of liquid ammonia was added at -33oTo a solution of 1.3 g of the product 19 in 30 ml of dry THF. After stirring in the boiling ammonia for 4 h, the reaction mixture was treated with 20 ml of ethanol, and then the ammonia is evaporated in a constant stream of nitrogen. The residue was diluted with 50 ml water and was extracted with ethyl acetate. After concentration of the organic phase the residue triturated with heptane and was obtained 1.1 g of pure intermediate dianalove ether, so pl. 190-192oC.

The obtained product was dissolved in 25 ml of THF and was treated with 5 ml of 6 N. sulfuric acid. After stirring for 6 h, the mixture was neutralized by adding PA2CO3and the product was extracted with ethyl acetate. The crude product was subjected to chromatographic purification and got 610 mg of compound 21 as a white foam, Rf0,25 (heptane/ethyl acetate = 7/3).

(7-alpha, 16-alpha, 17-alpha)-7-propyl-16,24-cyclo-19,21-Generala-1,3,5(10)-triene-3,17-diol (20)

To a solution of 600 mg of compound 19 in 5 ml of dry toluene was added 12 ml of 1M DIBAH (hydride diisobutylaluminum) in toluene. After heating under reflux for 2 h, the demethylation reaction was completed, the excess reagent was decomposed by careful addition of water, the sky layer was dried and concentrated, then the residue was treated with diisopropyl ether, and obtained 310 mg of the product 20; so pl. 240oS, Rf0,20 (heptane/ethyl acetate = 7/3).

Example III

(11-beta, 16-alpha)-11-methyl-16-[2-[(trimethylsilyl)methyl]prop-2-enyl]-variety-5-ene-3,17-dione 3-cyclo(1,2-ethandiyl) acetal (23)

To a solution of 12.7 ml hexamethyldisilazane in 50 ml of THF was added at -50oWith 40 ml of 1.5 M solution of BuLi in heptane. After stirring for 20 min at -50oWith was slowly added a solution of 16.5 g of compound 22 in 100 ml of THF. After stirring for a further 0.5 h was introduced a solution of 25 g of 3-iodine-2-trimethylsilylmethylamine in 25 ml of THF. The reaction mixture was stirred for 3 h at -20oWith, and then was poured into 400 ml of water. The product was extracted with ethyl acetate and was chromatographically on silica gel. After trituration with heptane was obtained 12.5 g of product 23;. so pl. 184-185oC; Rf0,55 (heptane/ethyl acetate = 7/3).

(11-beta, 16-beta,17-beta)-4',5',16,17-tetrahydro-17-hydroxy-11-methyl-4'-methylene-3 N-cyclopent[16,17] östra-5,16-Dien-3-one 3-cyclo(1,2-candirectly) (24)

A solution of 8.8 g of the product 23 in 200 ml of dry THF was treated with 4 ml of 1M tetrabutylammonium fluoride (TBAF) in THF. The resulting mixture was heated under reflux for 15 min before panonnian continued for another 1 h for the removal of 17-O-salelologa ether, formed in the reaction. Then the mixture was concentrated to small volume and diluted with water, then was extracted with ethyl acetate. After chromatographic purification was obtained 4.0 g of the product 24.: so pl. 141-142oS, Rf0,28 (heptane/ethyl acetate = 7/3).

(4'S, 11-beta, 16-beta, 17-beta)-4'5', 16,17-tetrahydro-17-hydroxy-4'-(hydroxymethyl)-11-methyl-3 N-cyclopent [16,17] -östra-5,16-Dien-3-one 3-cyclo(1,2-ethandiyl-acetal)(25) and 4'R-analog (26)

The solution borabicyclo (9-BBN) was obtained from 3 ml of 10 M brandimensions complex and 4 ml of 1,5-cyclooctadiene in 30 ml of dry THF. To this solution was added 3.8 g of compound 24 in 10 ml of THF.

The resulting mixture was stirred for 2 h, and then excess reagent was decomposed by careful addition of 1 ml of ethanol followed by the addition of 20 ml of 2 n NaOH solution and 10 ml of 30% H2ABOUT2. This mixture was stirred for another 3 h and then was diluted with water and extracted with ethyl acetate.

