The method of obtaining- substituted 4-aseankorea

 

(57) Abstract:

The invention relates to a new method of obtaining derivatives of 17 - substituted 4-aseankorea General formula (I)

< / BR>
in which R is hydrogen or C1- C3alkyl; R1- carboxamidine group, mono - or disubstituted by C1- C8alkyl group(s); or a free carboxyl group, esterified C1- C5alcohol; and - a single or double bond; and their salts. The method includes the interaction derived 17-halogen-4-aseankorea General formula (II)

< / BR>
in which R and a are defined above and X is chlorine, bromine or iodine, with primary or secondary alkylamino or C1- C5alcohol in the environment dimethyl-formamide or dimethyl sulfoxide in the presence of salts of palladium (II) and phosphines or palladium (II) complex and the Foundation in the form of tertiary amine in an atmosphere of carbon monoxide at 35 - 80oAnd then, if desired, converting the compounds obtained of General formula (I) into another compound of General formula (I) by hydrogenation, hydrolysis or salt-forming reactions.

The invention relates to a new method of obtaining derivatives of 17-substituted 4-aseankorea General formula (I)

< / BR>
The B> the alkyl (alkilani) straight or branched chain; or a free carboxyl group; or a carboxyl group, ethicurean alcohol C1-5with a straight or branched chain;

- single or double bond;

and their salts with pharmaceutically acceptable bases, in which R1a free carboxyl group.

Compounds of General formula (I) inhibit 5 - reductase and therefore they prevent the conversion of testosterone into dihydrotestosterone. Thus, compounds of General formula (I) are suitable for treatment of diseases caused by dihydrotestosterone, such as hyperplasia, acne vulgaris, seborrhea or female hirsutism.

According to literature sources [Europatent No. 4.949; and J. Med. Chem. 27, 1690 pages to 1701 (1984)] are known compounds of General formula (I) can be obtained by the proposed method.

After the reaction of pregnenolone (3-hydroxy-5-pregnen-20-it) with elemental iodine in pyridine received 21 pyridine iodide" split with sodium methoxide communication between C20and C21to obtain the corresponding derivative of 17-carbomethoxy". The obtained 3-hydroxy-17-carbomethoxyamino-5-ene oxidized by isopropoxide Alumini turn in "the acid chloride 17-carboxylic acid, using oxalicacid. This acid chloride transform, for example, in a derived "17-(N, N-diethylcarbamoyl) using diethylamine. After oxidation receive 17-(N, N-diethylcarbamoyl)androst-4-EN-3-one and transform it into a "seco-acid" periodates sodium tert-butanol in the presence of permanganate potassium, weight connection by entering into reaction with ammonia or other primary amine with ethylene glycol to obtain, for example, 3-oxo-4-methyl-4-Asandros-5-ene-17 -(N,N-diethylcarbamyl). This substance hydronaut in the corresponding derivative of 4-Aza-5-androstane in glacial acetic acid in the presence of hydrogen and catalyst (platinum oxide). After selecting the final products are cleaned in any way.

Raw material in the described way is pregnenolone, which are synthesized by hydrogenation to the double bond in position 16 acetate pregnanolone obtained by splitting diosgenin or solasodine of natural origin. However, pregnenolone less affordable for growing in Mexico Dioscorea species, the root of which is used for diosgenin, is on the verge of extinction. On the other hand, the cultivation of Solanum aviculare and allocation of solasodine from our experience is not economical.

With an account of the; however, this need for the above reason, it is increasingly difficult to satisfy using the known method of synthesis.

