The method of obtaining d-Östra-1,3,5(10)-triene-3-ol-17-she (estrone)
(57) Abstract:The invention relates to a method for producing D-östra-1,3,5(10)-triene-3-ol-17-she (estrone). The method includes reductive aromatization 17-atelectasia of androsta-1,4-diene-3,17-dione by its introduction into the reaction mixture containing metallic sodium and diphenyl in diglyme at elevated temperatures, and subsequent acid hydrolysis, and 17-atlantal of androsta-1,4-diene-3,17-dione is introduced into the reaction mixture in the form of a solution in the molten diphenyl in a stream of inert gas. The reaction mixture contains a quantity of diphenyl less than stoichiometric, and the remaining amount of diphenyl required for the reaction, add the introduction of the 17-atelectasia of androsta-1,4-diene-3,17-dione in the molten diphenyl. A solution of 17-atelectasia of androsta-1,4-diene-3,17-dione in the molten diphenyl performed by mixing equal weight quantities of 17-atelectasia of androsta-1,4-diene-3,17-dione and diphenyl at a temperature above the 75oC. an Additional amount of estrone remaining in the mother solution after separation of the base, isolated by extraction with an aqueous solution of sodium hydroxide, and extraction using 20 - 40% aqueous sodium hydroxide solution. number, isolated by regeneration diglyme and diphenyl. The method provides a uniform flow of the reaction, a complete selection of estrone and simultaneous partial regeneration of reagents used. 5 C.p. f-crystals. The invention relates to the chemistry of steroid compounds astranova number and relates to an improved method of producing D-östra-1,3,5(10)-triene-3 - ol-17-she (estrone)formula 1
< / BR>Estrone (D-östra-1,3,5(10)-triene-3-ol-17-one) is not only a female sex hormone, but also a valuable steroid product and semi-product of the pharmaceutical industry, produced in the world by hundreds of pounds a year. Estrone (and its esters) is used as the active active principle, and as a key intermediate material in the manufacture of many steroid drugs based on estrogenic, gestagenna, antigestagens, anabolic and contraceptive action of various steroids.Oil solution of estrone is a drug used in gynecology called follikulin.Currently estratriene steroids are produced mainly by chemical synthesis from D-androsta-1,4-diene-3,17-dione (ADD), produced, in turn, microbiological of transformationof of ADD, both of which get estrone.In the first method uses a high temperature (500-700oC) pyrolysis solution ADD in the solvent - hydrogen donors (xylene, kerosene) [U.S. Patent (Mitsubishi Chemical Industry Ltd.) 3,994,938, class C 07 J 1/00, publ. 30.11.1976; patent Germany (Schering AG) 3,931,820, class C 07 J 1/00, publ. 28.03.1991]. Although the method allows to obtain a high yield estrone, it requires a complex installation, precise control and maintain extreme mode pyrolysis (contact time up to 1 s, rapid cooling) and periodic cleaning installation products from charring.The second way to remove it from ADD angular 19-methyl group (i.e. the so-called aromatization of the steroid) used the reaction of Dryden (H. L. Dryden, G. M. Webber, J. J. Wieczorek, J. Am.Chem.Soc., 1964, 86, 742; H. L. Dryden, G. M. Webber, U.S. patent 3,274,182, class NCI 540 - 17, publ. 24.12.1964; N. Men'shov. I. Shuvalov S. D., RF patent 2056430, class C 07 J 1/00, publ. 20.03.96 bull. N 8). The method consists in interaction 17-atlantal of androsta-1,4-diene-3,17 - dione (17-atelectasia ADD) with interaction products of polycyclic aromatic hydrocarbons with at least one alkali metal in the solvent environment. Moreover, as a result of transfer of electrons is formed radical-ASM anion 17-atelectasia estrone, which is then hydrolized to estrone. This method allows to obtain a high total yield estrone (approximately 60%) and does not require special equipment.The closest analogue of the present invention is a method in which sodium metal is subjected to interaction with polycyclic aromatic hydrocarbons in the environment of a solvent of formula 2:
CH3(OCH2CH3)nOCH3where n2 (2)