The crude product was chromatographically on silica gel (eluent: toluene/acetone) was obtained 2.1 g of the product 25 (so pl. 178oS, Rf0,47 (toluene/acetone = 1/1) and 1.2 g of the product 26 (Rf0,55, toluene/acetone = 1/1)).

(4R', 11-beta, 16-beta,17-beta)-4'5',16,17-tetrahydroindazole) (31)

A solution of 1.2 g of the product 26 and 0.8 g of tosylchloramide in 5 ml of pyridine was stirred for 2 h at 0-5oC. Then the mixture was diluted with water with ice, stirred for 15 min and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain 1.6 g mainly net connection 31; Rf0,52 (toluene/ethyl acetate = 7/3).

(4'R, 11-beta, 16-beta, 17-beta)-4'-butyl-4'5'16,17-Tetra-hydro-17-hydroxy-11-methyl-3 N-cyclopent-[16,17]östra-5,16-Dien-3-one (32)

Cuprate reagent was prepared by adding 12 ml of a 2M solution of bromide propylene/ether to 2.3 g CuI in 20 ml of THF at -20oC. After stirring for 15 min the solution was added 600 mg of compound 31 in 3 ml of THF. Stirring was continued for another 2 h at -20oC. To the reaction mixture were added 60 ml of saturated NH4Cl and 10 ml of 10% aqueous ammonia, and then the mixture was extracted with ethyl acetate. The crude product was chromatographically and received 420 mg of product 32; so pl. 97-98oC. Rfto 0.45 (hexane/ethyl acetate = 7/3).

(4'R, 11-beta, 16-beta,17-beta)-4'-butyl-4'5'16,17-tetrahydro-17-hydroxy-11-methyl-3 N-cyclopent[16,17] östra-4,16-Dien-3-one (33)

A solution of 400 mg of the product 32 in 5 ml of acetone was treated with 2 ml of 4 N. N2S04. After incubation for 2 h with the key received 360 mg mainly net connection 33 in the form of an amorphous product; Rf0,27 (heptane/ethyl acetate = 7/3).

(4'S,11-beta,16-beta,17-beta)-4'5',16,17-tetrahydro-4'- (hydroxymethyl)-11-methyl-17- [(trimethylsilyl)oxy] -3 N-cyclopenta[16,17]-östra-5,16-Dien-3-one 3-cyclo(1,2-candirectly) (27)

The response of the protection of a functional group of 17 HE performed in several stages. First, the primary alcohol was azetilirovanie. To do this, to a solution of 750 mg of compound 25 in 2 ml of pyridine was added 5 mg of 4-dimethylaminopyridine (DMAP), and then 0.5 ml of acetic anhydride. After stirring for 1 h was added 10 g of ice water and the product was extracted with ethyl acetate. Organic material was concentrated and the residue was treated with heptane/diisopropyl ether to obtain 730 mg of monoacetate, so pl. 112oC.

The resulting substance was dissolved in 3 ml of DMF containing 200 mg of imidazole. After you add 240 ál of tributyltinchloride the mixture was stirred for 0.5 h at room temperature. After adding 15 ml of water the product was extracted with ether. In the drying and concentration was received 900 mg mainly net derivative salelologa ether; Rf0,54 (heptane/ethyl acetate = 7/3). This product was dissolved in 3 ml of dry THF was added 70 mg LiAlH4. After stirring for 10 min cm is centered to obtain 700 mg of the compound 27 in the form of an amorphous substance;f0,29 (heptane/ethyl acetate = 7/3).

(4'S, 11-beta,16-beta,17-beta)-3,3-[1,2-atanderson(hydroxy)]-4',5',16,17-tetrahydro-11-methyl-17-[trimethylsilyl)oxy] -3 N-cyclopent[16,17] -östra-5,16-Dien-4'-carboxaldehyde (28)

To a solution of 600 mg of the product 27 in 15 ml of methylene chloride was added 1.5 g of anhydrous sodium acetate, 2.5 g of silica gel and 2 g Harrogate pyridinium. The resulting mixture was stirred for one hour at room temperature. After adding 50 ml of ether and additional stirring for 15 min, the reaction mixture was filtered through celite, and then the volatiles evaporated and received 420 mg mostly clean carboxaldehyde 28; this substance is slowly solidifies on standing; Rf0,48 (heptane/ethyl acetate = 7/3).