Therefore, the basis of the invention is to devise a way that would be feasible with the use of readily available raw materials. From this point of view acceptable new derivatives of 17-halogen-4-aseankorea General formula (II)

< / BR>
Unexpectedly it was found that the method that fully meet the specified requirements, obtain the target compounds of General formula (I) may be carried out:

interaction derived 17-halogen-4-aseankorea General formula (II) in which R and link types defined above, and X is chlorine, bromine, or iodine, with primary or secondary alkylamines with altergroup1-8or alcohol group C1-5with normal or branched chain, environment, dimethylformamide or dimethyl sulfoxide in the presence of salts of palladium (II) and phosphines or palladium (II) complex and the Foundation in the form of tertiary amine in an atmosphere of carbon monoxide at a temperature in the range of 35-80oC. and then, if desired,

the hydrogenation of compounds of General formula (I) containing a double bond, in the presence of a catalyst, to obtain a compound of General formula (I), with the m compound of General formula (I), containing esterified carboxyl group as R1in the compound of General formula (I) containing a free carboxyl group as R1and/or

to turn obtained by the above method, the compound of General formula (I) containing a free carboxyl group as R1in its salt by reacting with a pharmaceutically acceptable base.

According to a preferred variant of the invention, the compound of General formula (II) is injected into the reaction with a primary or secondary amine in dimethylformamide in the presence of palladium (II) acetate, triphenylphosphine and triethylamine in an environment of carbon monoxide at 60oC for 90-120 minutes After completion of the reaction of the amines and the dimethylformamide is distilled off under reduced pressure, the VAT residue is dissolved in chloroform and washed sequentially with water, aqueous hydrochloric acid, aqueous sodium bicarbonate solution and again with water until neutralization. After drying and evaporation of the solvent the residue is purified chromatography or recrystallization, or by using both methods.

Optionally, the double bond [in position 16 or at positions 5 and 16, depending on the source soedineniju group as R1may be gidrirovannah in formic acid in the presence of gaseous hydrogen and a palladium catalyst on charcoal medium, or in glacial acetic acid in the presence of hydrogen and catalyst in the form of platinum oxide.

To obtain the compounds of General formula (I) containing alkoxycarbonyl group as R1the compound of General formula (II) is preferably introduced into the reaction with alcohol C1-5in dimethyl sulfoxide in the presence of a mixture of palladium (II) acetate, 1,4-bis (diphenylphosphine) butane and triethylamine in an environment of carbon monoxide at 60oC for 10-15 hours After completion of the reaction, the volatile components are distilled off under reduced pressure, the VAT residue is dissolved in chloroform and water-soluble components are removed by washing with water. After drying of the solution and evaporation of the solvent the residue is purified chromatography or recrystallization, or by using both methods.

If desired, the compound obtained of General formula (I) hydronaut, as described above, i.e. formic acid in the presence of hydrogen in palladium catalyst on charcoal medium, or in glacial acetic acid in the presence of hydrogen and platinum oxide as catalysis"ptx2">

In the method according to the invention as phosphine, preferably using 1,4-bis(diphenylphosphino)-butane,1,2 bis(diphenylphosphino)ethane, triphenylphosphine or 1,3-bis(diphenylphosphino)propane, although it may be also applied these phosphines with salts of palladium (II): for example, the reaction is carried out at 35-60oC with primary or secondary amines and 40-80oC with C1-5alcohols in the presence dichloride bis(triphenylphosphine)palladium (II).

The method according to the invention allows it to be used as raw materials readily available derivatives of 3-keto-4that can be obtained by decomposition of sitosterol. According to the invention the introduction of the 17-carboxamid - or 17-carbalkoxy group can be easily performed, and a step by step process required for industrial use, does not cause any problems.

Raw materials used in the method according to the invention, such as derivatives of 4-Aza-17-hydrazone, and also compounds of General formula (II) are new. Similarly, new and unsaturated derivatives of 4-Aza-17-carboxamide and 4-Aza-17-alkoxycarbonyl General formula (I). Saturated derivatives of 4-Aza-17-carboxamide, and SS="ptx2">

New derivatives of 17-halogen-4-aseankorea General formula (II) used as raw material in the method according to the invention, can be obtained as follows.

4-Aza-5-androsten-3,17-dione, 4-methyl-4-azandracta-3,17-dione and 4-Asandros-5-ene-3,17-dione (hereinafter referred to as 4-Aza-17-ketopropane), which are known compounds, can be obtained by a method described in the literature [J. Pharm.Sci.63, pages 19 to 23 (1974); J. Med.Chem.27 pages 1690 to 1701 (1984); J. Org.Chem.46, pages 1442 to 1446 (1981)] of the famous 17-hydroxyandrost-4-EN-3-one.