in the temperature interval 98-105oC to 70oC (N. Men'shov.And., Shuvalov S. D. , RF patent 2056430, class C 07 J 1/00, publ. 20.03.96 bull. N 8). To the reaction mass, containing polycyclic aromatic hydrocarbons, add 17-atlantal of androsta-1,4-diene-3,17-dione in the form of a powder in a countercurrent of inert gas. Reductive aromatization is carried out in the temperature interval 105-70oC. the Selection of the target product is as follows: the reaction mass was added sequentially a lower alcohol, water, after cooling down to 30-32oC the resulting mixture was treated with concentrated hydrochloric acid and maintained at 622oC for 1 h the Mixture is cooled to room temperature, then add the water, an aromatic hydrocarbon (e.g. toluene) and VIPRE room temperature for 8-12 hours The precipitated crystals of the product is filtered. Output technical estrone is 86-88%.Necessary and sufficient condition of this method is the use of only one solvent, in an environment which was possible as getting anion-radicals of polycyclic aromatic hydrocarbons and the recovery of flavoring.However, the proposed method has several disadvantages. Since the 17 - atlantal ADD is introduced into the reaction mixture in the form of a powder, the introduction is uneven in addition, some of the powder deposited on the plant, resulting in a loss of reagent and creates difficulties in the production of estrone on an industrial scale. In addition, in the mother solution after separating the main portion of estrone crystallization remains a significant amount of estrone. In the proposed method of allocating the remaining amount of estrone was not made.In U.S. patent No. 3, 274, 182 (class NCI 540-17, publ. 24.12.1964) remaining in the mother solution, estrone emit extraction of dilute potassium hydroxide solution. However, this process requires a large amount of aqueous alkali.Due to these defects, the method according to the prototype aquahot estrone low purity (with T. pl. 251 - 252oC) with recurring access to 69-71% (allocating an additional amount of estrone from the mother liquor). In this regard, there is a need to develop an improved method for obtaining estrone.The present invention is to provide a method of obtaining estrone, in which the steroid substrate is injected in the form of a solution that provides a uniform flow of the reaction, the completeness of the selection of the target product and the simultaneous partial regeneration entering the reaction of the reactants.This task is solved by the present invention.In a method of producing D-östra-1,3,5(10)-triene-3-ol-17-she (estrone), including reductive aromatization 17-atelectasia of androsta-1,4 - diene-3,17-dione by its introduction into the reaction mixture containing metallic sodium and diphenyl in diglyme at elevated temperatures, and subsequent acid hydrolysis, according to the invention 17-atlantal of androsta-1,4-diene-3,17-dione is introduced into the reaction mixture in the form of a solution in the molten diphenyl in a stream of inert gas.When this reaction mixture preferably contains the amount of diphenyl less than stoichiometric, and the remaining amount of diphenyl, the required number of diphenyl use for preparation of a solution of 17-atelectasia of androsta - 1,4-diene-3,17-dione in the molten diphenyl mixing equal weight quantities of 17-atelectasia of androsta-1,4-diene-3,17-dione and diphenyl at a temperature above the 75oC.The additional amount of estrone remaining in the mother solution after separation of the base can be isolated by extraction with an aqueous solution of sodium hydroxide.For extraction use 20-40% introductory sodium hydroxide solution.Alternatively, the additional amount of estrone remaining in the mother solution after separation of the base, is isolated by regeneration diglyme and diphenyl.Thus, diphenyl is used both as a reagent and as a solvent for the 17-atelectasia ADD, which is introduced into the reaction mixture in the form of a solution in the molten diphenyl that provides a slow and smooth flow of the substrate.Almost full allocation remaining in the mother solution of estrone is produced by extraction with an aqueous solution of sodium hydroxide or, alternatively, the release of organic stock solution of diphenyl and diglyme in the process of regeneration, which leads to a fairly complete crystallization of the steroid.Information confirming the possibility of carrying out the invention.The proposed method of producing estrone is one of the variant is erway stage of the method, received by metallizatsiei D-androsta-1,4-diene-3,17-dione (ADD), heating in vacuum solution ADD ethylene glycol in the presence of a catalyst tosilata pyridinium (Py.TsOH).The reaction scheme:
