The method of obtaining 7-substituted 4-azaandrostane-3-ones and method for producing substituted 7-alkyl-androst-5-ene-3-ones

 

(57) Abstract:

Describes a new method for producing 7-substituted 4-Aza-5-androstane-3-ones and related compounds, which are inhibitors of 5-reductase, which consists in the restoration of the relevant androstenone lithium and liquid ammonia, contacting the product with an isomerizing agent, the oxidation product to scaricati and the interaction of this scaricati with amine with cyclization and formation of 5-Aza-5-androstane-3-ones. 2 S. and 3 C.p. f-crystals, 2 tab.

The invention relates to a new process for the preparation of 7-substituted 4-Aza-5-androstane-3-ones and related compounds and to the use of such compounds as inhibitors of 5-reductase.

It is known that certain undesirable physiological manifestations, such as common acne, hirsutism, typical male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Previous attempts to offer a chemotherapeutic drug to counter the undesirable consequences of hyperandrogenism, led to the discovery not the us, for example, not only counteract the effect of androgens, but in addition have feminizing effects. Also developed non-steroidal antiandrogens such as 4'-nitro-3'-triftormetilfullerenov (Neri, et al., Endo., v. 91, No. 2, 1972). However, these products, although exempt from the hormonal effects are perifericheskie active, competing with natural androgens for receptor locations, and, therefore, tend to demonizirovat owner masculine or fetus is male, the master and feminine.

It is known that the main carrier of androgenic activity in some target organs is a 5-dihydrotestosterone, and that it is formed locally in the target organ under the action of testosterone-5-reductase. It is also known that inhibitors of testosterone-5-reductase will serve to prevent or reduce symptoms of hyperandrogenic stimulation.

The number of 4-Aza-steroid compounds known in the field as an inhibitor of 5-reductase. For example, in U.S. patents 4377584, 4220775, 4859681, 4760071 and articles in J. Med. Chem. 27, p. 1690-1701 (1984) and in J. Med. Chem. 29, 2998-2315 (1986) Rasmusson, et al., U.S. patent 4845104, Carlin, et al. and the U.S. patent 4732897, Cainelli, et al. describe 4-Aza-17-substituted 5-androsten-3-ones and mentioned that they fit on the groin, what hyperandrogenic disease are the result of a single 5-reductase, there are reports that considers the presence of other isomers of 5-reductase both in rats and in humans. For example, Bruchovsky, et al., (J. Clin. Endocrinol, Metab., 67 806-816, 1988) and Hudson (J. Steroid Biochem., 26, p. 349-353, 1937) found the activity of different 5-reductase in the stromal and epithelial fractions in the human prostate. In addition, Moore and Wilson has described two different reductase person with peaks of activity when either pH 5.5 or pH 7-9 (J. Biol., Chem. 251, 19, p. 5895-5900, 1976).

Recently Andrsson and Russel was isolated DNA which encodes a 5-reductase rat liver (J. Biol. Chem. 264, p. 16249-16255, 1989). They found one mRNA, which encodes the reductase as the liver and prostate of the rat. The sequence of this rat gene was later used to highlight prostate cDNA human coding 5-reductase, designated 5-reductase 1" (Proc. Nat' 1. Acad. Sci., 87, p. 3640-3644, 1990).

Later on, another, more rich reductase ( 5-reductase 2) was cloned from human prostate and its properties identified with the form found in crude extracts of a man's prostate (Nature, 354, p. 159-161, 1991).

Later in "Syndromes of Androgen Resistane" - The Biology of Reproduction, v. 46, p. 168-173, (1992), Jean O. Wilson indicated that the enzyme 5-redouane at least two genes for 5-reductase and two different isomers of 5-reductase in humans. Both forms are present in prostate tissue, in which more than 5-reductase 2, and the other isomer of 5-reductase 1, is considered to be more in the tissue of the scalp.

In the treatment of hyperandrogenic painful conditions, such as benign prostate hyperplasia (national Department of standardization), it would be desirable to have one is a real drug that is active against both enzymes 1 and 2 in the prostate, to substantially inhibit the formation of dihydrotesterone (DHT). On the other hand, it would be desirable to have a real drug, which is highly selective for inhibition associated with the scalp of the enzyme 5-reductase 1, for use in the treatment of diseases of the skin and scalp, such as acne and alopecia. This drug can also be used in combination with PROSCAR(finasterid), which is highly selective for the enzyme prostate 5- -reductase 2 for combination therapy in the treatment of national Department of standardization.

Continuously searching for new, more efficient and environmentally ways to obtain 7 - substituted androstane-3-ones, which are effective against both enzymes-R is drostan-3-one, suitable for inhibition of isomers 1 and 2 5- -reductase, and, in particular, is effective in the selective inhibition of 5-reductase-1, associated in the scalp, and inhibiting isomers 1 and 2 during oral, parenteral or topical treatment of benign prostate hyperplasia, acne, hirsutism, typical baldness in men, androgenetic alopecia, prostate, and for the prevention and treatment of prostate cancer.

In accordance with the invention features a method that includes the steps:

a) bringing into contact connections IV

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where

Alk represents a (C1-C4)-alkyl, allyl and (C3-C6-cycloalkyl, and A represents a Deputy, inert under the reaction condition, restoring system containing metallic lithium and liquid ammonia in an inert organic solvent at a temperature in the range from -45 to -78oC for a time sufficient for the stereoselective obtain 7 - connection V

,

b) bringing into contact of the compound V with an agent isomerization of a double bond in an inert organic solvent at a temperature of from 40 to 65oC under conditions in which the radical A is inert during the unity VI with an oxidant in an inert solvent at a temperature in the range from 23oC to 80oC under conditions in which the radical A is inert in a period of time sufficient for the formation of scaricati VII

,

(d) contacting scaricati VII with an amine of the formula R-NH2in which R represents H, (C1-C4)-alkyl, benzyl or allyl, at a temperature of from 100 to 200oC in an inert solvent, under conditions in which A is inert, with the formation of 4-Aza-steroid VIII

,

(e) contacting the compound VIII with a platinum catalyst in an inert organic solvent at room temperature for time sufficient for the formation of 7 - Alk-4-Aza-steroid VII

,

Thus, it is proposed a process comprising stages a) bringing into contact connections IV

,

where Alk is a (C1-C4)-alkyl, alkyl (C3-C6- cycloalkyl, and A represents a Deputy, inert under the reaction conditions, with restoring system containing metallic lithium and liquid ammonia in an inert organic solvent at a temperature in the range from -45 to -78oC for a time sufficient for the stereoselective obtain 7 - connection V

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b) bringing into contact of the compound V with an agent who Yah, in which the radical A is inert, in a period of time sufficient for the formation of isomerizing connection VI

,

c) bringing into contact of the compound VI with an oxidant in an inert solvent at a temperature in the range from 23 to 80oC in the conditions under which the radical A is inert, in a period of time sufficient for the formation of scaricati VII

,

d) bringing into contact scaricati VII with an amine of the formula R-NH2where R represents H, (C1C4)-alkyl, benzyl or allyl, at a temperature of from 100 to 200oC in an inert solvent under conditions in which A is inert with formation of 4-Aza-steroid VIII

,

e) bringing into contact of the compound VIII with a platinum catalyst in an inert organic solvent at room temperature under conditions in which A is inert, in a period of time sufficient for the formation of 7 - Alk-4-Aza-steroid VII

.