The famous "4-Aza-17-ketopropane" enter into reaction with hydrazinehydrate in ethanol in the presence of triethylamine; after the formation of the reaction mixture (obtained in accordance with example 1) allocate the resulting derived hydrazone and raw foods immediately used without any purification for obtaining derivatives of 17-halogen-4-aseankorea General formula (II), as described hereafter.

To obtain the derivatives of 17-iodine-4-aseankorea "hydrazone derivative" is dissolved in chloroform or benzene, or mixtures thereof, or in tetrahydrofuran, and then injected into the reaction with elemental iodine in the presence of a base in the form of a tertiary amine at room temperature. the derivatives of 17-halogen-4-sandrolini, containing in position 17 chlorine or bromine, derived hydrazone" dissolved in pyridine, optionally substituted C1-4the alkyl, and injected into the reaction respectively with N-chloro - or N-bromosuccinimide at a temperature in the range from -10 to 10oC. the resulting compounds of General formula (II) was isolated as described in example 7.

Example 1. Getting 17-hydrazone-4-Aza-5-androstane-3-one.

To a suspension containing 10 g (0,0346 mol) of 4-Aza-5 - androsten-3,17-dione in 100 ml of ethanol, add 14 ml (0.1 mol) of triethylamine and 50 ml (1.0 mol) of hydrazine hydrate is added, and the mixture is refluxed 3 hours the Course of the reaction is controlled by thin-layer chromatography. After completion of the reaction the mixture is cooled, the solution is evaporated to one-tenth the original volume and the product precipitated by adding approximately ten-fold volume of water. After sealing the precipitate is filtered off, washed with water until neutralization and dried to obtain compounds according to the invention.

The product yield 9,44 g (90%), tn254-258oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,86 (s, 3H, 18-CH3), of 0.93 (s, 3H, 19-CH3), is 2.41 (m, 2H, H-2), of 3.07 (dd, 1H, H-5), of 4.77 (br, 2H, NH2), 5,74 (br, 1H, NH).

Example 2. Getting 1 is, described in example 1, using 4-Asandros-5-ene-3,17-dione as raw materials.

Yield 35%, tn379 - 382oC.

IR (KBr) : 1633 (C=C), 1661 (C=N), 1693 (C=O), 3200 (NH), 3350 (NH2) cm-1.

Example 3. Getting 17-hydrazone-4-methyl-4-Aza-5-androstane-3-one.

To obtain compounds according to the invention performs the process described in example 1, using 4-methyl-4-Aza-5-androsten-3,17-dione as raw materials.

Yield 75%, tn211 - 218oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,86 (s, 3H, 18-CH3), of 0.91 (s, 3H, 19-CH3), with 2.93 (s, 3H, N-CH3), 3,05 [dd(J=3,6; J=12,6), 1H, H-5], 4,78 (v br, 2H, NH2).

Example 4. Getting 17-iodine-4-Aza-5-androst-16-EN-3-one.

After dissolution of 9.1 g (0.03 mol) of 17-hydrazone-4-Aza-5-androsten-3-one in 1200 ml of a mixture of chloroform/benzene 1:1 and add 90 ml of triethylamine in this solution are added dropwise 11.4 g (0.045 mol) of iodine dissolved in 110 ml of benzene.

The reaction mixture is additionally stirred for 60 to 90 min at room temperature, monitoring the reaction by thin-layer chromatography. After completion of the reaction, the obtained solution is diluted with 500 ml of chloroform and successively washed with 10% aqueous solution salaakhen, water and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure the residue chromatographically purified on silikagelevye column using first chloroform and then a mixture of chloroform/acetone 95:5 as eluents. The resulting product will recrystallized from ethanol to obtain compounds according to the invention.

Yield 5.9 g tn278 - 282oC.

