Br15.15-dialkylamide connection, the retrieval method, the compounds and method of production thereof

 

(57) Abstract:

Describes the new br15.15-dialkylamide the compounds of formula I, where R1and R2independently of one another are each hydrogen, R3and R4independently from each other are non-branched alkyl containing 1 to 10 carbon atoms, or a branched alkyl containing 3 to 10 carbon atoms. Compounds have high estrogenic efficacy when administered orally. Describes how they obtain and the initial substances for carrying out this method and the method of their derivation. 4 C. and 4 h.p. f-crystals, 1 Il.

(I)

The present invention relates to new br15.15-dialkylamides derivatives of estradiol General formula I:

< / BR>
in which R1and R2, independently of one another, are each a hydrogen atom, an unbranched alkanoyloxy group containing from 1 to 10 carbon atoms, branched alkanoyloxy group containing from 3 to 10 carbon atoms, alkanoyloxy group of 3 to 10 carbon atoms containing cycloaliphatic structure in the form of a 3-6-membered ring of carbon atoms, or benzoline group, and

R3and R4independently from each other, are each nonbranched is up to 10 carbon atoms.

The radicals R1and R2may be the same or different.

The radicals R1and/or R2preferably denote a hydrogen atom.

As acyl groups, R1and R2suitable radicals of organic carboxylic acids containing from 1 to 10 carbon atoms. Such radicals are derived from aliphatic, cycloaliphatic, alifaticheskii-cycloaliphatic and aromatic monocarboxylic acids. The number of carbon atoms in the cyclic structures may vary from 3 to 6. As R1and R2preferred acyl groups are acetic acid, propionic acid, butyric acid, somaclonal acid, pavlinovoi acid, Caproic acid, heptane acid, Caprylic acid, pelargoniums acid, decanoas acid, 3-cyclopentylpropionic acid and benzoic acid.

As radicals R3and R4preferred groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. However, the highest, homologous unbranched and branched alkyl groups of up to decile radicals are also suitable.

The radicals R3and R4can be ozinkovannyj groups. As particularly preferred compounds according to the invention may be mentioned br15.15-dimethylester-1,3,5(10)-triene 3,17-diol.

Compounds of General formula I according to the invention have a strong affinity to the estrogen receptor and, in particular, have high estrogenic efficacy when administered orally.

As compounds with high estrogenic effectiveness is known, for example, estrogens are naturally occurring estradiol and estriol (E. Schroeder, C. Rufer and R. Schmiechen, Pharmazeutische Chemie [Pharmaceutical Chemistry], 1982, Georg Thime Verlag, Stuttgart - New York, p. 568 ff).

However, they are metabolically unstable and after oral administration catabolized by oxidation of the 17-hydroxyl group to the corresponding, less effective derivative of estrone. Based on this rapid metabolic inactivation, they are unlikely to be suitable for oral administration.

By introducing, for example, etinilnoy group in position 17 (levonorgestrel, Poc. cit., p. 574), oxidation of the 17-hydroxyl group can be prevented, and therefore the related derivatives have high estrogenic efficacy when administered orally.

Only recently it became possible floor is the bottom of the skeleton, and by modification of the steroid skeleton. Thus, the binding of the carbon atoms in positions 14 and 17 atenolil or ethane bridge blocks the oxidation of the 17-hydroxyl group (J. Chem. Commun., 1986, 451 - 453 or International Patent Application PCT/DE 87/00361).

Derivatives of estradiol, which contain 14,15-methylene group, are compounds with high estrogenic efficacy by oral administration (US-A 4 231 946).

When oral administration of estrogenic activity of compounds of General formula I according to the invention is comparable with that of a standard 17-ethinylestradiol. In the compounds according to the invention the attack steroid-17-hydrogenase is blocked by introducing two alkyl groups at the C-15 position and, thus, inhibited the metabolic oxidation of the 17-hydroxyl group despite the presence of a hydrogen atom when the atom C-17.

A brief description of the drawing

To fully appreciate and better understand various other objectives, features and attendant advantages of the present invention can be viewed together with the accompanying drawing, which shows a graph demonstrating the stability of estradiol and br15.15-dimethylester-1,3,5(10)-triene-3,17-diol relative to 17 - hydroxysteroid-hydro is unity according to the invention, i.e. br15.15-dimethylester-1,3,5(10)-triene-3,17-diol (B) to 17 - hydroxysteroid-hydrogenase from human placenta, the subjects matter stood with placental microsomes in the presence of NADP (nicotinamide-adenylylsulfate; 0.5 mmol).

Steroids (source substrate and product) were extracted and separated using HPLC (liquid chromatography high resolution). For evaluation were obtained by electronic integration of the peak areas of the corresponding reaction product (namely, the alleged 17-catasetinae) and the initial substance and built a graph of the dependence on the exposure time (see drawing). While estradiol (A) under the influence of 17-hydroxysteroiddehydrogenase largely converted into estrone, the connection according to the invention br15.15-dimethylester-1,3,5(10)-triene-3,17-diol (B) is a substrate for 17-hydroxysteroid-hydrogenase only in a moderate way.

This may explain the effectiveness of the oral introduction of the newly described substances.

Estrogenic activity of compounds according to the invention can be demonstrated by the test results on the binding of the estrogen receptor. In this test, conducted in vitro, prepare the drug of the invention br15.15-dimethylester-1,3,5(10)-triene-3,17-diol, respectively, has a coefficient of competition, equal to 1.5.

The invention also relates to the use of compounds of General formula I to obtain pharmaceutical agents.

Compounds according to the invention may be introduced into the compositions and used in the same way as with levonorgestrel, which is the most widely used estrogen. They are processed in the usual form of the pharmaceutical agent with additives, carriers and/or flavoring substances, which are usually used in galenical pharmacy, in accordance with known industry methods. For oral administration are particularly suitable are tablets, coated tablets, capsules, granules, suspensions or solutions. For parenteral administration are especially suitable oil solutions, such as, for example, solutions in sesame (sesame) oil or castor oil, which may not necessarily contain optionally a diluent, such as, for example, benzyl benzoate or benzyl alcohol.