Detailed description of the invention and the preferred variants of its implementation.

Used here, the term "(C1-C4)- alkyl denoted, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

Used ZV CLASS="ptx2">

The method of the invention is illustrated in the General scheme of the process is given at the end of the description.

The number of 7-alkyl-17-A

The compounds obtained according to the invention, which also include 7-alkyl group, e.g. methyl, ethyl, isopropyl, tert-butyl, allyl, and in which A has the values set below can be obtained according to the scheme presented in the General drawings on the General scheme of the technological process.

Used herein, the designation Alk 7-substituent in the formula mean (C1-C4)-alkyl, linear or branched, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and cycloalkyl.

Deputy Alk can be entered in ring B 4-Aza-steroid in the General case by the reactions of addition of ORGANOMETALLIC compounds to carbonyl group, for example, through reaction of Grignan, in which 7-carbonyl group can react with a Grignard reagent containing Alk as R-radical and RMgX. For how acceptable are the reactions proceed by a carbonyl group, using ORGANOMETALLIC compounds of lithium and zinc, which are known in the art.

The term "A" is denoted by 17-Deputy, the AI under particular reaction conditions at each stage, represented in the overall scheme of the technological process.

Group A may also be a protected hydroxyl or a protected amino group, which runs the specified sequence of reactions, and subsequently the protective group is removed, or it can be removed during a certain stage provided that will not affect the specified reaction. For example, when A is a 17-0-TBDMS, i.e. tert-butyldimethylsilyloxy, silyl protective group may be removed, for example, during stage circuit ring scaricati VII to 4-azasteroid VIII, so that subsequent stage is performed with 17-OH-connection. Also the original group A can be a precursor to need A group and turn it in passing in one of the stages of the process. For example, when A contains a double bond, for example, in the analog stigmastane, the double bond in the side chain at position 17 can also be oxidized during the formation of scaricati in the transition form VI VII.

Examples of group 17-A include H, a protected hydroxyl group, for example, dimethyl-tert-butylhydroxytoluene, a hydroxyl group, a protected amino group, for example, acetylamino, amino group, (C1-C10)-alkyl, the l-substituted (C1-C10)- alkyl, for example, omega-phenylpropyl, heteroaryl-substituted (C1-C10)-alkyl, for example, omega-(4-pyridyl)-butyl, group, ether carboxylic acids, for example, carbomethoxy, carboxamido group, for example, N-N-diisopropylcarbodiimide group, carboxylate groups, urethane groups, for example, group, tert-butylcarbamoyl, for example, n-tert-BUTYLCARBAMATE, groups, ethers, for example, n-butylacrylate etc.

The starting substances for the process are usually 3-acetoxy-androst-5-ENES, which are known and available.

As can be seen from the General scheme of the technological process, using the General formula in which A has the above-mentioned values, the original 3-acetoxy-androst-5-ene-17-A I are oxidized to the corresponding 5-ene-7-it II by processing, for example, tert-butylperoxide hydrogen and hexacarbonyl chromium, for example, acetonitrile boiling under reflux. In other solvents that may be used included propionitrile, butyronitrile. The reaction temperature usually ranges from 40 to 85oC, and the reaction is carried out in dry conditions, and for its completion, as a rule, it takes about 24 hours

reorganizuemogo connection to a carbonyl group, for example, using the Grignard reaction using, for example, methyl, allyl or cycloalkylation, for example, in anhydrous THF at 0-23oC, with the formation of 7-Alk-7-hydroxicut III. The conditions of the Grignard reaction are conventional and include the use of methylacrylamide, ethylacetamide, allylanisole, cyclopropylmagnesium, etc. Other suitable dry solvent include diethyl ether, dimethoxyethane, di-n-butyl ether. The reaction is carried out without access of moisture, typically at a temperature in the range from 0 to 40oC. Usually for completion of the reaction requires from 6 to 24 hours Can be used for the reaction of addition of other ORGANOMETALLIC compounds by a carbonyl group.

The adduct III is then oxidized, for example, isopropoxy aluminum and cyclohexanone (oxidation Oppenauer), for example, in boiling toluene, with the formation of 7-alkyl-4,6-Dien-3-one IV. Other reagents that can be used are atoxic aluminum or tert-piperonyl aluminum. Other solvents that may be used are methyl ethyl ketone and xylene. Temperature range, as a rule, is the interval from 60 to 120oC, the reaction is carried out stage is the key, when the Grignard adduct IV restore metallic lithium, in liquid ammonia, THF and toluene at -78oC to stereoselective release of 7 - alkyl-5-ene-3-one V. the Other metals that can be used for such restoration, are sodium, potassium and calcium. Other amines which may be used are methylamine and ethylamine. Other solvents that may be used are n-butyl ether and dimethoxyethane. The reaction is usually carried out in anhydrous conditions in the temperature range from 23 to 78oC and for completion of the reaction requires 2-10 PM

In the next stage of the Delta-5 double bond will isomerized to 4-ene VI using DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), for example, in boiling tetrahydrofuran (THF), and get 7-alkyl-4-EN-3-one. Other reagents isomerization, which can be used include diisopropylethylamine and DBU (Aldrich), which represents 1,5-diazabicyclo [4.3.0]non-5-ene. Other solvents that can be used are toluene, and dimethyl ether. The reaction is usually carried out in dry conditions at temperatures in the range from 40 to 60oC and typically requires 1-2 hours to complete the reaction.

C is tilava alcohol, when 80oC with the formation of the corresponding scaricati VII. Other oxidizing agents that can be used include ruthenium tetroxide, and ozone. Other solvents that may be used are CH3CN, CCl4, MeOH and CH2Cl2. The reaction generally requires from 2 to 4 hours to get through.