(4'S, 11-beta, 16-beta, 17-beta)-4'-ethynyl-4',5',16,17-tetrahydro-11-methyl-17-[(trimethylsilyl)oxy] -3 N-cyclopent[16,17]östra-5,16-Dien-3-one 3-cyclo(1,2-ethane-vilareal) (29)

To 1.3 g of chloride methyltriphenylphosphonium in 25 ml THF was added 1.7 ml of 1.5 M solution of BuLi in hexane at -40oC. After 30-minute stirring was added 400 mg of the product 28 in 2 ml of THF. The resulting mixture was heated to room temperature for about half an hour, and then extinguished by pouring 100 ml of water. The product was extracted with dietan/ethyl acetate = 7/3); for the original product Rf=0,23.

(4'S, 11-beta, 16-beta, 17-beta)-4'-ethynyl-4'5', 16,17-tetrahydro-11-methyl-17-hydroxy-3 N-cyclopent[16,17]östra-4,16-Dien-3-one (30)

A solution of 260 mg of the product 29 in a mixture of 3 ml of THF and 3 ml of 4 N. sulfuric acid was stirred for 2 h at 45oC. Then the reaction mixture was neutralized with 5% solution of NaHCO3and the product was extracted with ethyl acetate.

The residue was chromatographically on a short column with silica gel and received 150 mg of compound 3Q; Rf0,25 (heptane/ethyl acetate = 7/3).

Example IV

3-[[1,1-dimethylethyl)dimethylsilane] oxy] östra-1,3,5(10)-triene-17-she dimethylhydrazone (35)

To a solution of 15.5 g of dimethylhydrazone 3-hydroxyestra-1,3,5 (10)-triene-17-she (34) in 200 ml DMF was added 13 g of imidazole, and then was added dropwise 15 g TBDMSC1 in 20 ml of ether. After stirring for a further 16 h, the reaction mixture was poured into 2 l of water and the resulting mixture was stirred for another 10 minutes the Precipitate was filtered and dried in vacuum to obtain 20 g of the product 35, so pl. 100-103oC.

(16-alpha)-3-[[1,1-dimethylethyl)dimethylsilane] oxy] -16-(4-butenyl) östra-1,3,5(10)-triene-17-she dimethylhydrazone (36)

The alkylation reaction of the steroid was performed using anion formed from 4-bromo-1-butyne. Dunn is down BuLi in hexane. After stirring for 1 h at -20oTo the reaction mixture was cooled to -70oC. To this mixture was added dropwise a cold solution of the anion of 4-bromo-1-butyne (obtained by adding 36 ml of BuLi to 7.7 g of 4-bromo-1-butyne in 50 ml of THF at -78oC), and the reaction mixture was heated to room temperature. Then the reaction mixture was stirred for another 1 h and was poured into 300 ml of 10% aqueous solution of NH4Cl. The product was extracted with ethyl acetate. After chromatography was obtained 9.5 g of compound 36 in the form of an oily substance. Rf0,85 (toluene/ethyl acetate = 6/4).

(16-alpha)-3-[[1,1-dimethylethyl)dimethylsilane] oxy]-16-(4-butenyl)östra-1,3,5(10)-triene-17-one (37)

To a solution of 9 g of compound 36 in 100 ml of THF and 70 ml of 1M acetate buffer (pH 4.5) was added 15 g of periodic acid in 40 ml of ethanol. The resulting mixture was stirred 24 h After adding 500 ml of water the product was extracted with ethyl acetate. The crude product was chromatographically and got to 4.2 g of compound 37.