The concentration of active ingredient in the pharmaceutical composition depends on the method of introduction and applications. So, for example, capsules or tablets for the treatment of symptoms of estrogen deficiency may contain about 0.001 to 0.05 mg of the active ingredient, makanannya ointments can contain about 0.1 - 10 mg per 100 ml of ointment. For the female contraceptive estrogens according to the invention can be used in combination with gestagens, commonly used in hormonal contraceptives or proposed for use in such preparations, for example, such as progesterone, medroxyprogesterone acetate, gestonorone caproate, chlormadinone acetate, lynestrenol, hydroxyprogesterone caproate, norethindrone and its esters (for example, acetate, norgestrel, levonorgestrel, ciproteron acetate, desogestrel, norgestimate, dihydropyrazine and gestodene. Tablets or coated tablets for daily administration preferably contain about 0.003 to 0.05 mg of estrogen in accordance with the invention, and preferably about 0.05 - 0.5 mg progestogen.

Compounds according to the invention can be used in case of symptoms of estrogen deficiency in women, such as, for example, amenorea, dysmenorrhea, infertility, endometritis, obesity and menopausal symptoms (hormone replacement therapy) and prevention of osteoporosis. Further, these compounds can be used as estrogenic components of hormonal contraceptives (single-phase and multi-phase and multi-stage drugs). Moreover, they are the face-to-face pessaries, media implantable active ingredients, as well as in systems intended for transdermal administration. Possible fields of application of the compounds of General formula I according to the invention in such transdermal systems are a means of birth control for women and hormone replacement therapy (HRT).

Increased solubility in fat, in comparison with estradiol and 17 - ethinylestradiol, due to the lipophilic alkyl groups at position 15, make connections according to the invention particularly suitable for use in such securities.

The new compounds of General formula I:

< / BR>
in which R1and R2, independently of one another, are each a hydrogen atom, an unbranched alkanoyloxy group containing from 1 to 10 carbon atoms, branched alkanoyloxy group containing from 3 to 10 carbon atoms, alkanoyloxy group of 3 to 10 carbon atoms containing cycloaliphatic structure in the form of a 3-6-membered ring of carbon atoms, or benzoline group, and

R3and R4, independently of one another, are each an unbranched alkyl group containing from 1 to 10 carbon atoms, or Razvitie the Oia General formula II:

< / BR>
in which R1'is an unbranched alkyl group containing from 1 to 10 carbon atoms or a branched alkyl group containing from 3 to 10 carbon atoms, and

R3and R4have the meanings indicated in formula I, split in accordance with standard methods 3-hydroxy-group, optional etherification, and then, subsequently, optional atrificial 17-hydroxy-group. Alternatively, the 3 - and 17-hydroxyl group is optional aeriferous at the same time, and received 3,17-dellaccademia selectively omelet to 3-hydroxy-17-allacciamento.

The alkyl groups of R1'with the number of carbon atoms up to 10 represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, or other higher homologues of the above groups. Preferred is a methyl group.

The splitting of the 3-Olkiluoto ether conduct standard ways of splitting of steroid esters. So, splitting 3-alilovic esters can be carried out by heating to boiling, for example, a Lewis acid in an inert solvent. As Lewis acids are used, for example, apirat of boron TRIFLUORIDE or a hydride diisobutylaluminum the following optional esterification of phenol and tertiary hydroxyl groups can be used known methods, used for the esterification in the chemistry of steroids.

The etherification is carried out, for example, via interaction with galogenangidridy (chloride or bromide) of the corresponding carboxylic acid or anhydride of carboxylic acid (number of carbon atoms depending on the desired R1and/or R2in the final product) in the presence of a base, such as, for example, 4-dimethylaminopyridine at a temperature of preferably about 20 to 80oC. If tertiary amines are used simultaneously pyridine and 4-dimethylaminopyridine, etherification can be carried out by radicals of the lower carboxylic acid, preferably at room temperature, and higher carboxylic acids, preferably at about 40 to 80oC. as example can be mentioned the reaction with acetic acid or acetic anhydride in the presence of strong acids, such as, for example, triperoxonane acid, Perlina acid or p-toluensulfonate acid, at room or slightly elevated temperature.

The syntheses of the two possible profirov occur by partial esterification or partial saponification:

a) on the Basis of 3,17-dihydroxytoluene, 3 acyloxy 17 guide is by interacting with the appropriate acid anhydride in the presence of a nitrogen-containing heterocyclic aromatic compounds, preferably pyridine. Suitable reaction temperatures are, for example, temperatures from room temperature up to the boiling temperature of the reaction mixture. Selective esterification of the 3-hydroxyl group may also be regulated by the amount entered tarifitsiruemih reagent.

b) on the Basis of 3,17-decyloxybenzoic, 3-hydroxy 17 - allacciamento can be obtained by the selective saponification phenolic alloctype. The synthesis is carried out by reacting with a carbonate of an alkali metal or alkaline earth metal, preferably potassium carbonate or calcium carbonate, in aqueous-methanolic solution. The reaction temperature may, for example, have values from room temperature to the boiling temperature of the reaction mixture.

Obtaining the compounds according to the invention is represented in the following diagram, from which you can also see the change in the stereochemistry of the carbon atom in position 15.

With this purpose, the described method for the preparation of 3-methoxy-15-methyl-östra-1,3,5(10)-triene-17-it (R. V. Cumbs, U. S. Patent 3 766 224; Chem. Abstr. 1974, 80, C) was modified. Cm. the following reaction scheme.

The enolate obtained by adding dialkylamino lithium LiCuR23or with the lyst (for example, CuI, CuCN) to 3-methoxy-östra-1,3,5(10),15-tetraen-17-ONU (compound I), is converted in situ by adding trimethylchlorosilane in the appropriate selenology ether, which interacts optional, without further purification with palladium acetate in the process of dehydrogenation by EAC (J. Tsuji et al., Chem. Letters 1133, 1984) with the formation of 3-methoxy-15-alkylester-1,3,5(10),15-tetraene (see compound 3, 7, or 10). By re-adding dialkylamino lithium LiCuR23or appropriate alkylpolyglucoside (alkyl = R4the halide = Br, I) in the presence containing copper (I) catalyst (e.g., CuI, CuCN) to the unsaturated ketone (see compound 3, 7, or 10), get br15.15-dialkylamino connection that turn by restoring the C-17-carbonyl group in accordance with standard methods, 17-gidroksosoedinenii (see compounds 12, 13, 14, or 15), which is the starting compound of General formula II.