Processing scaricati the corresponding amine, for example, hydroxychlorides of methylamine and sodium acetate in ethylene glycol at 180oC results in, for example, 4-methyl-4-Aza-androst-5-ene-3-one VIII. Other amines which may be used are ethylamine, ammonium acetate, substituted benzylamine, for example, 4-methoxybenzylamine, etc. Other acceptable reaction solvents include acetic acid and xylene. The reaction is usually carried out at a temperature in the range from 100 to 200oC and requires, as a rule, from 2 to 8 hours to complete.

Structure VIII in turn catalytically hydronaut, for example, Pt, to restore the 5-Delta double bond with formation of 5 - hydrogenated compounds IX. The solvent for the reaction recovery is a typically acetic acid, but is also suitable EtOH. The catalysts for this is hydrogenator with vibration (Shaker hydrogenation apparatus) at room temperature and at a pressure of H2from 40 to 2000 F./inch2(from 0.28 to 14.1 kPa), and usually requires 1 to 24 hours to complete.

Similarly, Sakakibara VII can be treated with ammonia generated from ammonium acetate, with the formation of the corresponding N-H-compound X, which can then be processed similarly to the above-described catalytic platinum in an atmosphere of hydrogen with formation of the corresponding 5-4N-H-compound XI.

Throughout this series of reactions of group 17-A shall be inert or may not affect the conditions of the individual reactions in the introduction of the substituent in position 7 of the steroid ring B. the General scheme of processes A and B are given at the end of the description.

7-alkyl-17-hydroxy-androstane.

The method of the invention is also applicable, for example, when 17-A is a hydroxy-group or a protected hydroxyl group. The corresponding 7-alkyl group, e.g. methyl, ethyl, isopropyl, can be entered according to the scheme presented at the General schemes A and B.

As shown on the diagram of the process A, 3-acetoxy-androst-5-ene-17-one 1 interacts with sodium borohydride in a suitable solvent, for example ethanol, at -10oC, with stereospecific restoration of the 17-ketone to 17-chloride with 2 in a suitable solvent, such as DMF, in the presence of a proton acceptor, for example imidazole at room temperature with the formation of 3.

After protection of the hydroxyl group of this compound is oxidized in position 7 to the corresponding 5-ene-7-it 4 treatment 3 tert-butylperoxide hydrogen and hexacarbonyl chromium, for example in acetonitrile, while boiling under reflux. Alkyl group such as methyl, can be entered at this point by means of the Grignard reaction using, for example, methylacrylamide in anhydrous THF at 0 - 1oC with the formation of 7-methyl-7-hydroxy-adduct 5. This product is the Grignard reaction is then oxidised by isopropoxy aluminum and cyclohexanone (oxidation Oppenauer) in boiling toluene with the formation of 7-methyl-4,6-Dien-3-one 6. It, in turn, restore, using metallic lithium, in liquid ammonia, THF and toluene at -78oC, to selective release of 7-methyl-5-ene-3-one 7. In the next stage of the Delta-5 double bond will isomerized to 4-ene using DBU (1,8-diazabicyclo[5,4,0] undec-7-ene) in boiling tetrahydrofuran (THF) with the formation of 4-ene-3-one 8. Then split the ring A by treatment with potassium permanganate, periodates sodium tert-butyl alcohol at 80oC results in a 4-Aza-androst-5-ene-3-one 10. Then remove the protective TBS group, for example, aqueous HF in acetonitrile at 0oC, and get the alcohol 17-B 11. This alcohol is in turn selectively restore to remove 5-Delta-double bond, and get a 5-hydrogen compound 12.

Analogues of 7-ethyl-cholestane.

Deputy 7-ethyl enter in the number of cholestane as shown in the General scheme of processes C and D, provided at the end of the description, using techniques similar to those described in the General scheme of the process and in schemes A and B.

Source cholesterylester CA commercially available (Aldrich). This connection process using the method of oxidation with hexacarbonyl chromium, tertBUTYLPEROXY hydrogen and acetonitrile (described in ICS Perkin Trans 1985, p. 267, A. J. Pearson) and get 3-acetoxy-cholesterol-5-ene-7-he 1a. This connection may interact with ultilateral Grignard reagent, for example with ethylmagnesium, with the formation of the adduct 2a. This adduct are oxidized under the reaction conditions on Oppenauer education dienone 3a, which can then be subjected to recovery of the metal and ammonia with the formation of 7-ethyl-5-ene-3-one 4a. Compound 4a will isomerized with the PTA can be treated with amines, for example methylamine, with the formation of 4-methyl-4-Aza-compounds 7a with A closed-ring. This connection in turn can be catalytically gidrirovanie with the formation of 7-ethyl-5-alpha-4-methyl-4-Aza-cholestan-3-8a.

Similarly, when processing scaricati 6a with ammonium acetate and acetic acid to obtain the corresponding 4-NH-similar connection 9a, which may be catalytically gidrirovanie with the formation of 7-ethyl-5-4-Aza-cholestan-3-10a.

The above-mentioned 7-substituents can be introduced in all connections, for which here is set to group 17-a, with corresponding similar methods.

The following examples illustrate embodiments of the invention and should not be construed as limiting the scope and essence of the invention.

Given the values of Rfget a standard thin-layer chromatography on silikagelyakh plates. Used for elution of the solvent system is given in round brackets after the values of Rf.

Mass spectral values are given in both FAB, i.e., obtained by bombardment with accelerated atoms, and are in the form of peaks of molecular ions (M+1), which is molekulyarnoe peaks of molecular ions and are indicated in round brackets either in the form (M), or (M+2), i.e., molecular weight MW or MW plus two atomic mass units.

NMR data obtained at 400 MHz in CDCl3and summarized in table.1 NMR data for each connection at the end of the examples. The interaction constant J are given in Hertz.

Example 1. Synthesis of 3-acetoxy-androst-5-ene-17-ol (2).

To a solution of 100 mg (0,303 mmol) 3-acetoxy-androst-5-ene-17-it is 1 in 3 ml E OH if -10oC added under stirring to 22.9 mg (0,606 mmol) of sodium borohydride. After stirring the reaction mixture for half an hour the mixture is diluted with 10 ml of water, the solvent is ethanol removed under vacuum and the residue extracted with ethyl acetate. The organic layer was washed with aqueous Na2CO3, saline solution, dried over sodium sulfate, concentrate, get in the crude residue mentioned in the title compound 2. Connection structure confirmed by proton NMR spectrum.