1H-NMR (300 MHz, CDCl3) million-1: to 0.73 (s, 3H, 18-CH3), of 0.91 (s, 3H, 19-CH3), and 3.1 (dd, 1H, H-5), 6,18 (m, 1H, H-16), 6,9 (br, 1H, NH).

Example 5. Getting 17-iodine-4-azaindole-5,16-Dien-3-one.

Perform the process described in example 4, using 17-hydrazone-4-azaindole-5-ene-3-one as a raw material for production of the compounds according to the invention.

Yield 57%, tn227 - 230oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,78 (s, 3H, 18-CH3), of 1.13 (s, 3H, 19-CH3), 4,9 [dd (J=2,4; J=5,1), 1H, H-6], 6,15 [dd (J=3,2; J=1,7), 1H, H-16], of 8.27 (br, 1H, NH).

Example 6. Getting 17-iodine-4-methyl-4-Aza-5-androst-16-EN-3-one.

Perform the process described in example 4, using 17-hydrazone-4-methyl-4-Aza-5-androsten-3-one as raw material and carrying out the reaction in benzene. The connection according to the invention to be obtained with a yield of 52%, >), to 2.94 (s, 3H, N-CH3), 3,07 [dd (J=3,7; J=12,6), 1H, H-6], 6,13 [dd (J=3,2; J=1,7), 1H, H-16].

Example 7. Getting 17-chloro-4-methyl-4-Aza-5-androst-16-EN-3-one.

A solution containing 4 g (0,0126 mol) 17-hydrazone-4-methyl-4-Aza-5-androsten-3-one in 40 ml of anhydrous pyridine, cooled to 0oC and added dropwise with vigorous stirring a solution of 3.2 g (0,024 mol) N-chlorosuccinimide in 40 ml of pyridine. After cessation of rapid excretion of nitrogen gas, the reaction mixture was additionally stirred for 15 minutes and then added dropwise to 800 ml of water. After the seal precipitate the crude product is filtered off, washed with water until neutralization and dried over phosphorus pentoxide under reduced pressure at room temperature. The obtained crude product is chromatographically purified on silikagelevye column using chloroform as eluent. After recrystallization evaporated sludge from petroleum ether to obtain the product according to the invention with the release of 2.15 g (53)%, tn139 - 140oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,88 (s, 3H, 18-CH3), of 0.93 (s, 3H, 19-CH3), 2,89 (s, 3H, N-CH3), and 3.0 (dd, 1H, H-5), of 5.53 (m, 1H, H-16).

Example 8. Getting 17-bromo-4-methyl-4-Aza-5-androst-16-EN-3-one.

Perform the process described in Priya compounds according to the invention.

Yield 55%, tn159 - 161oC.

1H-NMR (300 MHz, CDCl3) million-1: of 0.82 (s, 3H, 18-CH3), of 0.91 (s, 3H, 19-CH3), of 2.86 (s, 3H, N-CH3), and 3.0 (dd, 1H, H-5). of 5.68 (m, 1H, H-16).

Example 9. Obtaining 3-oxo-4-Aza-5-androst-16-ene-17-N-tributyltinoxide).

To a solution containing 3,99 g (0.01 mol) of 17-iodine-4-Aza-5-androst-16-EN-3-one in 150 ml of dimethylformamide, add 0,224 g (0.001 mol) palladium (II) acetate, 0,524 g (0.002 mol) of triphenylphosphine, 10 ml of triethylamine and 15 ml (0.14 mol) of tert-butylamine, and the mixture is heated to 60oC in the environment of carbon monoxide 90 - 120 minutes, controlling the reaction of thin-layer and gas chromatography. After completion of the reaction of the amines and the dimethylformamide is distilled off under reduced pressure, then VAT is dissolved in 150 ml of chloroform and successively washed with water, 5% aqueous solution of hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride to neutralize, and finally dried over anhydrous sodium sulfate. After evaporation of the solvent sludge chromatographically purified on silikagelevye column with ethyl acetate as eluent to obtain compound according to the invention.