< / BR>In pear-shaped flask with a volume of 50 ml with a magnetic stirrer, equipped with a nozzle vyurts with a thermometer attached to the side branch with a source of vacuum, put 6.5 ml of ethylene glycol and 0.2 g (2 wt.% from downloadable ADD) tosilata pyridinium (Py.TsOH) (in the reaction can be used from 0.1 to 0.3 g tosilata pyridinium (1-3% of the downloadable ADD) without significant changes in the yield and composition of the reaction products). The mass was stirred at room temperature for 5 minutes to dissolve the Py.TsOH and added 10 g ADD. The resulting suspension was heated to 110-115oC under stirring until complete dissolution of ADD (5-10 min) (providing complete dissolution ADD to evacuating the reaction vessel and intensive mixing is necessary in order to avoid possible "bursts" of suspension ADD in ethylene glycol under vacuum) and then was evacuated at 25-35 mm RT.article and 125-130oC and vigorous stirring. Precipitation 17-atelectasia ADD observed in 5-8 min after reaching the above-mentioned temperatures and Waco is). The resulting suspension was kept further at 130-135oC if possible, with stirring, over time, three times greater than the exposure time to sedimentation (i.e. 15-24 min). Attempts to significantly increase the dwell time of the reaction mass after sedimentation (up to 1 h) leads to the accumulation of the products of the aromatization in the mixture and do not give significant increase in the yield of the target product. The termination of the process immediately after sedimentation 17-atelectasia ADD gives a lower yield of the target product (9.2 g, 79.6%). However, upon dilution of the mother liquor with water unreacted ADD precipitates in the form of crystals, which after separation, washing with water and drying (obtained 1.9 g, 19%) can be re-in, getting a 1.7 g of 17-atelectasia ADD (77.5% re-introduced in ketalization number), which increases the overall output of 17-atelectasia ADD per ADD up to 94.3%.The reaction vessel then was devaluationary at 100-110oC and 90-100oC added 0.3 ml of triethylamine and one portion 27 ml of 45% (by volume) solution of H2O in MeOH, pre-heated to 50 - 60oC. If the mixing is stopped, it is restored through nannou suspension was stirred 2 h at the temperature decreases from the 90oC to 20oC, a white crystalline precipitate was filtered on a porous glass filter and washed 5 times with water (30 ml each time with mixing and pressing of the crystals on the filter. The obtained white powder 17-atelectasia ADD dried to constant weight in a vacuum desiccator (20oC, 2 mm RT. Art. , 12 h). Yield 10.2 g (88% of theoretical), the purity of the obtained product was more than 99%, the main impurity (up to 1%) is the original ADD (by TLC analysis). White crystalline powder, so pl. 168-170oC, Rf0.40 (TLC - plates Silufol UV 254, hexane-acetone-benzene, 45:20:5, two manifestations).Toilet pyridinium used in the reaction in the catalyst can be prepared in advance and can be stored in closed containers for at least 2 years. Toilet pyridinium obtained as follows.To a solution of 20 g of the monohydrate of p-toluenesulfonic acid in 20 ml of ethanol is added over 5 min at 10oC 10.9 g of pyridine. A clear solution is stirred for 1 h at room temperature, the ethanol is evaporated in vacuum to dryness, the remaining crystalline mass is added 30 ml of toluene and again evaporated to dryness to free from an excess of pyridine. This procedure is repeated one more time. PM CaCl2(2 mm RT.art., 12 h). Output tosilata pyridinium in the form of a white or very light cream crystalline powder is 25.3 g (97.3%), so pl. 118oC.Thus obtained 17-atlantal ADD subjected to aromatization in atlantal estrone by the reaction of Dryden.Anion-radicals are formed by the interaction of metallic sodium and diphenyl in diglyme. It was required to provide a slow and uniform addition of 17-atelectasia ADD to the reaction mixture, in which you cannot use significant amounts of diglyme or similar solvent, and the solubility of 17-atelectasia ADD in these solvents is low (50% (w/v) solution of 17-atelectasia ADD in diglyme is formed only at the 120oC). Found the original solution is added