Example 2. Synthesis of 17-tert-butyldimethylsilyl ester 3-acetoxyethyl-5-ene-17-ol (3).

To a solution of androstane-17-ol 2 obtained in example 1, 4.5 g (13,55 mmol) dissolved in 50 ml of dimethylformamide at 23oC added 2.76 g (40,65 mmol) of imidazole and then 3,063 g (20,32 mmol) tert-butyldimethylsilyloxy. R is camping stirred for another night. The mixture is then poured into 1 l of water, the solid is filtered off and washed with water. The solid is dissolved in ethyl acetate, the organic layer washed with brine and dried over sodium sulfate, concentrate, and get protected silyl group 7-ol-3 connection named in the title. Proton NMR confirmed the structure.

Example 3. Synthesis of 17-tert-butyldimethylsilyl ester 3-acetoxy-androst-5-ene-7-one-17-ol (4).

To a solution of protected TBMS - group 17-ol 3 of example 2, containing 5.6 g (12,55 mmol) in 100 ml of acetonitrile, 23oC add 90% tert-butylperoxide hydrogen 3,958 g (43,92 mol) and 138 mg of hexacarbonyl chromium. After boiling the mixture under reflux in nitrogen atmosphere for 24 h, the reaction mixture was poured into 1 l of water, the solid is filtered off, the residue was washed with 500 ml of water, and the residue is dissolved in 350 ml of methylene chloride. The organic layer is washed with brine, dried over sodium sulfate and concentrate, get a raw substance. Thin layer chromatography (hexane: ethyl acetate, 3: 1, silica gel) shows the presence of the original substance. The solid is purified column chromatography on silica gel with elution 7% atlatna.

Example 4. Synthesis of 17-TBMS ester of 3,7-dihydroxy-7-methyl-androst-5-ene-17-ol (5).

To a solution of the product 4 from example 3, containing 440 mg (0,956 mmol) of the substance in dry tetrahydrofuran, at 0oC is added dropwise over 5-10 min methylaniline. The reaction mixture is then continued to stir at room temperature for 24 h and then poured into a saturated aqueous solution of ammonium chloride. The solvent THF is removed under vacuum, and the aqueous phase extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated and get the crude product. Proton NMR confirms the structure named in the title compound 5, which is used in the next stage without additional purification.

Example 5. Synthesis of 17-tert-butyldimethylsilyl ester 7-methyl-androst-4,6-Dien-3-one-17-ol (6).

The above-mentioned reaction product of a Grignard reagent 5 (3.5 g, 7,142 mmol) is dissolved in 50 ml toluene and 50 ml of toluene and 50 ml of cyclohexanone and 20 ml of solvent is distilled off under vacuum. To the residue add 4,54 g isopropoxide aluminum, and the reaction mixture is boiled for night - for 15 hours the Mixture is cooled, diluted with ethyl acetate, washed with natinalities, salt solution, and orgpromaudit salt solution, dried, and purified column chromatography on silica gel, elwira 5% EtOAc in hexane, and get named in the title compound 6.

Example 6. Synthesis of tert-butyldimethylsilyl ester 7-methyl-androst-5-ene-3-one-17-ol (7).

To a solution of 370 mg of compound 6 of example 5, 5.5 ml of ammonia, and 1 ml of toluene, 1 ml of THF add small pieces 50 ml of metal lithium. After mixing blue solution for 2 h add a solution of 1,2-dibromethane in 2 ml of THF. After stirring the solution at -78oC for 10 min add 250 mg of ammonium chloride and the mixture is stirred for 10 minutes, the Excess ammonia is removed by evaporation in nitrogen vapor. The reaction mixture was diluted with brine, extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated, get a raw substance 7.

Example 7. Synthesis of tert-butyldimethylsilyl ester 7-methyl-androst-4-EN-3-one-17-ol (8).

To a solution of compound 7 of example 6, containing 432 mg of the compound in 4 ml of THF, under nitrogen atmosphere with stirring, add 150 μl of DBU (1,8-diazabicyclo[5.4.0] -undec-7-ene). The mixture is refluxed for 1.5 h, then cooled and diluted with a solution of NH4Cl. Dissolve is the target, dried and concentrated under reduced pressure to get crude compound. Named in the header 8 product purified by chromatography on silica gel, using as eluent 10% EtOAc in hexane.

Example 8. Synthesis of 17-(tert-butyldimethylsilyloxy) -7-methyl-5-oxo-A-nor-3,5-secondrate-3-OIC acid (9).

To a solution of 884 mg of compound 8 in 15 ml of tert-butyl alcohol at 80oC add 248 mg of sodium carbonate in 1.5 ml of water, and then added dropwise over 15-20 min the mixture 2,273 g periodate sodium and 16.8 mg of potassium permanganate in 8 ml of water. The reaction mixture is heated at 80oC for 2 h, cooled, filtered, the residue is washed with water, and then the extract was concentrated under vacuum. The extract is acidified with aqueous HCl, extracted with ethyl acetate, and the organic layer washed with aqueous NaHSO3, saline solution, dried and concentrated, to obtain crude compound 9. Proton NMR confirmed the expected structure.

Example 9. Synthesis of tert-butyldimethylsilyl ether, 4,7-dimethyl-4-Aza-androst-5-ene-3-one-17-ol (10).

To a solution of compound (9), 840 mg, in 5 ml of ethylene glycol added 1.5 g of sodium acetate and 737 mg of methylamine hydrochloride. After stirring the reaction mixture for 4 h € crude named in the header of the connection 10. Proton NMR confirms attributed to him structure.

Example 10. Synthesis of 4,7-dimethyl-4-Aza-androst-5-ene-3-one-17-ol (11).

To a solution of 700 mg of compound 10 of example 9 in 20 ml of acetonitrile at 0oC add 500 ál of aqueous HF. After stirring the reaction mixture for 1 h HF is neutralized with an aqueous solution of sodium carbonate, diluted with water, acetonitrile removed under vacuum, and the residue is extracted with ethyl acetate. The organic layer is dried, concentrated, and get soggy named in the title compound 11, which is then purified by preparative chromatography on silica gel using mixtures of chloroform with acetone in a ratio of 3:1.

Example 11. Synthesis of 4,7-dimethyl-4-Aza-androstane-3-one-17-ol (12).