The radicals R3and R4can be varied in the desired manner within the framework of the General formula I with the appropriate dialkylamino lithium to obtain by similar compounds 12, 13, 14 or 15. The source compounds of General formula II required for the synthesis of all compounds of General form is giving 3-methoxycoumarin formula II, when using the appropriate higher 3-alkoxyamino of compound I as starting material can be obtained from other 3-alkoxysilane formula II. Cm. US 3766224.

If R3and R4should vary, the stereochemistry at the carbon atom 15 can be set through a sequence of stages alkylation. The group R3the first two groups, introduced in position C-15, is located in the final product in position.

< / BR>
< / BR>
4 R3, R4Me 12 16

5 R3Me, R4Et 13 17

8 R3Et, R4Me 14 18

11 R3Pr, R4Me 15 19

17-Hydroxycodone General formula II and 17-catasetinae, through which their synthesis, are new and, taken together as the original substances of General formula IIa, also belong to the scope of this invention.

< / BR>
where

R1'is the alkyl group is unbranched, having from 1-10 carbon atoms, or branched, having 3-10 carbon atoms;

R3and R4independently from each other represents each unbranched alkyl having 1-10 carbon atoms, or a branched alkyl having 3 to 10 carbon atoms; and

Z represents a hydrogen atom and - gidroksilnuyu, using the preceding description, will be able to apply the present invention to the fullest extent. Therefore, the following specific preferred embodiments of should be considered only as illustrative, and not limiting in any way the content of this discovery or invention in the rest part of it.

In the preceding and following examples, all temperatures are invariably indicated in degrees Celsius and unless otherwise indicated, all proportions and percentages are by weight.

The full content of all applications, patents and publications, cited above, and of corresponding application German P 4326240.6, registered on August 2, 1993, incorporated herein by reference.

Examples

The following examples are used for a more detailed explanation of the invention.

Example 1

3-Methoxy-15-methylestra-1,3,5(10)-triene-17-one (2)

Dimethylbutyl lithium (0,63 mmol) in anhydrous diethyl ether (1 ml) [obtained from copper iodide (I) (120 mg; 0,63 mmol) and metallyte (0.75 ml; 1.6 M; 1.20 mmol)] cooled to -78oC. Add triethylamine (0.1 ml; 0.8 mmol) and chlorotrimethylsilane (0.1 ml; 0.78 mmol), and then add15-17-ketone (1) (84 mg; 0.30 mmol) in anhydrous tetrahedronal the mixture is stirred at 20oC for 15 minutes. The residue after processing (ethyl acetate) (72 mg) chromatographic on silica gel (6 g), and elution with a mixture of ethyl acetate-toluene (1:4) gives 3-methoxy-15 - methylestra-1,3,5(10)-triene-17-one (2) (65 mg; 92%), so pl. 127 - 129oC (from a mixture of acetone-methanol) (lit. so pl. 122-124oC); []D+74oC (s, 1,0);max1725 cm-1(CO)Hof 1.07 (3H, c, 13-Me ); of 1.16 (3H, d, J 7.4 Hz, 15-Me ), only 2.91 (2H, m, 6-H2), with 3.79 (3H, s, 3-OMe), 6,69 (1H, d, J 2.7 Hz, 4-H), was 6.73 (1H, DD, J 8.6 and 2.7 Hz, 2-H), 7,21 (1H, d, J 8.6 Hz, 1-H);C17,0 (15-Me), And 17.9 (C-18), A 25.6 (C-15), And 26.8 (C-11), With 27.7 (C-7) And 29.5 (C-8), 34,1 (C-16), Or 35.9 (C-12), 44.5cm (C-6), With 44.8 (C-9), And 47.5 (C-13), Only 55.2 (3-OMe), Byr111.4 (C-2), To 113.9 (C-4), 126,0 (C-1), 132,5 (C-10), 137,8 (C-5), 157,7 (C-3), and 221,3 (C-17).

(Found: C, 80,7; H, 8.6 per cent; M+, 298. Calculated values for C20H26O2: C, 80,5; H, 8.8 PERCENT; M, 298).

3-Methoxy-15-methylestra-1,3,5(10)-tetraen-17-one (3)

(a) a Solution of diisopropylamide lithium (5,28 mmol) in anhydrous tetrahydrofuran (4 ml) [obtained at 0oC from Diisopropylamine (1.5 ml; of 10.58 mmol) in anhydrous tetrahydrofuran (4 ml) and utility (3,3 ml; 1.6 M; 5,28 mmol)] cooled to -78oC and slowly add 15 - methyl-17-ketone (2) (315 mg; 1.05 mmol) in anhydrous tetrahydrofuran (5 ml). The mixture was stirred at -78oC for 30 minutes. Add chlorotrimethylsilane (1,4 ml; 11.0 mmol) and allow the mixture to heat up mania. The residue after processing (ethyl acetate) (385 mg) was dissolved in acetonitrile (10 ml). Add palladium acetate (11) (233 mg; 1.04 mmol) and the mixture is stirred at boiling point for 15 minutes. The reaction mixture is cooled to 20oC, filtered and evaporated to obtain a dark crystalline product (484 mg). The chromatography was carried out on silica gel (24 g) with a mixture of ethyl acetate-toluene (1:19) as eluent gives 3-methoxy-15-methylestra-1,3,5(10)-tetraen-17-one (3) (267 mg; 86% from 2), so pl. 156-158oC (from a mixture of ethyl acetate: methanol);

[]D-17(1,0);max1688 cm-1(CO)Ha 1.11 (3H, c, 13-Me ); of 2.25 (3H, s, 15-Me), to 2.94 (2H, m, 6-H2), with 3.79 (3H, s, 3-OMe), 5,77 wide (1H, c, 16-H), 6,69 (1H, d, J 2.5 Hz, 4-H), to 6.75 (1H, DD, J 8.6 and 2.5 Hz, 2-H), and of 7.23 (1H, d, J 8.6 Hz, 1-H);CTo 20.9 (C-18), 21,5 (15-Me), A 25.6 (C-11), With 27.7 (C-7), 29,2 (C-9), Of 29.3 (C-8), To 36.8 (C-12), 45,2 (C-6), Was 52.6 (C-13), Only 55.2 (3-OMe), 57,3 (C-14), 111,5 (C-2), 113,6 (C-4), 126,1 (C-1), 128,7 (C-16), 132,0 (C-10), 137,3 (C-5), 157,7 (C-3), 175,2 (C-15), and 212,1 (C-17). (Found: C, a 81.3; H, 8,15%; M+, 296. Calculated values for C20H24O2; C AND 81.0; H, 8.2 PERCENT; M, 296).