dropwise to 50% (w/w) solution of 17-atelectasia ADD in the molten diphenyl. This solution is formed by mixing equal weight quantities of 17-atelectasia ADD and diphenyl when 90-95oC and remains the solution to the 75oC and easily and reliably can be added dropwise at this temperature. The number used in the reaction of diphenyl not increased for dissolution 17 - atelectasia ADD used 2/5 part of tepano, in the course of the reaction.The selection of the target product is produced as follows. To the reaction mixture are added successively lower alcohol, adjusting the rate of addition so that the foaming was not excessive, then add water, then with vigorous stirring was added concentrated hydrochloric acid and maintained at 60-70oC for 1 h, stop stirring and leave to cool slowly. The number added to the reaction mixture of hydrochloric acid and water is minimized so that the water layer is minimal and almost saturated formed during the neutralization of alkali chloride. This provides a stratification of diglyme (mixed with clean water in all respects) and the aqueous layer that is used for partial regeneration diglyme. On the other hand, a large mutual Miscibility 2 layers accelerates the hydrolysis reaction is insoluble in aqueous media 17-atelectasia ADD.To the cooled mixture is added a small (to facilitate regeneration diglyme) the amount of toluene for the selective dissolution of the drop-down together with estrone of diphenyl and the best bundle, stirred the mixture at 40-45oC and from a warm solution of adfilternone estrone.It was found that the number of estrone remaining in the mother solution after separating the main portion of estrone by crystallization from diglyme-toluene mixture is significantly higher than the solubility of estrone in toluene (15 mg/100 ml) and diglyme. The reason for this, apparently, is the presence in the mother solution, a large number of diphenyl significantly increase the solubility of estrone (diphenyl - good solvent for 17 - atelectasia ADD). On the other hand, the selection of this dissolved estrone by extraction in an aqueous solution of sodium hydroxide requires a large amount of aqueous alkali. It was suggested two ways of allocating the residual amount of estrone.1. Extraction of estrone from the organic layer 2-4 ml (1 g extractable estrone) 20-40% aqueous sodium hydroxide solution. Unlike potassium sodium salt of estrone poorly soluble in water. When the specified proportions and volumes is quite complete loss of sodium salt of estrone in the form of a dark viscous oil adhering to vessel walls, and the organic layer (now devoid of estrone) is easily separated by decantation. Sticky residue in the flask under stirring with the acidic aqueous mother liquor obtained in the selection is the release of organic stock solution of diphenyl (and diglyme). This occurs in the process of the proposed regeneration diglyme and diphenyl, consisting in the separation by distillation in 4 fractions diglyme-toluene layer the mother liquor after separating the main portion of estrone by filtration. All these 4 fractions sharply differ in boiling point and can be easily separated through distillation without a column:
1) toluene (distillation at atmospheric pressure);
2) diglyme (low vacuum);
3) diphenyl (in high vacuum);
4) steroids (non-volatile residue).Besides solving the problem of allocation of additional quantities of estrone, this process allows you to regenerate approximately 1/3 used in the reaction of diglyme. The rest of diglyme is located in the water layer of mother liquor. It was possible to regenerate an extra amount of diglyme distillation of the azeotrope of diglyme with water containing 20-40% of diglyme (in the literature there is no information about this azeotrope), and delamination of the last strong alkalinization of distillate (up to 40% concentration of alkali). Regeneration diglyme can significantly reduce the cost of obtaining estrone.The invention is illustrated by the following examples.Example 1. In the reaction th funnel was filled pounded mixture of 16 g 17-atelectasia ADD and 16.7 g of diphenyl. The entire apparatus was purged for 5 min with dry argon and left throughout the reaction under mild (1-2 mm water column) pressure of argon. At the same time began heating oil bath and steam generator. Upon