(16-alpha,17-alpha)-3-[[(1,1-dimethylethyl)dimethylsilane]oxy]-16,23-cycle-19,24-Generala-1,3,5(10),20-tetraen-17-ol (38)

The solution naphthalenide lithium obtained from 3.4 g of naphthalene and 150 mg lithium shavings in 30 ml of anhydrous THF. This solution dropwise dpi. After stirring for another 10 min, the reaction mixture

was poured into 30 ml of NH4Cl and the product was extracted with ethyl acetate.

After chromatographic purification was obtained 150 mg of crystalline product 38.

(16-alpha, 17-alpha)-16,23-cyclo-19,24-Generala-1,3,5(10), 20-tetraen-3,17-diol (39)

A solution of 130 mg of product 35 in 5 ml of 5% chlorine-hydrogen acid in methanol was stirred for 2 h at room temperature. Then the reaction mixture was treated with 3 ml of pyridine, concentrated and diluted with 10 ml of water. The product was extracted with ethyl acetate and was purified using chromatography, resulting in a received 65 mg of compound 39, so pl. 203-205oC.

Example V

(7-alpha, 16-alpha)-7-methyl-16-(prop-2-enyl)-variety-5(10)-ene-3,17-dione, 3,3-dimethylacetal (41)

The solution diisopropylamide lithium obtained from 16.6 ml of 1.5 M utility in hexane and 3.85 ml of Diisopropylamine in 35 ml of THF at -20oC. After stirring for 20 min was added a solution of 8.3 g of the steroid 40 in 30 ml of THF, and the resulting mixture was stirred for 20 min at -20oC. After cooling to -40oWith added 2.2 ml of allylbromide, and then the stirring was continued for further 4 hours at -20oWith, after which TLC indicated completion of reaction. The reaction is the result chromatography on silica gel (eluent: hexane/5% ethyl acetate) was obtained 1.2 g of the product 41 as a white solid, so pl. 85-86oC.

(7-alpha, 16-alpha,17-beta)-7-methyl-16,17-bis(prop-2-enyl)-17-hydroxy-variety-5(10)EN-3-one 3,3-dimethylacetal (42)

To a solution of 15 ml of 1 M bromide Allemagne in 30 ml of THF was added at -40oTo a solution of 4.5 g of compound 41 in 30 ml of THF. After stirring for 30 min at this temperature, the mixture was poured into 250 ml of 10% solution of NH4Cl and extracted with ethyl acetate. Thus obtained product was chromatographically and obtained 3.2 g of 16-alpha,17-alpha-dialiawah derivative 42 in the form of a white amorphous substance.

(7-alpha, 16-alpha, 17-alpha)-7-methyl-17-hydroxy-16,24-cyclo-19,21-Generala-5(10),22-Dien-3-one 3,3-dimethylacetal (43)

To a solution of 1.3 g of compound 42 in 30 ml of methylenechloride was added 200 mg dichloride bis(tricyclohexylphosphine)benzyladenine. The mixture was stirred until the reaction is completed. The solvent was partially removed by concentration and the residue product was chromatographically on a column of silica gel, which was obtained 1.1 g of compound 43 as a white amorphous substance Rf0,38 (heptane/ethyl acetate = 7/3, V/V).

(7-alpha, 16-alpha, 17-alpha)-7-methyl-17-hydroxy-16,24-cyclo-19,21-Generala-4, 22-Dien-3-one (44)

A solution of 1 g of the product 43 in 30 ml of acetone obrabecim the and. The mixture was neutralized with 5% solution Panso3was extracted with ethyl acetate and the obtained product was passed through a short column with silica gel. Thus obtained product was treated with diisopropyl ether and was obtained 0.65 g of compound 44, so pl. 130-131oS, Rf0,14 (heptane/ethyl acetate = 7/3).

Example VI

(7-alpha, 16-alpha, 17-alpha)-7-methyl-16-(prop-2-enyl)-17-hydroxy-pregn-5(10),20-Dien-3-one 3,3-dimethylacetal (45)

The solution vinylite was obtained by adding 0.8 ml, 1.6 M solution of utility in hexane to 0,32 ml vinyltrimethylsilane in 3 ml of THF at -50oC. After stirring for 20 min was added dropwise a solution of 300 mg of compound 41 in 2 ml of THF. After another 15-mine mixing, the reaction was suppressed by adding 20 ml of 10% aqueous solution of NH4Cl and the product was extracted with ethyl acetate. After purification by chromatography was received 120 mg of product 45 in the form of an amorphous substance, Rf0,56 (heptane/ethyl acetate = 7/3 V/V).