(b) Dimethylbutyl lithium (0,79 mmol) in anhydrous diethyl ether (1 ml) are obtained as described previously. The reagent is cooled to -78oC, add triethylamine (0.1 ml; 0.8 mmol) and chlorotrimethylsilane (0.1 ml; 0.78 mmol), and then add15-17-ketone (1) (ia. The residue after processing (ethyl acetate) is a colourless oil (109 mg).

Specified product would be processed in terms of dehydrosilybin, similar to those described above [66 mg of palladium (II) acetate in 5 ml of acetonitrile], obtaining 15-methyl15-17-ketone (3) (93 mg; 85% 1).

3-Methoxy-br15.15-dimethylester-1,3,5(10)-triene-17-one (4)

To a solution of dimethylsulfate lithium (0,79 mmol) in anhydrous diethyl ether (2 ml) [obtained in the standard manner at 0oC of copper iodide (I) (150 mg; 0,79 mmol) and metallyte (1.3 ml; 1.6 M; of 2.08 mmol)] at -78oC add complex of boron TRIFLUORIDE in diethyl ether (0.1 ml; 0.80 mmol), and then add 15-methyl -15-17-ketone (3) (163 mg; 0.55 mmol) in anhydrous tetrahydrofuran (2 ml). After 30 minutes, add saturated aqueous solution of ammonium chloride. Standard processing (ethyl acetate) gives a crystalline residue, the chromatography was carried out which on silica gel (5 g) with elution by the mixture of utilizatorul (1:19) gives br15.15-dimethylketone (4) (146 mg, 70%), so pl. 145-148oC (from a mixture of ethyl acetate-methanol); []D+75(1,0);max1727 cm-1(CO)Hof 1.10 (3H, c, 13-Me ); of 1.28 and 1.29 (each 3H, c, 15 - a and 15-Me ), of 1.84 (1H, d, J 10,9 Hz, 14-H ), 2,09, and 2,61 (each 1H, d, J, and 19.4 Hz, 16 -, and 16-H ), with 2.93 (2H, m, 6-H2), of 3.78 (3H, s (C-12), 34,6 (15-Me), 35,5 (C-15), A 37.5 (C-8), With 44.9 (C-9), 50,2 (C-13), 53,6 (C-16), Only 55.2 (3-OMe), 58,4 (C-14), 111,6 (C-2), 113,6 (C-4), 126,4 (C-1), 132,2 (C-10), 137,4 (C-5), 157,6 (C-3) and 221,4 (C-17) (Found: C, 80,5; H, 8.8 percent; M+, 312. Calculated values for C21H28O2: C 80,7; H, 9,0%; M, 312).

15 - Ethyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-one (5)

The solution acylanilides (2.5 mmol) in anhydrous diethyl ether (2 ml) [obtained at 20oC magnesium (60 mg; 2.5 mmol) and ethyliodide (iodine ethyl) (0.2 ml; 2.5 mmol)] cooled to 0oC add iodide copper (I) - (47 mg, 0.25 mmol) and the mixture stirred for 5 minutes. Add 15-methyl15-17-ketone (3) (148 mg; 0.5 mmol) in anhydrous tetrahydrofuran (2 ml). The reaction mixture is stirred at 20oC for 15 minutes. Add saturated aqueous solution of ammonium chloride and ammonia, and the residue after processing (ethyl acetate) (150 mg; 92%) crystallized from diisopropyl ether to obtain 15 - ethyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-she (5) (135 mg), so pl. 104-107oC (from a mixture of diisopropyl ether-methanol); []D+90(1,0);max1724 cm-1(CO)Hof 0.94 (3H, t, J 7,6 Hz, 15-CH2CH3), of 1.09 (3H, s, 13-Me ); 1,22 (3H, s, 15-Me ); and 1.63 and 1.76 (each 1H, degenerate DQC, J 15,2 and 3 x 7,6 Hz, 15-CH2CH3), 1,87 and 2,80 (each 1H, d, J 19,3 Hz, 16 - and 16.3 (C-18), 25,9 (C-151), A 27.4 (C-11) And 28.6 (C-7), To 29.8 (C-6), 30,3 (C-12), 34,4 ( 15-Me ), 37,3 (C-8), To 39.4 (C-15), 45,1 (C-9), For 48.9 (C-16), For 49.8 (C-13), Only 55.2 (3-OMe), To 59.8 (C-14), 111,6 (C-2), 113,6 (C-4), 126,4 (C-1), 132,3 (C-10), 137,4 (C-5), 157,6 (C-3), and to 220.3 (C-17) (Found: C of 80.9; H, 9.6 per cent; M+, 326. Calculated values for C22H30O2: C OF 80.9; H, 9,3; M 326).

15 - Ethyl-3-methoxyacetone-1,3,5(10)-triene-17-one (6)

The solution acylanilides (3.8 mmol) in anhydrous diethyl ether (1 ml) [obtained from magnesium (91 mg, 3.8 mmol) and ethyliodide (0.3 ml; 3.8 mmol)] cooled to 0oC. Add iodide copper (I) - (71 mg, and 0.37 mmol). Slowly add a solution of Aenon (1) (200 mg; of 0.68 mmol) in anhydrous tetrahydrofuran (5 ml) and conduct stirring at 20oC for 10 minutes. The mixture is cooled to 0oC and add saturated aqueous solution of ammonium chloride. The residue after processing (ethyl acetate) (207 mg; 93%) not recrystallizing with getting 15 - ethyl-3-petoksista-1,3,5(10)-Trient-17-she (6) (198 mg), so pl. 125-129oC (from a mixture of chloroform-methanol); []D+85(C 0,95);max1727 cm-1(CO)Hof 0.95 (3H, t, J 7.5 Hz, 15 - CH2CH3), of 1.02 (3H, s, 13-Me ); 1,34 and of 1.65 (each 2H, m, 15-CH2CH3), 1,90 (1H, DD, J 9.3 and 2.7 Hz, 14-H , 2,39 (2H, m, 16 -, and 16-H ), of 2.92 (2H, m, 6-H2), with 3.79 (3H, 3-OMe), of 6.66 (1H, d, J 2.9 Hz, 4-H), 6,72 (1H, DD, J 8.4 and 2.9 Hz, 2-H), t 7,20 (1H, d, J 8,4 Hz, 1-H);CA 13.9 (C-152+, 312. Calculated values for C21H28O2; C 80,7; H, 9,0%; M, 312).