reaching 95oC drip funnel is formed movable transparent melt, and the temperature of the support in the funnel steam before it emptied. Upon reaching in an oil bath of 85oC begin mixing the dark blue reaction mixture, bringing the temperature in the bath to 100-105oC. After stirring at this temperature for 10 min while maintaining the same temperature started adding dropwise from the funnel of a solution of 17 - atelectasia ADD in the molten diphenyl with such speed that constantly remained dark blue color of the reaction mixture, which took 35 minutes Capacity funnel was washed with 5 ml of diglyme, which also has pricipal in the flask.Turning off the heat, waited cooling bath to 80oC (30 min) from the funnel and added dropwise 8.9 ml of methanol, adjusting the rate of addition so that the foaming was not excessive. Under vigorous stirring the reaction mixture thickened waited for the disappearance of blue color and shiny pieces of metal hydroxide C. From the funnel quickly added dropwise 42 ml of water, then formed a solution of brick color temperature in the bath 65oC.Under vigorous stirring was added from the funnel 42 ml of concentrated hydrochloric acid with such speed that there was no boiling mixture. Formed light-brick two-layer mixture, on the border of layers began to fall yellow precipitate (formed estrone), at the bottom of a small amount of heavy white precipitate (NaCl). Maintaining the bath temperature 60-70oC, the mixture was stirred 1 h, after which the stirring was stopped and the entire unit is left overnight to cool slowly.The cooled mixture consists of a yellow semi-solid mass at the top (crystalline estrone and diphenyl in diglyme), colorless acidic aqueous layer in the middle and a small amount of heavy white precipitate at the bottom (NaCl). To the mixture was added 30 ml of toluene to dissolve diphenyl and the best separation, the mixture was mixed at 40-45oC and warm the solution on a porous glass filter was filtered with suction estrone. The crystals on the filter is washed with 10 ml heated to 40-45oC toluene and 20 ml of water and dried 2 h at 90-95oC in a vacuum of 3 mm, before the termination of the deposition on the cold 9.234 g (70.1% of theory) of estrone in the form of white crystalline powder, so pl. 261-262oC, pure by TLC (Rf0.33 (TLC-plates Silufol UV 254, cyclohexane-ethyl acetate, 67:33).The mother liquor consists of organic and aqueous layers. The layers were separated and processed separately.The organic layer is reddish-brown liquid with white crystals in it (diphenyl) was fractionally by distillation. With a bath temperature of up to 130-140oC at atmospheric pressure and then vacuum of 50 mm was distilled toluene (collected 38 ml, 95%), in a deeper vacuum distilled diglyme so when Kip. 86-105oC/27 mm (collected 12 ml, 32%), in the limiting vacuum drove diphenyl so when Kip. 91 - 96oC/3 mm (collected 34.6 g, 92%). A dark resinous residue in the distillation flask is used to allocate an additional portion of estrone. The water layer with strongly acidic reaction (100 ml) was distilled at atmospheric pressure, collecting so Kip. 96-104oC acid azeotrope of water with digimon and stopping the distillation at the beginning of the distillation of the azeotrope of hydrochloric acid. In distilled water (50 ml) was dissolved 20 g of caustic soda; this formed layer of diglyme (18 ml, 49%), which was separated.The residue from the distillation was dissolved in 10 ml of toluene, was added a seed crystal (1 mg tankomaster estrone) and the dark solution was left for 2 days. Dropped Chris is received 0.926 g (7%) estrone, yellow crystalline powder, so pl. 256-257oC.Example 2. The reaction of Dryden, hydrolysis of atelectasia estrone, highlighting the main portion of estrone is produced, as described above. For additional portions of estrone to the mixture of steroids (3.3 g) obtained in a similar experience (8 g 17-atelectasia ADD) after separating the main portion of estrone, in solution in 130 ml of toluene (containing 18 g of diphenyl), was added 4 ml of 20% aqueous NaOH solution (subsequently found that it is better to use a 40% solution) and two-layer mixture was intensively stirred 5 min. Lower aqueous layer turned into a layer of a viscous dark resin, and the organic layer was outdoorsy. The organic layer was separated