To a solution of compound 11 of example 10 containing 350 mg of the compound in 10 ml of acetic acid, add 100 mg of catalytic platinum dioxide, and the resulting mixture is pumped and passed with hydrogen. The reaction mixture was shaken overnight at room temperature under hydrogen pressure of 40 pounds/inch2(0,28 kPa). The solution is filtered and concentrated to residue. The residue is treated with ethyl acetate, the organic layer is then concentrated under vacuum, shaky in the header of the connection 12. Mass spectrum: 320, (M+1).

In table. 1 shows the proton NMR (400 MHz in CDCl3for each connection. In the data s - singlet, d - doublet, m - multiplet, J is the interaction constant. Absorbance values are given in Delta units () and are illustrated for the methyl protons of the corners of the ring C-18, C-19 and C-21, and protons associated only with these parts of the molecule.

The numbering of the atoms in the steroid is given in accordance with the following structural formula.

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Additional experimental data.

Example 12.

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1,083 ml liquid NH3placed in a 5 l 3-necked round bottom flask, equipped with reflux condenser with dry ice and a mechanical stirrer and stirred in a bath at -78oC. Type of 69.2 g of compound I in 181 ml of toluene and 181 ml of THF (both solution pre-purge N2). Add 12,38 g of lithium wire (2,74 m, 11,5 equiv.) remove bath and boil blue solution under reflux for 3 h Then the reaction mass is stirred in a bath of dry ice/acetone and quenched by slow addition of 74.3 ml dibromethane 309 ml of degassed THF, stirred for 10 min and treated with 46 g of solid NH4Cl, stirred for 10 miin). Diluted with 3 l of EtOAc, separating the upper layer re-extracted with 3 l of EtOAc, collected organic extracts, dried over MgSO4, filtered through Na2SO4and evaporated, dried in vacuum and using the compound obtained directly in the next stage of the synthesis in the form of a dark orange foam.

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to 70.9 g of compound II (5,6steroid) is dissolved in 619 ml of degassed THF, add 29 ml of DBU and refluxed for 4 hours Then the mixture was stirred at room temperature overnight. Add 325 ml of a saturated aqueous solution of NH4Cl, diluted with EtOAc, separated layers, then re-extracted with an aqueous solution, the combined organic layers washed with saturated brine, dried over MgSO4. The mixture is filtered and evaporated, dried in vacuo and was isolated by TLC on silica gel, elwira 10% EtOAc/hexane, receive and 67.2 g butter dark orange color.

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73,57 g (0,165 mol) of compound III (3-one steroid) is dissolved in 95,6 m t-BuOH in a 3-l 3-necked flask. Add to 25.8 g of Na2CO3in 120 ml of H2O and heated to 80oC under stirring. To the reaction mixture slowly add the hot solution 244 g of Na2IO4(pre-heated at parout the reaction mass under reflux for 1-2 h and then the reaction mass is then cooled and filtered through a mesh filter to remove t-BuOH, extracted with CH2Cl2and bring the pH to 3 with a 2.0 NHCl. Thrice extracted with CH2Cl2, washed with 5% NaHSO3, saturated brine, dried and evaporated obtaining of 62.3 g of white foam. The yield of 83.4%.

Elemental analysis for C26H48O4Si:

Calculated,%: C 69,78; H 10,41.

Found,%: C 67,04; H 10,26.

Example 13. Synthesis of 7-arseholery-3-acetate (1).

Cholesterylester (HA) is a compound known in this field of chemistry, and it can be oxidized to the famous 7-oxopropanal 1 in the manner similar to that described above (article Pearson log JCS Parkins).

Example 14. Synthesis of 7-ethyl-7-hydroxycholesterol (2).

To a solution of compound 1 from example 1 in the amount of 5.0 g (11,32 mmol) in dry tetrahydrofuran at 0oC added dropwise at 56.6 ml of methyl etermine (1 M) within 5-10 minutes the Reaction mixture was then stirred at room temperature for 24 h, then poured into a saturated aqueous solution of ammonium chloride. Remove the THF under vacuum and extracted the aqueous phase with ethyl acetate. The organic layer was washed with brine, dried and concentrated to obtain a light yellow foam. R1= 0,2 (30% EtOAc/hexane). Range PMR confirmed structure. Synthesis of 7-ethyl-cholesterol-4-Dien-3-one-(3).

The product of the Grignard reagent 2, 5,13 g (11.9 mol) is dissolved in 50 ml of toluene and cyclohexanone, and about 40 ml of the solvent is evaporated in vacuum. To the reaction mass is added 7.2 g of isopropoxide aluminum and boil it under reflux for 15 hours the Mixture is cooled, diluted with ethyl acetate, washed with tartrate of potassium (sodium), brine, the organic layer was concentrated in vacuo and the residue is distilled. The residue is extracted with ethyl acetate. An ethyl acetate layer was washed with brine, dried and purified column chromatography on silica gel, elute with 5% EtAOc/hexane to obtain specified in the title compound 3. Rf= 0,58 (20% EtOAc/hexane). Mass spectrum: 412 (M = 1) FAB, the calculated 411,9.

Example 16. Synthesis of 7-ateljeest-5-EN-3-one (4).

To a solution consisting of 3.1 g of compound 3 from example 3 in 46 ml of ammonia, 10 ml of tetrahydrofuran and 10 ml of toluene, add 449 g of lithium metal in the form of small pieces. After mixing blue solution for 2 h at -78oC add a solution of 1,2-dibromethane in 2 ml of tetrahydrofuran. After stirring the solution at -78oC for 10 min add 2.1 g of ammonium chloride, and the mixture is stirred for 10 minutes, Excess is the acetate. The organic layer was washed with brine, dried and concentrated, resulting in a receive connection 4 in the form of a crude brown viscous liquid, which is used as such in example 5. The value of Rfis 0.70 (20% solution of ethyl acetate in hexane). Get the following mass spectrum: 412 (ionization by electron impact); calculated molecular weight MW was 412,70.

Example 17. Synthesis of 7-atilhan-4-EN-3-one (5).

To a solution of compound 4 from example 4, in the form of 3.1 g in 30 ml of tetrahydrofuran, add 1.1 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, in a nitrogen atmosphere with stirring. The mixture is heated in a vessel under reflux for 1.5 h, then cooled and diluted with a solution of ammonium chloride. Then tertrahydrofuran ring the solvent is removed under vacuum, and the residue is extracted with ethyl acetate. The organic layer is then washed with water, brine, dried and concentrated under reduced pressure, resulting in a gain of crude viscous oily substance. Product named 5 purify by chromatography on silica gel using as eluent a 10% solution of ethyl acetate in hexane. Get mass spectral line 412 (electron impact ionization is and in hexane).