15-Ethyl-3-petoksista-1,3,5(10)-tetraen-17-one (7)

The solution diisopropylamide lithium (7.8 mmol) in anhydrous tetrahydrofuran (3 ml) [obtained at 0oC from Diisopropylamine (2.2 ml; 15.8 mmol) in tetrahydrofuran (3 ml) and utility (4,9 ml; 1.6 M; 7.8 mmol)] cooled to - 78oC. Slowly add a solution of 15 - ethylketone (6) (495 mg; 1,58 mmol) in anhydrous tetrahydrofuran (12 ml). After 30 minutes exposure at - 78oC add chlorotrimethylsilane (2.5 ml; of 19.7 mmol) and stirred at 0oC for 15 minutes. Add saturated aqueous solution of ammonium chloride. The residue after processing (ethyl acetate) (577 mg) was dissolved in acetonitrile (20 ml). Add palladium (II) acetate (340 mg; is 1.51 mmol) and the mixture is heated to boiling point for 20 minutes. The solution is cooled to 20oC, filtered and evaporated. The chromatography was carried out residue (470 mg) on silica gel (25 g) and elution with ethyl acetate (1: 19) gives 3-methoxy-15-methylestra-1,3,5(10)- tetraen-17-one (7) (419 mg; 85% from 6), so pl. 103-106oC (from a mixture of chloroform-methanol); []D-14(from 0.9);max1689 cm-1(CO)Ha 1.11 (3H, s, 13-Me ); 1,24-H), of 6.73 (1H, DD, J of 8.3 and 2.8 Hz, 2-H), 7,22 (1H, d, J 8,3 Hz, 1-H);CTHE 11.6 (C-152), A 21.5 (C-18), A 25.6 (C-11) AND 27.3 (C-7), 28,0 (C-12), 29,2 (C-151), 29,4 (C-6), 37,0 (C-8), 45,3 (C-9) Was 52.6 (C-13), Only 55.2 (3-OMe), 57,2 (C-12), 111,6 (C-2), 113,6 (C-4), 125,7 (C-16), 126,2 (C-1), 132,1 (C-10), 137,3 (C-5), 157,5 (C-3), 181,1 (C-15), and 212,2 (C-17). (Found: C, 81,1; H, 8.5 per cent; M+, 310. Calculated values for C21H26O2:C, AN 81.25; H, 8.4 PER CENT; M, 310).

15-(Tyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-one (8)

The solution metalmilitia (2.5 mmol) in anhydrous diethyl ether (2.5 ml) [obtained at 20oC magnesium (60 mg; 2.5 mmol) and under the conditions (0.16 ml; 2.5 mmol)] cooled to 0oC. Add iodide copper (I) - (46 mg, 0.24 mmol). After 5 minutes at 0oC add a solution of 15-ethyl -15- 17-ketone (7) (150 mg, 0.48 mmol) in anhydrous tetrahydrofuran (3 ml). The mixture is stirred at 20oC for 15 minutes. Add saturated aqueous solution of ammonium chloride and ammonia, and the residue after processing (ethyl acetate) (150 mg; 96%) crystallized from chloroform to obtain 15 - ethyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-she (8) (127 mg; 81%), so pl. 110-113oC (from a mixture of chloroform-methanol); []D+90(1,0);max1724 cm-1(CO)Hto 0.89 (3H, t, J 7.4 Hz, 15-CH2CH3), of 1.12 (3H, s, 13-Me ); 1,25 (3H, s, 15-Me ); 1,36 and 1.76 (each 2H, degenerate DQC, J 14,8 and 3 is DD, J of 8.6 and 2.9 Hz, 2-H), and then 7.20 (1H, d, J 8.6 Hz, 1-H) C9,4 (C-152), AND 18.2 (C-18), AND 21.8 (C-151), And 26.1 (C-11), And 28.3 (C-7), And 29.9 (C-6), 34,2 (C-12), A 37.5 (C-8), 38,1 (15-Me) , For 38.9 (C-15), With 44.9 (C-9), Of 49.8 (C-16), 50,0 (C-13), Only 55.2 (3-OMe), At 56.6 (C-14), 111,6 (C-2), 113,6 (C-4), 126,5 (C-1), 132,2 (C-10), 137,4 (C-5), 157,6 (C-3), and 220,4 (C-17) (Found: C, 81,2; H, 9.5 percent; M+, 326. Calculated values for C22H30O2: C OF 80.9; H, 9.3 PER CENT; M, 326).

15 - Isopropyl-3-petoksista-1,3,5(10)-triene-17-one (9)

The complex of copper iodide (I) with dimethyl sulfide (107 mg; 0.42 mmol) and hexamethylphosphoramide (1.1 ml; 3.6 mmol) are added to a solution of isopropylacrylamide (4,25 mmol) [obtained at 0oC magnesium (102 mg; of 4.25 mmol) and Isopropylamine (0.4 ml; 4.26 deaths mmol)] in anhydrous diethyl ether (5 ml) at 0oC. After 5 minutes of incubation at this temperature, slowly add a solution of Aenon (1) (200 mg, 0.71 mmol) and chlorotrimethylsilane (0.8 ml; 6,30 mmol) in anhydrous tetrahydrofuran. The mixture was stirred at 0oC for 20 minutes. Add saturated aqueous solution of ammonium chloride and ammonia. The residue after processing (ethyl acetate) (205 mg) chromatographic on silica gel (20 g), and elution with a mixture of ethyl acetate-toluene (1:49) gives a 15 - isopropyl-3-petoksista-1,3,5(10)-triene-17-one (9) (201 mg; 87%), so pl. 104-108oC (from diisopropyl ether); []D+ 106oC17,4 (C-18), and 21,8 24,3 ( 15 - CHMe2), and 25.4 (C-11), 28,2 (C-7); to 29.5 (C-6), and 32.3 (C-8), to 34.8 (C-12), 38,0 (C-15), 42,4 (C-9), 45,0 (C-16), and 45.5 (C-14), which is 46.5 (C-13), only 55.2 (3-OMe), 55,4 ( 15 - CHMe2), byr111.4 (C-2), to 113.9 (C-4), 126,6 (C-1), 132,4 (C-10), 137,9 (C-5), 157,7 (C-3), and 222,8 (C-17) (Found: C, 80,5; H, 9.3 per cent; M+, 326. Calculated values for C22H30O2: C OF 80.9; H, 9.3 PER CENT; M, 326.