-CH3), 1,0 (s, 3H, 18-CH3), and 1.4 (s, 3H, C(CH3)3), of 2.15 (m, 2H, H-15a+H-15b), and 2.4 (m, 2H, H-2), is 3.08 [dd (J=4,5; J=7,0), 1H, H-5], of 5.48 (br s, 1H, NH), 5,6 (br s, 1H, NH), 6,18 [dd (J=1,7; J=1,4), 1H, H-16].

Example 10. Obtaining 3-oxo-4-Aza-5-androst-16-ene-17 -[N-(2,2-dimethylpropyl)carboxamide].

Perform the process described in example 9, using 17-iodine-4-Aza-5-androst-16-EN-3-one as raw material and 2,2-dimethylpropylene (neopentylene) as a reagent for obtaining compounds according to the invention.

Yield 82%.

1H-NMR (300 MHz, CDCl3) million-1: to 0.92 (s, 9H, C(CH3)3), of 0.95 (s, 3H, 19-CH3), of 1.02 (s, 3H, 18-CH3), and 2.4 (m, 2H, H-2), 3,1 (m, 3H, NCH2, H-5), to 5.66 (br s, 1H, NH), of 5.85 (br s, 1H, NH), and 6.3 (br s, 1H, H-16).

Example 11. Obtain methyl ester of 4-methyl-3-oxo-4-Aza-5-androst-16-ene-17-carboxylic acid.

Mixture of 0.41 g (0.001 mol) of 17-iodine-4-methyl-4-Aza-5-androst-16-EN-3-one, 0,0224 g (0.1 mol) of palladium (II) acetate, 0,0213 g (0.05 mol) of 1,4-bis(diphenylphosphine)butane, 0.3 ml of triethylamine, 2 ml of methanol and 15 ml of dimethyl sulfoxide, stirred under carbon monoxide at 60oC 10 - 15 hours , monitoring the progress of the reaction thin-layer or gas chromatography. After completion of the reaction the mixture is evaporated under reduced pressure, the residue is dissolved in 15 ml of chloroform, rest is chromatographically purified on silikagelevye column, using a mixture of ethyl acetate/petroleum ether 1:10 as eluent. Get the connection according to the invention with the release of 0.014 g (40%), tn182 - 186oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,93 (s, 6H, 18-CH3+19-CH3), a 2.45 (m, 2H, H-2), to 2.94 (s, 3H, NCH3),3,07 (dd, 1H, H-5), and 3.72 (s, 3H, OCH3), 6,76 (br s, 1H, H-16].

Example 12. Obtaining 3-oxo-4-Aza-5-androst-16-ene-17-carboxylic acid.

Perform the process described in example 11, using 17-iodine-4-Aza-5-androst-16-EN-3-one as a raw material for production of the compounds according to the invention. Yield 42%, tn270oC.

1H-NMR (300 MHz, CDCl3) million-1: to 0.92 (s, 3H, 19-CH3), were 0.94 (s, 3H, 18-CH3), 2.4 m, 2H, H-2), of 3.07 (dd, 1H, H-5), and 3.72 (s, 3H, OCH3), x 6.15 (br s, 1H, NH), 6.75 in (br s, 1H, H-16).

Example 13. Obtaining 3-oxo-4-azaindole-5,16-Dien-17 -(N-tert-BUTYLCARBAMATE).

Perform the process described in example 9, using 17-iodine-4-Aza-5-androst-5,16-Dien-3-one as raw materials and tert-butylamine as a reagent for obtaining compounds according to the invention.

Yield 78%, tn266 - 269oC.

1H-NMR (300 MHz, CDCl3) million-1: 1,04 (s, 3H, 18-CH3), to 1.14 (s, 3H, 19-CH3), to 1.38 (s, 9H, C(CH3)3), 2,5 (m, 2H, H-2), 4,88 [dd (J=2,4; J=2,7), 1H, H-6], and 5.5 (br s, 1H, N is carboxamido).

a) Perform the process described in example 9, using 17-iodine-4-methyl-4-Aza-5-androst-16-EN-3-one as raw diethylamine as the reagent. Thus obtained compound according to the invention with a yield of 84%, tn205 - 210oC.