Example 18. Synthesis of 7-ethyl - 17-(6-methyl-2-heptyl)-5-oxo-A-nor-3,5-secondrate-3-OIC acid (6).

To a solution consisting of 1.0 g of compound 5 in 18 ml of tert-butyl alcohol at 80oC add 300 mg of sodium carbonate in 1.8 ml of water, and then added dropwise over 15-20 min the mixture consisting of 2,74 g periodate sodium from 20.3 mg of potassium permanganate in 15 ml of water. The reaction mixture is heated at 80oC for 2 h, cooled, filtered, the residue is washed with water, and then the filtrate is concentrated under vacuum, acidified with aqueous HCl solution, extracted with ethyl acetate, and the organic layer was washed with aqueous solution of NaHSO3, brine, dried and concentrated, to give crude compound 6. Proton nuclear magnetic resonance confirmed the presence of the proposed structure. In terms of ionization fast atom bombardment the value of the ratio of mass-to-charge m/z of the molecular ion are equal 434 (M+2); calculation get 432,69.

Example 19. Synthesis of 7-ethyl-4-methyl-4-assholes-5-ene-3-one (7).

To a solution of compound 6, taken in amounts of 500 mg or 10 ml of ethylene glycol, add 1.3 g of sodium acetate and 1.0 g of methylamine hydrochloride. After stirring reactioncontinue, in result get soggy named connection 7. Proton nuclear magnetic resonance confirmed the presence of the proposed structure. The value of Rfis 0.70 (20% solution of ethyl acetate in hexane). Mass spectral ratio mass-to-charge m/z ion (fast atom bombardment) is 429 (M+2); calculation get 427,72.

The calculation for C29H49NO:

Calculated,%: C 81,44; H 11,55; N - 3,27.

Found,%: C 82,19; H 10,92; N - 3,11.

Example 20. Synthesis of 7-ethyl-4-methyl-4-assholestar-3-one (8)

To a solution of compound 7 of example 7, prepared from 180 mg in 5 ml of acetic acid, added 54 mg of platinum dioxide, and the resulting mixture is pumped out and rinsed with hydrogen. The reaction mixture was shaken over night at room temperature in the environment of hydrogen. Filter, wash the solid with ethyl acetate; combined an ethyl acetate layers washed with aqueous solution of NAHCO3, brine, dried, concentrated to obtain the titled compound 8. Mass-spectral analysis with ionization fast atom ratio of mass-to-charge ion m/z found equal 431 (M+2); calculation get 429,74.

The results of the analysis for C29H51NO:
the t-5-ene-3-one (9).

Scaricato 6 in the amount of 0.5 g and ammonium acetate in the amount of 0.5 g in 3.5 ml of acetic acid is heated in a vessel under reflux for 3 hours, the Reaction mixture is cooled, water is added and then extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to obtain residue, which elute in the column with silica gel, 10% solution of ethyl acetate in hexane, resulting in the pure titled compound 9, the melting temperature is 147 - 149oC. Mass spectral analysis receive 414 (M+1); calculation are 413,69. The value of Rfis 0.45 (30% solution of ethyl acetate in hexane).

The results of the analysis for C28H49NO molecular weight 413,69:

Calculated, %: C 81,30; Of 11.45 H; N 3,39.

Found, %: C 81,30; H 11.87 Per; N 3,45.

Example 22. Synthesis of 7-ethyl-4-Aza-5-cholestan-3-(10).

Following the General method described in example 8, compound 9 catalytically hydronaut with obtaining these compounds 10. Chromatography on silica gel with elution 50% solution of ethyl acetate in hexane get pure product; melting point is 169 - 170oC.

The results of the analysis for C28H49With NO molecularium analysis of the value of the ratio of mass-to-charge are equal 416 (M+1).

The value of Rfis of 0.30 (30% solution of ethyl acetate in hexane).

Example 23. Synthesis of 7-allyl-3,7-dihydroxyaryl-5-ene (11).

Following the same General method of carrying out the Grignard reaction described in example 2, methyl Allemagne interacts with compound 1 in dry tetrahydrofuran, resulting in receive product named 11. Proton nuclear magnetic resonance confirmed the expected structure.

Mass-spectral analysis of the value of the ratio of mass-to-charge are equal 441 (M+1); calculated receive 440,71. The value of Rf0.25 (30% solution of ethyl acetate in hexane).

Example 24. Synthesis of 7-alligant-4,6-Dien-3-one (12).

Following the same General methods of carrying out the oxidation reaction of Oppenauer set forth in example 3, compound 11 was oxidized, resulting in getting a named connection 12. Proton nuclear magnetic resonance confirmed the presence of the proposed structure, and mass-spectral analysis set (fast atom bombardment) that the ratio of mass to charge is 423 (M+1); calculated received 422,35. The value of Rfis 0.78 (30% solution of ethyl acetate in hexane).

f0.5 (5% solution of ethyl acetate in hexane).

Example 26. Synthesis of 7-alligant-4-EN-3-one (14).

Following the General method of isomerization catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-Yong, in the conditions of example 5 similarly treated with compound 13, resulting in a get a named connection 14. Mass spectral analysis by fast atom bombardment the value of the ratio of mass-to-charge are equal to 425 (M+1); calculated receive 424,37. The value of Rfis 0.45 (5% solution of ethyl acetate in hexane).

Example 27. Synthesis of 7-profilelist-4-EN-3-one (18).

7-Allyl-northward (compound 14) in an amount of 1.0 g, 5 ml of ethyl acetate and 50 mg of chloride triphenylphosphine (Wilkinson catalyst) is stirred for 2 h (in the environment of H2). The products of the reaction is filtered through silica gel with a volume of 25 ml and evaporated to dryness, resulting receive a fairly pure product named 18, which is confirmed by conducting proton nuclear magnetic resonance. Mass-spectral analysis of the value of the ratio of mass-to-charge are equal 427 (M+1); calculated receive 426,39. The value of Rf0.15 (5% CLASS="ptx2">

Following the General method of example 6, which describes the conduct of oxidative rupture of the ring And the connection 18 (7-through similar) should be treated in a similar way, resulting in a gain above scaricato 19. Proposed structure is confirmed proton nuclear magnetic resonance. Mass-spectral analysis of the value of the ratio of mass-to-charge are equal 447 (M+1) (fast atom bombardment); calculation get 446,38. The value of Rf0.1 (20% solution of ethyl acetate in hexane).