(Alfa, beta, beta)-16,17-dihydro-17-hydroxy-5 N-cyclopent[16,17] östra 5(10),16-Dien-3-one 3,3-dimethyl-acetal (46)

To a solution of 120 mg of compound 45 in 4 ml of methylenechloride was added 30 mg dichloride bis(tri-cyclohexyloxy)benzyladenine. After paramashiva 80 mg of compound 46, Rf0,40 (heptane/ethyl acetate = 7/3 V/V).

(7-alpha, 16 beta, 17-beta)-7-methyl-16,17-dihydro-17-hydroxy-5 N-cyclopent[16,17]östra-4,16-Dien-3-one (47)

A solution of 80 mg of the product 46 in 2 ml of acetone was treated with 0.2 ml of 2 N. Hcl. After stirring for 2 h at room temperature the reaction mixture was neutralized by adding Panso3and diluted with water. The product was extracted with ethyl acetate, passed through a short column with silica and received 45 mg of compound 47: T. pl. 175-176oC. Rf0,49 (heptane/ethyl acetate = 1/1 V/V).

Example VII

Test to prevent induced by oophorectomy bone loss in rats (test antiosteoporosis activity)

Introduction

Removal of the ovaries (oophorectomy) in rats leads to bone loss (osteoporosis) due to deficiency of estrogen. The introduction of estrogenic compounds can prevent this effect. This test was performed to assess the connection on his antiosteoporosis activity in ovariectomized rats. The effect of this compound on bone mass can be determined by measurement of mineral density of spongy bone substance using peripheral quantitative computed tomogr who's female rats, Wistar, weighing 225-250 g Strain: Hsd/Cpd:Wu, SPF-crossed Harlan, CPB, Zeist, The Netherlands.

Experiment

In day 1 of the experiment, rats were weighed and distributed to the cells in accordance with the weight of their bodies. The rat with the lowest body weight was in the first cage and the rat with the highest body weight was in the last cell. Treatment of rats of each block was performed in an arbitrary order. The unit (group of 3 + n treatments consisted of 1 rats, which were not removed ovaries and which was given a placebo, 1 ovariectomized rats, which was given a placebo; 1 ovariectomized rats, which have introduced the well-known compound; and 1 rats, which were subjected to each of the n treatments.

False operation (i.e. the operation in which not had their ovaries removed) and the operation oophorectomy was performed under anesthesia. After recovery, animals from anesthesia, after 24 h the animals for 4 weeks once or twice a day was administered, respectively, a filler, a known compound or the test compound.

Measurement of bone mineral density using the computerized tomography (pQCT)

Mineral density (mg/cm3) spongy bone substance in the area of the metaphysis of the femur was measured with pomodon after autopsy. Were taken two scans (360oC), which was due to x-ray standard thickness of 1 mm. These scans have permission 0,148 x 0,148 mm One scan was taken at 5.5 mm from the distal end of the femur, which was measured mineral density of spongy bone in the area of the metaphysis. Another scan was taken in the area of the diaphysis at a distance of 13.5 mm from the distal end, which did not contain spongy bone substance. When the last scan was defined mineral density of the cortical layer of the bone and geometrical parameters such as the thickness of the cortical layer, the total surface area of the bone, and internal and external diameter. Internal and external experimental deviations in the measurement of mineral density of spongy bone substance was about 2-3%. XART-A was calibrated using standard hydroxyapatite in the acrylic polymer.

Interpretation of results

Ovariectomy resulted in a statistically significant decrease in mineral density of spongy bone substance (P0,05, two-factor analysis of variance ANOVA). Compound was considered active if the mean values of mineral density of spongy bone washes the La ovariectomized control group.

Active dose (ED50means the dose, which is achieved sredneprodolzhitelny the differences in mineral density of spongy bone substance by 40-60% compared to linearizovannogo and ovariectomized groups.