1H-NMR (300 MHz, CDCl3) million-1: 0,93 (s, 3H, 19-CH3), of 1.09 (s, 3H, 18-CH3), of 1.13 (t, 6H, N(CH2CH3)2), to 2.94 (s, 3H, NCH3), 3,06 (dd, 1H, H-5), of 5.26 (m, 1H, H-16).

b) Perform the process described in example 9, using 17-bromo-4-methyl-4-Aza-5-androst-16-EN-3-one as raw diethylamine as the reagent. Thus obtained compound according to the invention with the release of 85%, tn205 - 210oC.

Example 15. Getting 4-methyl-3-oxo-4-Aza-5-androsten-17 -(N,N-diethylcarbamyl).

A suspension containing 1 g of palladium catalyst on charcoal medium in 6 ml of water are added to a solution of 1 g (2.6 mol) of 4-methyl-3-oxo-4-Aza-5-androst-16-ene-17 -(N,N-diethylcarbamyl) in 40 ml of formic acid in a nitrogen atmosphere. The heterogeneous mixture was stirred at room temperature for 4 to 5 hours before until using thin-layer chromatography recovery has been observed. After completion of the reaction the catalyst is filtered off and washed with a mixture of chloroform/methanol 1:1. After evaporation of the water, receiving a connection according to the invention with the release of 0.88 g (87%), tn180 - 181oC.

Example 16. Obtaining 3-oxa-4-Aza-5-androsten-17 -(N-tert-BUTYLCARBAMATE).

Perform the process described in example 15 using 3-oxa-4-Aza-5-androst-16-ene-17 -(N-tert-BUTYLCARBAMATE) as raw material for production of the compounds according to the invention. Yield 90%, tn283 - 286oC.

Example 17. Obtaining methyl ester 3-oxa-4-Aza-5-androsten-17-carboxylic acid.

Perform the process described in example 15, using methyl ether 3-oxa-4-Aza-5-androst-16-ene-17-carboxylic acid as raw materials for producing the compounds according to the invention with the release of 85%, tn301 - 304oC (after recrystallization from ethyl acetate).

Example 18. Obtaining 3-oxo-4-Aza-5-androstane-17 -(N-tert-BUTYLCARBAMATE).

Perform the process described in example 15 using 3-oxa-4-Asandros-5,16-ene-17 -(N-tert-BUTYLCARBAMATE) as raw material for production of the compounds according to the invention with an output of 70%, tn283 - 286oC.

1. A method of obtaining a 17-substituted 4-aseankorea General formula I

< / BR>
where R is H or C1- C3-alkyl;

R1- carboxamidine group, mono - ilosone esterified WITH1- C5alcohol;

a single or double bond,

includes stage hydrogenation in the presence of a catalyst of the existing double bond, characterized in that the 17-halogen-4 - azandracta General formula II

< / BR>
where R and a have the above meanings;

X is a chlorine atom or iodine,

subjected to interaction with primary or secondary1- C8-alkylamino or1- C5alcohol in the environment of dimethylformamide or dimethyl sulfoxide, respectively, in the presence of salts of palladium (II) and phosphines or palladium (II) complex and the Foundation in the form of tertiary amine in an atmosphere of carbon monoxide at a temperature of 35 - 80oC, followed optionally by hydrogenation in the presence of a catalyst of the available double bonds or hydrolysis existing esterified carboxyl group to obtain compounds of General formula I, where R1a free carboxyl group.

2. The method according to p. 1, characterized in that the use of triethylamine as a tertiary amine.

3. The method according to p. 1 or 2, characterized in that the use of palladium (II) acetate as the salt of palladium (II).

4. The method according to PP.1 to 3, characterized in that the use of triphenylphosphine or 1,4-bis(diphenylphosphine) palladium diacetate as palladium (II) complex.

6. The method according to PP.1 to 5, characterized in that the process is carried out at 50 - 60oC.

7. The method according to PP.1 - 6, characterized in that during the hydrogenation of the double bond using palladium catalyst.