Example 29. Synthesis of 7-propyl-4-methyl-4-assholes-5-ene-3-one (20).

Following the General method of example 7, compound 19 is treated similarly by methylamine hydrochloride and sodium acetate in ethylene glycol, resulting in a gain above the liquid product 20. Proposed structure is confirmed proton nuclear magnetic resonance. Mass-spectral analysis of the value of the ratio of mass-to-charge are equal 442 (M+1) (fast atom bombardment); calculation get 441,74. Conduct analysis for carbon, hydrogen and nitrogen for these compounds, considering it containing 0.2 parts of H2O; the value of the molecular weight are equal 441,74:

Calculated,%: C 80,91; H 11,63; N 3,15.

Example 30. Synthesis of 7-propyl-4-methyl-4-Aza-5-cholestan-3-(21).

Following the same General method of example 8, compound 20 catalytically hydronaut in acetic acid, resulting in a gain of the mentioned fluid connection 21. Proton nuclear magnetic resonance confirmed the expected structure. Mass-spectral analysis of the value of the ratio of mass-to-charge are equal 444 (M+1) (fast atom bombardment). For these compounds are analyzed for carbon, hydrogen and nitrogen; the molecular weight was 443,41:

Calculated, %: C 81,19; H 12,05; N 3,16.

Found,%: C 80,78; H 12,06; N 3,22.

The value of Rfis 0.17 (20% solution of ethyl acetate in hexane).

Example 31. Synthesis of 7-propyl-4-assholes-5-ene-3-one (22).

Following a similar method of example 9, compound 19 is treated with ammonium acetate in acetic acid, resulting in getting a named connection 22. By recrystallization from a mixture of ethyl acetate with diethyl ether to obtain white crystalline solid with a melting point 91-94oC. Analysis for carbon, hydrogen and nitrogen is carried out, considering the mentioned substance is a hydrate containing 0.25 H2O; calculated molecularly analysis of the value of the ratio of mass-to-charge are equal 428 (M+1).

Example 32. Synthesis of 7-propyl-4-Aza-5-cholestan-3-(23).

Following the same methodology described in example 8, compound 22 catalytically hydronaut, resulting in getting a named connection 23; melting point is 65-68oC. Analysis for carbon, hydrogen and nitrogen spend, considering a named connection hydrate containing 0.25 H2O:

Calculated,%: C 80,21; H 11,95; N 3,23.

Found,%: C 80,20; H 12,14; N 3,07.

Spend proton nuclear magnetic resonance. Mass-spectral analysis of the value of the ratio of mass-to-charge are equal to 430 (M+1); calculated molecular weight is 429,40. The value of Rfis 0.12 (20% solution of ethyl acetate in hexane).

Example 33. Synthesis of 7-methyl-7-hydroxycholesterol (24).

Following the same methodology of carrying out the Grignard reaction described in example 1, cholesterylester-7-he I is subjected to interaction with methyl-Metalmania doing it in the standard conditions of the Grignard reaction, resulting in getting a named connection 24 in the form of solids. Nuclear magnetic resonance confirms the proposed structure, and mass spectral analysis confirmed the molecular weight.

Primetouch the reaction of the Grignard reagent 24 is subjected to oxidation Oppenauer, in the result, get a named connection 7-metalholic-4,6-Dien-3-one 25.

Example 35. Synthesis of 7-metalholic-5-ene-3-one (26).

Following a similar method of example 4 to restore using metal and ammonia, the connection 25 is treated similarly lithium in ammonia, tetrahydrofuran and toluene, resulting in a get a named connection 26.

Example 36. Synthesis of 7-metalholic-4-EN-3-one (27).

Following the General method of isomerization of example 5 using 1,8-diazabicyclo[5.4.0] undec-7-ene in tetrahydrofuran, the connection 26 is treated in a similar way, resulting in getting a named connection 27.

Example 37. Synthesis of 7-methyl - 7-(2,6-dimethyloctyl)-5-oxo-A-nor-3,5-secondrate-3-OIC acid (28).

Following the General method of example 6 by oxidative destruction of the ring A, the connection 27 is processed in the same way, resulting in a gain above scaricato 28. Proton nuclear magnetic resonance confirmed the expected structure.

Example 38. Synthesis of 7-methyl-4-assholes-5-ene-3-one (29).

Following the General method of example 9, compound 28 similarly treated with ammonium chloride in uksusnaya mass-to-charge ion m/z (fast atom bombardment) found equal 400,2 (M+1), (M+2); calculating receive 399.

Example 39. Synthesis of 7-methyl-4-assholestar-3-one (30).

Following the same General method of example 8, compound 29 catalytically hydronaut in acetic acid, resulting in getting a named connection 30. Mass-spectral analysis with ionization by electron impact the value of the ratio of mass-to-charge ion are equal 401, calculation get 401.

Example 40. Synthesis of 7-methyl-4-methyl-4-assholes-5-ene-3-one (31).

Scaricato 28 is treated in a similar manner as in the case of example 7, resulting in the pure titled compound 31. Mass-spectral analysis of the value of the ratio of mass-to-charge ion fast atom bombardment are equal 414 (M+1); calculated receive 413.

Example 41. Synthesis of 7-methyl-4-methyl-4-Aza-5-cholestan-3-(32).

Following the same General procedure described in example 8, compound 31 catalytically hydronaut, resulting receives the name of the connection 32. Chromatography on silica gel with elution 30% solution of ethyl acetate in hexane get pure product. Mass-spectral analysis (ionization by electron impact) the value of the ratio of mass-to-charge are equal 415; calculation of floor-4-assholes-5-ene-3-one 33, in the result, get a named connection 34 (U.S. patent N 3264301 issued to Dorenbos (Doorenboos) and an article in the journal J. Org. Chem. 1961, v. 26, p. 4548). The connection 33 is heated at 70oC with a mixture consisting of pyridinium of bichromate and tert-butylhydroperoxide in benzene for 3-4 h, resulting in a receive connection 34.

Example 43. Synthesis of 7-acetoxy-4-methyl-4-Aza-5-cholestan-3-(37).

The connection 34 hydronaut similar to the method of example 8, resulting in a gain of 7-H-similar 35 and 7 olove connection 36. The acylation of compound 36 with acetic anhydride in presence of pyridine, 4-dimethylaminopyridine in methylene chloride at 23oC for 24 h are called the connection 37.