15-Isopropyl-3-petoksista-1,3,5(10), 15-tetraen-17-one (10)

A solution of 15 - isopropylene (9) (210 mg; 0.64 mmol) in anhydrous tetrahydrofuran (10 ml) are added to a solution of Diisopropylamine lithium (3.2 mmol) [obtained at 0oC from Diisopropylamine (0.9 ml; 6,35 mmol) in tetrahydrofuran (2 ml) and utility (1.9 ml; totaling 3.04 mmol)] at - 78oC. After 30 minutes of incubation at this temperature, add chlorotrimethylsilane (1 ml; 7,88 mmol). Mixture is allowed to warm to 0oC for 20 minutes. Add saturated aqueous solution of ammonium chloride and the residue after processing (ethyl acetate) (242 mg) was dissolved in anhydrous acetonitrile (20 ml). Add palladium (II) acetate (140 mg; of 0.62 mmol) and the mixture is heated to boiling point for 20 minutes. The solution is cooled to 20oC, filtered and evaporated. The remainder chromatographic on silica gel (23 g), and e.sq. 113 - 116oC (from a mixture of chloroform-methanol); []D-18(C, 1,0);max1690 cm-1(CO) Hof 1.10 (3H, s, 13-Me ); of 1.16 and 1.22 (each 3H, J 6.6 Hz, 15 - CHMe2), to 2.57 (1H, DD, J 11.2 and 2.7 GHz, 14-H), of 2.92 (2H, m, 6-H2), with 3.79 (3H, s, 3-OMe), 5,80 (1H, DD, J 2.7 and 1.2 Hz, 16-H), of 6.65 (1H, d, J 2.7 Hz, 4-H), 6,74 (1H, DD, J 8.6 and 2.7 Hz, 2-H), and from 7.24 (1H, J 8.6 Hz, 1-H);C21,1 (C-18), to 21.6 and 21.7 (15-CHMe2), a 25.6 (C-11), 28,1 (C-7), of 29.1 (C-6), and 29.7 (C-8), 30,8 (15-CHMe2), or 37.4 (C-12), to 45.4 (C-9), for 52.6 (C-13), only 55.2 (3-OMe), 56,3 (C-14), 111,6 (C-2), 113,6 (C-3) 123,9 (C-16) 126,3 (C-1), 132,2 (C-10), 137,2 (C-5), 157,7 (C-3), 185,7 (C-15), and 212,4 (C-17) (Found: C, to 81.6; H, 8.9 per cent; M+, 324. Calculated values for C22H28O2: C, 81,4; H 8,7%; M, 324).

15-Isopropyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-one (11)

The solution dimethylcarbamate lithium (0.61 mmol) in anhydrous diethyl ether (1.5 ml) [obtained at 0oC of copper iodide (I) (118 mg; 0.61 mmol) and metallyte (0.8 ml; 1.6 M; 1.28 mmol)] cooled to -78oC. Sequentially added triethylamine (0.1 ml; to 0.72 mmol) and chlorotrimethylsilane (0.1 ml; 0,79 mmol). Within 5 minutes hold stirring at -78oC, and then added dropwise a solution of Isopropylamine of Aenon (10) (100 mg; 0.31 mmol) in anhydrous tetrahydrofuran (3 ml). The reaction mixture is stirred for further 30 minutes at 0oC. Add a saturated aqueous solution x is mesh stirred at 20oC for 15 minutes. The residue after processing (ethyl acetate) (97 mg) chromatographic on silica gel (10 g), and elution with a mixture of utilizatorul (1:49) gives a 15-isopropyl-3-methoxy-15 - methylestra-1,3,5(10)-triene-17-one (11) (92 mg; 86%), so pl. 113-115oC (from diisopropyl ether); []D+87oC (0,9);max1724 cm-1(CO)H(C6D6), was 0.68 (6H, d, J 6.0 Hz), 15 - CHMe2), of 0.87 (3H, s, 15-Me ), and 0.98 (3H, s, 13-Me ), 1,62 fuzzy (1H, q, J 6.0 Hz, 15 - CHMe2), are 1.95 and 2.15 (each 1H, d, J 19.1 Hz, 16 -, and 16-H ), 2,68 (2H, m, 6-H2), 3,44 (3H, s, 3-OMe), 6,70 (1H, d, J 2.6 Hz, 4-H), 6,79 (1H, DD, J 8.8 and 2.6 Hz, 2-H), and to 7.09 (1H, d, J 8,8 Hz, 1-H);H(CDCl3), 0,89 0,87 and (each 3H, d, J 6,7 Hz, 15-CHMe2), of 1.13 (3H, s, 13-Me), 1,32 (3H, s, 15-Me ), 2,23 fuzzy (2H, d, J 18.7 Hz, 16 and 16-H ), 2,87 (2H, m, 6-H2), of 3.77 (3H, s, 3-OMe), of 6.68 (1H, d, J 2.8 Hz, 4-H), to 6.75 (1H, DD, J 8.8 and 2.8 Hz, 2-H), and then 7.20 (1H, d, J 8,8 Hz, 1-H);Cof 17.8 (C-18), an 18.4 and 18.8 (15-CHMe2), 23,0 (C-11), and 26.1 (C-7), while 27.8 ( 15-Me ), 30,0 (C-8), 34,5 (C-12), 36,9 ( 15 - CHMe2), 37,7 (C-6), of 41.5 (C-15) and 44.6 (C-9), 45,0 (C-16), a 49.9 (c-13), only 55.2 (3-OMe), 111,6 (C-2), 113,6 (C-4), 126,5 (C-1), 132,2 (C-10), 137,4 (C-5), 157,6 (C-3), and to 220.3 (C-17) (Found: C, 81,2; H, 9.6 PER CENT; M+, 340. Calculated values for C23H32O2. (C, 81,1; H, 9.5 PERCENT; M, 340).