Bibliography

- T. J. Wronski & Yen, C. F. The ovariectomised rat as an animal model for postmenopausal bone loss. Cell and Materials, Supp., 1 (1991): 69-76.

- I. Yamasaki & Yamaguchi H. Characteristics of ovariectomised osteopenic rat model. J. Bone Min. Res. 4 (1989): 12-22.

Ederveen A. G. H., Spanjers C. P. M., Quaijtaal J. H. M. & Kloosterboer, H. J.: Effect of treatment with tibolone (Org OD 14) or 17-ethinyl estradiol on bone mass, bone turnover and biomechanical quality of cortical and trabecular bone in mature ovariectomised rats Osteoporosis Int. in press, 1998.

Example VIII

Test for binding to the receptor in vitro

The relative affinity of binding of the compounds of the present invention with the progesterone receptor was measured for cytoplasmic progesterone receptor present in the cell tumors of human breast cells MCF-7, incubation time of 16 h, the temperature of the 4oC) and compared with the affinity of (16)-16-ethyl-21-hydroxy-19-norpregna-4-ene-3,20-dione (in accordance with the method described by E. W. Bergink et al. , J. Steroid Biochem., Vol. 19, 1563-1570 (1983)). The relative affinity of the receptor binding of estradiol were measured in the same way, except for Yunosti in vivo

Estrogenic activity in vivo was determined using the well-known test-Allen-Doisy, described in F. Allen, L. A. Doisy, J. Amer. Med. Assoc., 81, 819-821 (1923).

Test progestogenic activity in vivo

Progestogenic activity in vivo was determined using the well-known test McPhail, described in McPhail, M. K.: The assay of progestin. Journal of discrimination, 1934, 83: 145-156.

Several compounds of examples I-VI, as well as other compounds of the present invention synthesized in a similar way, were subjected to the tests described in examples VII and VIII. The results of these tests are presented in the table showing the type a-ring and the substitution of carbon atoms of 7, 11 and 17. In the columns entitled E and P are the relative affinity of binding to estrogen receptors and progesterone; the results obtained for the ED50in tests conducted by the methods of Allen-Doisy and McPhail, indicated in μg/kg In the column entitled "Osteoporosis" includes the value of the ED50obtained in the test for antiosteoporosis activity (dose in mg/kg per day, as described above).

The following compounds were prepared and tested. It was found that they exhibit estrogenic and/or progestogenic properties:

Org 37351:

< / BR>
So pl. 145-146
7363:

< / BR>
Rf: (hept/FL. alcohol 1/1) 0,78

NMR: of 3.80 (m, 1, SNON), to 0.89 (s, 3, ZN3), was 0.77 (d, 3, 7 CH3)

Org 38706:

< / BR>
Rf:(tol./FL.the JV. 7/3) 0,40

NMR: 5,88 (m, 1, H4), 4,90, and is 4.85 (m, N with 2 methylene), to 0.89 (s, 3, CH3)

Org 38707:

< / BR>
So pl. 92-93

Rf: (CH2C12/AC 9/1) 0,49

NMR: 4,20 (m, 1, SNON), is 4.85 (m, N with 2 methylene), of 5.48 (m, 1,4), 0,86 (s, 3, CH3)

Org 38710:

< / BR>
So pl. 145-147

Rf: (hept/FL.the JV. 7/3) 0,33

NMR: 2,78 (CL, 2, N4), of 1.02 (s, 3, CH3)

Org 38738:

< / BR>
So pl. 218-219

Rf: (hept/FL. alcohol 1/1) 0,53

NMR: 2,78 (CL, 2, N4), of 0.90 (t, 3, ethyl), was 1.04 (s, 18-CH3)

Org 38739

< / BR>
Rf: (hept/FL. alcohol 1/1) 0,40

NMR: 0,98 (so 3 ethyl), of 1.03 (s, 3, 18-CH3), 5,86 (m, 1, H4)

Org 38840:

< / BR>
So pl. 130-132

Rf:(hept/FL. alcohol 6/4) 0,44

NMR: 0,98 (3, t, ethyl), 1,0 (s, 3, CH3), 4,17 (m, 1, CHOH), to 5.85 (m, 1, H4)