by decantation, the remaining in the resin flask was added 20 ml of toluene and half the acidic aqueous layer from the mother liquor remaining after separation of the principal amount of estrone (100 ml) and the mixture is vigorously stirred until the disappearance of the resin and formation of two-layer mixture with crystals of estrone on the phase boundary. Estrone was filtered, washed with 10 ml of toluene and 20 ml of water and dried as described above. Received 1.19 g of estrone in the form of a brown powder, which is subject to additional cleaning.Drip thief is whether silica gel and another layer of cotton wool) and poured the powder of the crude estrone. To the bottom of a funnel attached to the flask with toluene, and the upper cut insert a reverse refrigerator. Toluene in the flask intensively boil when fully open tap funnel. A pair of toluene through the bypass in the upper part of the funnel and then into the refrigerator, condense, hot toluene flow to estrone, passes through it, dissolving estrone before saturation, the solution is filtered through cotton wool (and cleaned coal or silica gel, if due) and through the valve flows back into the flask, which is gradually concentrated. After dissolution of all of estrone in the funnel boiling ceased, the flask was cooled and filtered vegascasinoonline estrone, rinsing with a small amount of pure toluene.Due to the very large difference in the solubilities of estrone in boiling and cold toluene extraction is fast, and the output is mainly determined by the purity of initial estrone.Thus, the proposed method allows to carry out the process in the environment of one solvent, slowly and evenly to introduce reagents into the reaction mixture, which provides a smooth and controlled reaction, allows full enough to allocate the target product when using small amounts of reagents is the product to regenerate the expensive reagents, that significantly reduces the cost of obtaining the target product. 1. The method of obtaining D-östra-1,3,5(10)-triene-3-ol-17-she (estrone), including reductive aromatization 17-atelectasia of androsta-1,4-diene-3,17-dione by its introduction into the reaction mixture containing metallic sodium and diphenyl in diglyme at elevated temperatures, and subsequent acid hydrolysis, characterized in that 17-atlantal of androsta-1,4-diene-3,17-dione is introduced into the reaction mixture in the form of a solution in the molten diphenyl in a stream of inert gas.2. The method according to p. 1, characterized in that the reaction mixture contains a quantity of diphenyl less than stoichiometric, the remaining number of diphenyl required for the reaction, add the introduction of the 17-atelectasia of androsta-1,4-diene-3,17-dione in the molten diphenyl.3. The method according to PP.1 and 2, characterized in that a solution of 17-atelectasia of androsta-1,4-diene-3,17-dione in the molten diphenyl performed by mixing equal weight quantities of 17-atelectasia of androsta-1,4-diene-3,17-dione and diphenyl at a temperature above the 75oC.4. The method according to PP.1 to 3, characterized in that the additional amount of estrone remaining in the mother solution after separation osnovnoj is the, for extraction use 20 - 40% aqueous sodium hydroxide solution.6. The method according to PP.1 to 3, characterized in that the additional amount of estrone remaining in the mother solution after separation of the base, is isolated by regeneration diglyme and diphenyl.
< / BR>where R1is CH3or C2C5; R2is HE; R3is N, CH3or CH2CN, or R2and R3together are O; R4is (2-5C) alkylene consists in the fact that the compound of formula II
< / BR>where R1and R2and R3have the previously given meanings, is treated in the presence of artefiera formula III
< / BR>where R4is (2-5C) alkylene, or orthoevra formula IV
< / BR>where R4has previously specified value, or a mixture of the alcohol corresponding to the General formula HOR4OH, where R4has the previously given significance
< / BR>where P1OKSO,-(-)hydroxy,-(-)-C1-4-alkoxy or-(-)benzyloxy; P2- C1-4-alkyl, hydroxy-C1-4-alkyl; P3missing or C1-4-alkyl; P4is hydrogen, oxo or hydroxy; P5- one or two hydrogen atoms, methyl or methylene; P6- hydrogen, which are ligand Poluchenie products, communicating with neuroepithelial receptor
FIELD: organic chemistry, steroids, pharmacy.
SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.
EFFECT: valuable properties of compounds and composition.
4 cl, 3 sch, 1 tbl, 8 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,
(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.
EFFECT: valuable medicinal properties of compounds.
10 cl, 2 tbl, 39 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):
wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.
EFFECT: valuable medicinal properties of compounds, improved method for treatment.
38 cl, 1 tbl, 18 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)
wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.
EFFECT: valuable medicinal properties of compounds.
22 cl, 7 tbl, 41 ex
FIELD: organic chemistry, steroids, chemical technology.
SUBSTANCE: invention describes a method for synthesis of 7-substituted steroid compounds of the general formula (I):
wherein R1 means hydrogen atom (H) or -COR2 group wherein R2 means (C1-C6)-alkyl, (C1-C6)-alkoxy-group; Z1 means -CH2- or wherein R3 is in α-configuration; R3 means H or -COR2; Z2 means -CH-, or Z1 and Z2 mean in common a double bond; Q means ,,,,,,; Y means -CN, -CH2-CH=CH2 or -CHR4C(O)Ar, -CHR4C(O)-(C1-C6)-alkyl, -CHR4C(O)XAr or -CHR4C(O)X-(C1-C6)-alkyl wherein R4 means -O-(C1-C6)-alkyl or aryl X means oxygen (O) or sulfur (S) atom that are intermediate compounds used in synthesis of eplerenon.
EFFECT: improved method of synthesis.
7 cl, 1 tbl, 2 dwg, 20 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.
EFFECT: valuable medicinal and biochemical properties of compounds.
9 cl, 5 dwg, 1 tbl, 10 ex
FIELD: organic chemistry, steroids, medicine.
SUBSTANCE: invention relates to steroid compounds of the general formula (I) given in the invention description wherein R1 means oxygen atom (O); R2 and R3 mean independently hydrogen atom (H), CH3, C2H5, and at least radical among R2 and R3 means CH3 and C2H5; R4 means H. Compounds are useful in treatment associated with androgens, such as androgen deficiency and contraception in males and females.
EFFECT: valuable medicinal properties of compounds.
5 cl, 1 tbl, 7 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention relates to compositions containing 16α-bromo-3β-hydroxy-5α-androstane-17-one semihydrate and one or more excipients wherein the composition contains less 3% of water. Compositions are useful in preparing improved pharmaceutical compositions. Invention describes methods for discontinuous dosing steroid compounds, such as analogs of 16α-bromo-3β-hydroxy-5α-androstane-17-one and compositions useful in such dosing regimens. Also, invention describes compositions and methods for inhibition of pathogenic viral replication, improving symptoms associated with disorders in immune response and modulation of immune response in a patient by using indicated compounds and their analogs. Also, invention describes methods for their preparing and using these immunomodulatory compositions.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.
63 cl, 3 tbl, 13 sch, 13 dwg, 37 ex
FIELD: organic chemistry, steroids, chemical technology.
SUBSTANCE: invention relates to novel effective methods for synthesis of 9,11-epoxy-17α-hydroxy-3-oxopregn-4-ene-7α,21-dicarboxylic acid, γ-lactone, methyl ester (eplerenone). Also, invention describes novel intermediate compounds of the general formula (I): wherein R1 means hydrogen atom (H), -COR4 wherein R4 means (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R3 means (C1-C)-alkyl; Z1 means compound of the formula wherein -O-COR4 is at α-position; Z2 means -CH-, or Z1 and Z2 form in common a double bond; Q means compounds of formulas .
EFFECT: improved methods of synthesis.
28 cl, 3 sch, 17 ex
FIELD: organic chemistry, pharmaceuticals.
SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV including oxidation of compound of formula II , wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.
EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.
8 cl, 46 ex, 9 dwg