3-Methoxy-br15.15-dimethylester-1,3,5(10)-trien-17-ol (12)

Alumoweld lithium (30 ml; 0,79 mmol) are added to a solution dimethylselenide ketone (4) (50 mg, 0.16 mmol) in anhydrous Ter the th solution of sodium bicarbonate and filtered mixture. Treatment of the filtrate (ethyl acetate) to give 3-methoxy-br15.15-dimethylester-1,3,5-(10)-trien-17-ol (12), (43 mg; 85%), so pl. 87 - 91oC (from a mixture of chloroform-hexane); []D+75(1,1);max3606 cm-1(OH);Hto 0.92 (3H, s, 13-Me); of 1.06 (1H, d, J 11.2 Hz, 14-H), 1.11 and 1.14 in (each 3H, s, 15 -, and 15-Me), 1,61, and 1,90 (each 1H, DD, J and 13,0 10,2, and 13.0 and 7.9 Hz, 16 -, and 16-H), of 2.86 (2H, m, 6-H2), 3,71 (1H, DD, J 10.2 and 7.9 Hz, 17-H), of 3.77 (3H, s, 3-OMe), 6,62 (1H, d, J 2.7 Hz, 4-H), of 6.71 (1H, DD, J 8.6 and 2.7 Hz, 2-H), 7,21 (1H, d, J 8.6 Hz, 1-H)C13,5 (C-18), 25,6 (15-Me), And 26.1 (C-11), 28,5 (C-7), And 29.9 (C-6), 35,0 (C-12), And 36.2 (C-15), 37,1 (C-8), 38,8 (15-Me), With 44.9 (C-9), Of 45.6 (C-13), 50,1 (C-16), Only 55.2 (3-OMe), To 58.1 (C-14), to 79.8 (C-17), byr111.4 (C-2), 113,6 (C-4), 126,3 (C-1), 132,9 (C-10), 137,7 (C-5), and 157,5 (C-3) (Found: C, 80,0; H, 9.5 percent; M+, 314. Calculated values for C21H30O2: C, AN 80.2; H 9,6%; M, 314).

15 - Ethyl-3-methoxy-15 - methylestra-1,3,5(10)-trien-17-ol (13)

Almoguera lithium (58 mg; 0.31 mmol) are added to a solution of 15-ethyl-15 - methylsiloxane ketone (5) (100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (2 ml) at 0oC. the Mixture was stirred at 0oC for 5 minutes. Add saturated aqueous solution of ammonium chloride and filtered mixture. Standard processing of the filtrate (ethyl acetate) gives a 15 - ethyl-3-methoxy-15 - methylestra-1,3,5(10)-trien-17-ol (13) (92 mg; 90%), in the form of oil, []D+70(s, 1,1);max3604 cm-1(OH); Hthe th (2H, m, 16 -, and 16-H), 2,84 (2H, m, 6-H2), 3,74 (1H, DD, J 9.9 and 8.2 Hz, 17-H ), of 3.78 (3H, s, 3-OMe), 6,63 (1H, d, J 2.8 Hz, 4-H), of 6.71 (1H, DD, J 8.4 and 2.8 Hz, 2-H), 7,21 (1H, d, J 8,4 Hz, 1-H);C8,6 (C-152), A 13.9 (C-18), 25,9 (C-151) And 28.6 (C-11), 29,0 (C-7), And 29.9 (C-6), 30,3 (C-12), To 36.8 (C-8), 39,0 ( 15-Me), 40,0 (C-15), 45,2 (C-9), And 45.5 (C-14), Only 55.2 (3-OMe), To 59.6 (C-13) And 79.5 (C-16), 80,0 (C-17), Byr111.4 (C-2), 113,6 (C-4), 126,2 (C-1), 133,0 (C-10), 137,7 (C-5) and 157,5 (C-3).

15 - Ethyl-3-methoxy-15 - methylestra-1,3,5(10)-trien-17 - ol (14)

Alumoweld lithium (48 mg; of 1.26 mmol) are added to a solution of 15-ethyl-15 - methylsiloxane ketone (8) (80 mg; 0.25 mmol) in anhydrous tetrahydrofuran at 0oC. Conduct stirring at a low temperature for 5 minutes. Add saturated aqueous solution of sodium bicarbonate and filtered mixture. Standard processing of the filtrate (ethyl acetate) gives a 15 - ethyl-3-methoxy-15 - methylestra-1,3,5(10)-triene 17-ol (14) (75 mg; 89%). so pl. 133 - 136oC (a mixture of chloroform-methanol); []D+67(from 0.9);max3604 cm-1(OH);Hto 0.88 (3H, t, J 7.2 Hz, 15 - CH2CH3), 0,93 (3, s, 15-Me), was 1.06 (3H, s, 13-Me ), 1,10 (1H, d, J 11,1 Hz, 14-H ), 1,32 fuzzy (2H, m, 15 - CH2CH3), 1,39, and 2,04 (each 1H, DD, J 13.2 and 10,0, and 13.2 and 7.9 Hz, 16 -, and 16-H), 2,84 (2H, m, 6-H2), of 3.60 (1H, DD, J 10.0 g and 7.9 Hz, 17-H ), of 3.77 (3H, s, 3-OMe), is 6.61 (1H, d, J 2.9 Hz, 4-H), 6,70 (1H, DD, J 8.6 and 2.9 Hz, 2-H)and then 7.20 (1H, d, J 8.6 Hz, 1-H);C9,4 (C-152), A 13.9 (C-18), WITH 23.7 (C-151), and 26.1 (C-11), 280), 137,7 (C-5), and 157,5 (C-3) (Found: C, 80,0; H, 9.7 percent; M+, 328. Calculated values for C22H32O2: C, 80,4; H, 9.8 PERCENT; M, 328).