8. The method according to p. 7, characterized in that the process of hydrogenation of the double bond is carried out in the environment of glacial acetic or formic acid.

9. The method according to PP.1 - 6, characterized in that use diethylamine or tert-butylamine as alkylamine.

10. The method according to PP.1 - 6, characterized in that as alcohol use methanol.

 

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< / BR>
in which R is hydrogen or C1-3alkyl group; X is chlorine, bromine or iodine and- single or double bond

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36 cl, 2 tbl, 72 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes an improved method for synthesis of 17β-substituted 4-azaandrost-1-en-3-one of the general formula (I): wherein R means -OH, (C1-C4)-alkyl, (C1-C4)-alkenyl, phenyl, benzyl and others, or their pharmaceutically acceptable salts. Method involves insertion protective groups into 3-keto-4-aza (lactam) form of compound of the general formula (II): wherein R has indicated values to form compound of the general formula (III): wherein R3 means trialkylsilyl, or in common with R4 residue -C(O)-C(O)- or -C(O)-Y-C(O)- wherein R4 means tert.-butyloxycarbonyl preferably; Y means -(CH2)n wherein n = 1-4, or ortho-phenylene. Then a synthesized compound is converted in the presence of a dehydrogenation catalyst of in the presence of benzoquinone, allylmethylcarbonate, allylethylcarbonate and/or allylpropylcarbonate, and ▵1-double bond is introduced in 1,2-position followed by removal of protective groups and, if necessary, (when R means -OH) conversion to salts. Method provides the high yield and purity degree of synthesized compounds.

EFFECT: improved method of synthesis.

21 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: description is given of thiomorpholine derivatives of steroids with general formula I . These steroids are characterised by presence of a thiomorpholine fragment, bonded to a C17 steroid skeleton through an alkylene spacer, where R4 and R4' are hydrogen and methyl, under the condition that, both R4 and R4' represent hydrogen at the same time.

EFFECT: invention can be successfully used for stimulating meiosis of human oocyte.

12 cl, 2 ex, 5 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to production of new tritiated analogues of physiologically active compounds - triterpene glycosides of holothurians Cucumaria of formula: .

EFFECT: there are produced new tritiated analogues of physiologically active compounds.

2 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to racemic 3,17β-dihydroxy-7α,18-dimethyl-6-oxaextra-1,3,5(10),8(9)-tetraene diacetate of formula .

EFFECT: production of the substance exhibiting osteoprotective, hypocholesteremic and antioxidant action with lowered uterotropic activity.

1 cl, 2 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-oxa- and 4-aza-16α, 17α-cyclohexanopregnanes (4-oxa- and 4-aza-pregna-D'-pentaranes), which can be used n medicine to treat malignant tumours, having general formula I , where X=0 or NR, R=R1=R2=R4=H where R1+R3 form a bond. Said compounds are obtained by oxidising ring A 16α, 17α-cyclohexano-progesterone with potassium permanganate and sodium periodate in the presence of sodium carbonate in 5-oxo-A-nor-3,5-secoacid followed by closure of ring A in 4-oxa-16α, 17α-cyclohexanopregn-5-en-20-one while treating with a sodium acetate dehydrating agent in Ac2O and in 4-aza-16α, 17α-cyclohexanopregn-5-en-20-one using ammonium acetate in acetic acid.

EFFECT: compounds are effective inhibitors of oestrogen-stimulated cell proliferation HeLa.

2 cl, 2 ex, 1 tbl

FIELD: biochemistry.

SUBSTANCE: disclosed is a composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing) containing natural brassinosteroid or analogue of brassinosteroid. Described is a method for preventing or treating Huanglongbing (HLB) disease in citrus, characterised by periodic application of brassinosteroid on plants. Described is use of brassinosteroid for making composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), where said composition is periodically applied.

EFFECT: described is a method for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), characterised by application of brassinosteroid compound on plant.

11 cl, 7 dwg, 3 tbl, 8 ex

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