Example 44. Synthesis of 7-methyl-4-Aza-5-cholesterol-1-EN-3-one (49).

To a solution consisting of 280 mg (0,698 mmol) of compound 30, which is in 4 ml of toluene, add 178,8 mg of 2,3-dichloro-5,6-dicyan-n-benzoquinone, 0,7186 mg bis-trimethylsilyltrifluoroacetamide and 8,163 mg triperoxonane acid, and the reaction mixture was stirred at room temperature for 24 hours Add to 8.1 mg methylacetoacetate, and the reaction mixture is heated in a vessel under reflux for 24 hours of Content is cooled, diluted with et is at over magnesium sulfate and concentrated to obtain an oily substance. The crude compound purified preparative thin-layer chromatography on silica gel, elute with a mixture of CHCl3with acetone, taken in the ratio of 3:1, resulting in a pure connection 49, in the case of which the data of proton magnetic resonance confirm the correctness of the proposed structure.

In table. 2 shows specific values of the proton nuclear magnetic resonance (400 MHz, CDCl3) corresponding to each connection. Data are presented with the following abbreviations: s - singlet, d - doublet, m - multiplet, J - constant communication. Absorption values are given in units of Delta () and are illustrated for C-18, C-19 and C-21 corner of the ring methyl protons and the protons associated with specific protons of the molecule.

The numbering adopted for 4-Aza-steroid, shown in the following diagram:

3

1. A method of obtaining a 7-substituted 4-Aza-5-androstane-3-ones of General formula IX

< / BR>
where Alk - C1-C2-alkyl;

A - hydroxy, a protected hydroxy-group, C1- C10-alkyl, optionally substituted by protected hydroxy-group,

characterized in that the conducting stage

a) contacting compounds of General formula IV

< / BR>
DG is ammonia, in an inert organic solvent at a temperature in the range (-45) - (-78)oC for a time sufficient for the stereoselective obtain 7-compounds of General formula V

< / BR>
where Alk and A have the above values,

b) contacting the obtained compound Y with the agent isomerization of a double bond in an inert organic solvent at a temperature (40 - 65)oC, the radical A has A protected hydroxy-group, in a period of time sufficient for the formation of isomerizing compounds of General formula VI

< / BR>
where Alk and A have the specified values

(C) contacting the compound VI with an oxidant in an inert organic solvent at a temperature of (23 - 80)oC for a time sufficient for the formation of scaricati General formula VII

< / BR>
where Alk and A have the above values,

d) contacting the resulting scaricati VII with an amine of the formula R - NH2where R represents H, C1- C4-alkyl, benzyl or allyl, at a temperature (100 - 200)oC in an inert solvent, and the radical A has A protected hydroxy-group, with the formation of 4-Aza-steroid of General formula VIII

< / BR>
where Alk, A and R have the above values,

e) contacting sedim radical A has A protected hydroxy-group, in a period of time sufficient for the formation of the target compounds IX.

2. The method of obtaining substituted 7-alkyl-androst-5-ene-3-ones of General formula V

< / BR>
where Alk - C1-C2-alkyl;

A - hydroxy, a protected hydroxy-group, C1- C10-alkyl, optionally substituted by protected hydroxy-group,

characterized in that conduct the contacting compounds of General formula IV

< / BR>
where Alk and A have the above values,

with the regenerative system comprising metallic lithium and liquid ammonia in an inert organic solvent at a temperature (-45) - (-78)oC for a time sufficient for the stereoselective formation of the target product V.

3. The method according to p. 2, wherein Alk represents methyl.

4. The method according to p. 1 or 2, characterized in that A represents O-tert.butyldimethylsilyl or 6-methyl-hept-2-yl.

5. The method according to p. 4, characterized in that A represents a 6-methyl-hept-2-yl.

 

Same patents:

- substituted 4-aseankorea" target="_blank">

The invention relates to a new method of obtaining derivatives 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- single or double bond; and their salts

The invention relates to new derivatives of 4-aseankorea General formula (1),

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

The invention relates to the field of veterinary medicine and can be used for contraception animals

The invention relates to the synthesis of biologically active analogues of steroid hormones, specifically to obtain 6-oxa-8-isanalogous steroid estrogens, having hypolipidemic activity and which intermediate compounds for the synthesis of other classes of substances

The invention relates to a series of new derivatives of steroids, which have the ability to suppress the activity or action of testosterone-alpha-reductase and therefore can be used for the treatment or prevention of prostate hypertrophy

The invention relates to covered bridge in position 1417thestratriene General formula I

< / BR>
where

if OR3is set tothen

R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3is in "beta", then

R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,

the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of Lech
The invention relates to the field of biotechnology and can be used in pharmaceutical, microbiological and chemical industry for preparation of intermediates for the synthesis of steroid drugs

The invention relates to the field of steroid compounds, such as esters of organic acids with alcohols of General formula I

< / BR>
(I) where R1methyl or ethyl;

G is phenyl, substituted in position 4 by the radical, selected from dialkyl(C1-C4)amino, alkyl(C1-C4)thio, acyl(C1-C4);

X means WITH-A-Z group, where a linear aliphatic divalent radical WITH1-C6Z denotes-COOH or SO3H-group, which may be in the form of a salt of an alkali metal;

Y means WithCH; CH=CH2; -CH=CH-CH3;WITH1;C-CH3wavy line in position 13 means that R1can beor-position

The invention relates to the chemistry of steroid compounds astranova number and relates to an improved method for semi - treatment extra-1,3,5(10)-triene-3-ol-17-she (estrone) of formula I:

< / BR>
(I)

Estrone is a key compound in the synthesis of a large number of drugs astranova number, for example, estradiol dipropionate, methylestradiol, ethinyl estradiol, penalolen, retabolil, cerabolini [1]

Drugs astranova series are also used as the estrogen component (levonorgestrel, methyl ether of estradiol), oral contraceptives (ipankonin, limovan)

The invention relates to the chemistry of astronav and relates to an improved method for obtaining variety-4-ene-3,17-dione (astrantia) of the formula (I)

< / BR>
(I)

Variety-4-ene-3,17-dione is used as an intermediate in the industrial synthesis of norethisterone and its acetate [1] used in medicine as gestagenna funds or gestagenna component in oral contraceptives

The invention relates to new steroid compounds exhibiting valuable pharmacological properties
The invention relates to biotechnology and can be used in pharmaceutical, microbiological and chemical industry for preparation of intermediates for the synthesis of steroid drugs

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) ,

(5) ,

(6) ,

(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

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