15 - Isopropyl-3-methoxy-15 - methylestra-1,3,5(10)-trien-17 - ol (15)

Alumoweld lithium (35 mg; 0,92 mmol) are added to a solution of 15 - isopropyl-15 - methylsiloxane ketone (11) (63 mg; 0,19 mmol) in anhydrous tetrahydrofuran ( 4 ml) at 0oC. After keeping at this temperature for 10 minutes, add saturated aqueous solution of sodium bicarbonate. The mixture is filtered and the clear solution is subjected to standard processing (ethyl acetate) to obtain 15 - isopropyl-3-methoxy-15 - methylestra-1,3,5(10)-trien-17-ol (15) (60 mg; 95%), []D+54(1.3);max3604 cm-1(OH);H(200 MHz) to 0.88 and 0.92 (each 3H, d, J 6.8 Hz, 15 - CHMe2), is 0.96 (3H, s, 13-Me ), of 1.13 (3H, s, 15-Me), 1,73 (1H, DD, J 13,4 and 10.2 Hz, 16-H), 2,13 (1H, DD, J 13,4 and 7.9 Hz, 16-H), of 3.54 (1H, DD, J 10.2 and 7.9 Hz, 17-H), of 3.78 (3H, s, 3-OMe), only 6.64 (1H, DD, J 2.7 Hz, 4-H), of 6.71 (1H, DD, J 8.5 and 2.7 Hz, 2-H), 7,22 (1H, d, J 8.5 Hz, 1 H);Ca 14.1 (C-18), of 18.2 and 18.6 ( 15 - CHMe2), and 23.6 (C-11), to 26.2 (C-7), 28,5 ( 15 - Me), and 29.9 (C-8), 36,6 (C-12), 37,3 ( 15 - CHMe2), or 39.3 (C-6), 40,7 (C-15), and 42.7 (C-13), to 44.7 (C-9), 46,0 (C-16), to 51.8 (C-14), only 55.2 (3-OMe), 80,8 (C-17), byr111.4 (C-2), 113,6 (C-4), 126,3 (C-1), 133,0 (C-10), 137, 6mm (C-5), and 157,7 (C-3) (Found: C, 80,4; H 9,9%; M+, 342). Calculated values for C23H34O2: C, 80,65; H, 10.0 PERCENT; M, 342.

Example 3

15-Ethyl-15 - methylestra-1,3,5(10)-triene-3,17 - diol (17)

So pl. 132-136oC (from ethyl acetate); []D+54(from 1.0 in ethanol) (Found: C, 80,4; H, 9.5 percent; M+, 314. Calculated values for C21H30O2: C, AN 80.2; H, 9.6 PER CENT; M, 314).

Example 4

15-Ethyl-15 - methylestra-1,3,5(10)-triene-3,17 - diol (18)

Obtained as a foam: []D+59(from 1.0 in ethanol) (Found: C, to 79.8; H, 9.5%, the M+, 314. Calculated values for C21H30O2: C, AN 80.2; H, 9.6 PER CENT; M, 314).

Example 5

15-ISO-Propyl-15 - methylestra-1,3,5(10)-triene 3,17 - diol (19)

So pl. 201 - 205oC (from ethyl acetate); []D+71(from 1.0 in tetrahydrofuran) (Found: C, 80,7; H, 9.8 percent; M+, 328.hastily reproduced when replacing used in the previous examples, reagents and/or conditions of the reactions in General or specifically described reactants and/or conditions of carrying out the reactions according to the present invention.

From the preceding description qualified professionals can easily set the essential characteristics of this invention and, without derogating from the essence of the invention and the scope of its volume, to make the invention various changes and modifications to adapt it for different conditions and applications.

1. br15.15-Dialkylamide the compounds of formula I

< / BR>
where R1and R2independently of one another are each hydrogen;

R3and R4independently from each other are non-branched alkyl containing 1 to 10 carbon atoms, or a branched alkyl containing 3 to 10 carbon atoms.

2. Connection on p. 1, where R3and R4independently of one another are each methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

3. Connection on p. 1, where R3and R4independently of one another are each methyl, ethyl, isopropyl.

4. Connection on p. 3 where the above-mentioned connection is br15.15-dimethylester-1,3,5(10)-triene-3,17-diola.

5. Connection on p. 2 where the above-mentioned compounds are 15-ethyl-15-methylestra-1,3,5(10)-triene-3,17-diola, 15-ethyl-15-methylestra-1,3,5(10) - Rev. by p. 1, characterized in that compounds of the formula II

< / BR>
where R1is non-branched alkyl containing 1 to 10 carbon atoms;

R3and R4independently of one another are each non-branched alkyl containing 1 to 10 carbon atoms, or a branched alkyl containing 3 to 10 carbon atoms,

put the splitting of the 3-alkylamino group.

7. The compounds of formula IIa

< / BR>
where R1'is non-branched alkyl containing 1 to 10 carbon atoms;

R3and R4independently of one another are each non-branched alkyl containing 1 to 10 carbon atoms, or a branched alkyl containing 3 to 10 carbon atoms;

Z represents an atom of the keto-oxygen.

8. The method of obtaining the compounds of formula II

< / BR>
where R1'is non-branched alkyl containing 1 to 10 carbon atoms;

R3and R4independently of one another are each non-branched alkyl containing 1 to 10 carbon atoms, or a branched alkyl containing 3 to 10 carbon atoms,

characterized in that it includes the interaction of the 3-R1'0-östra-1,3,5(10), 15-tetraen-17-about the connection with LiCuR23or alkylacrylate with 3 R1'0-15-R3-östra-1,3,5(10)-triene-17-she; chemical transformation in situ by adding chlorotrimethylsilane and subsequent additions of palladium (II) acetate with 3-R1'0-15-R3-östra-1,3,5(10), 15-tetraen-17-it; its interaction with LiCuR24or alkalinisation, where alkyl is an R4and the halide is Br or I, in the presence containing copper (I) catalyst to obtain 3-R1'0-15-R3-15-R4-östra-1,3,5(10)-triene-17-it; restore C-17-carbonyl him with obtaining the above-mentioned compounds of formula II, R1', R2, R3have the values listed in paragraph 1.

 

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wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

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