Org 38842:

< / BR>
So pl. 149-151

Rf: (hept/FL. alcohol 6/4) 0,39

NMR: 0,98 (c, 3, 18 CH3), 4,17 (m, 1, SNON), 5,42 (m, 1, H4)

Org 38843:

< / BR>
Rf: (hept/FL. alcohol 6/4) 0,48

NMR: 2,20 (d, 1, acetylene), of 1.07 (s, 3, 18 CH3), to 5.85 (m, 1, H4)

Org 38962:

< / BR>
(D): -167 (c=1, CNC)

NMR: 5,69 (m, 1, H44), of 1.12 (s, 3, CH3), to 0.89 and 0.94 (2 x t, 6, 2 x2H
R6represents H or -(CH2)mN, where m = 1 or 2;

R7represents H, C1-4-alkyl, C2-4alkenyl or2-4-quinil;

R11represents H, C1-4-alkyl, C2-4alkenyl,2-4-quinil;

E represents, including the carbon atoms 16 and 17 of the D ring, a 4-7-membered hydrocarbon ring, where the specified ring is in the position relative to the D-ring, substituted by a group REand optionally contains one endocyclic double bond;

RErepresents H, C1-5-alkyl, C2-5alkenyl,2-5-quinil,1-5-alkyliden, -(CH2)n-N3or -(CH2)n-SP, where n = 1 or 2, and where the alkyl group may be substituted by-OR, -OOCR where R is alkyl with 1-6 carbon atoms;

R17is-HE-or SIG or R, where R is alkyl with 1-6 carbon atoms, where the aforementioned steroid compound may be, but not necessarily, one double bond, 5(10), 4(5), or the ring may be aromatic.

2. Steroid compound under item 1, characterized in that the E-ring is 6-membered hydrocarbon ring.

3. Steroid what are saturated.

4. Steroid connection on p. 3, wherein R7represents-propyl, E-ring is 6-membered hydrocarbon ring, R3and R17are HE and R6, R11and RErepresent N.

5. Pharmaceutical composition having estrogenic and progestogenic activity containing the steroid compound according to any one of the preceding paragraphs in an effective amount and a pharmaceutically acceptable additive.

6. Steroid compound according to any one of paragraphs. 1-5, designed to produce a medicinal product for preventing or treating disorders associated with peri - and postmenopause.

7. Steroid connection on p. 6, characterized in that said violation is osteoporosis.

8. Steroid compound according to any one of paragraphs. 1-5, designed to produce a medicinal product with contraceptive activity.

9. The method of obtaining 16,17 - annulirovano steroid according to any one of paragraphs. 1-5, characterized in that the 17-ketosteroid having the formula

< / BR>
where the substituting group is defined in the preceding paragraphs, is attached at the carbon atom at position 16, i.e., adjacent to 17-ceocast, substituted or get-italkero group, and this is italkero group is subjected to reaction ring closure by treatment with ORGANOMETALLIC reagent.

10. The method of obtaining 16,17-annulirovano steroid according to any one of paragraphs. 1-5, characterized in that the 17-ketosteroid having the formula

< / BR>
where the substituting group is defined in the preceding paragraphs, attach each of the carbon atoms in position 16 and 17 substituted or unsubstituted alkenylphenol chain, and are shorting ring through olefin exchange reaction using a catalyst based on a transition metal.

 

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SUBSTANCE: invention proposes an agent enhancing the immunogenic properties of tetanus anatoxin (adjuvant). Invention proposes the vegetable triterpenic compound miliacin as an agent enhancing immunogenic properties of tetanus anatoxin. Agent enhances the immune response value in its applying as a vaccine preparation of tetanus anatoxin. The agent miliacin elicits its stimulating effect for both the first and repeated administration of vaccine that allows suggesting its possible applying for prophylactic vaccinations with tetanus anatoxin. Taking into account the high tolerance of miliacin in the broad range of its doses it is suggested its practical applying as an agent promoting to the enhanced formation of vaccinal immunity in prophylactic vaccinations with tetanus anatoxin.

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6 tbl

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