Antiandrogenna connection predecessor antiandrogenna compounds, pharmaceutical compositions

 

(57) Abstract:

Describes the new antiandrogenna compounds of General formula I, where the values of R4, R6, R17specified in paragraph 1 of the formula. Connections provide effective antagonistic effect and virtually no agonistic properties. Also described predecessor antiandrogenna compounds and pharmaceutical compositions based on compounds of General formula I, which are used for the treatment of androgen-dependent diseases. 5 S. and 3 C.p. f-crystals, 6 PL.

The invention relates to new inhibitors of the activity of sex steroid hormones, such as antiandrogenna compounds which provide effective antagonistic effect and virtually no agonistic properties. In particular, some preferred modes of carrying out the invention relates to certain analogs of testosterone, which have high affinity for the androgen receptor but does not activate these receptors. Some antiandrogens can also inhibit the reproduction of sex steroid hormones or their precursors.

During treatment some androgenicity it is desirable not only to block access to the androgen receptor with "anti-androgens", preventing androgens contact with these receptors and activate them, but also to reduce the concentration of androgens, are able to activate the receptor. Free androgen receptors, even in the absence of androgen, can be biologically active. For this reason, antiandrogens that bind and block the receptors may provide better therapeutic results than treatment, which only leads to the suppression of the reproduction of androgens.

Antiandrogens can have a significant therapeutic effect, slowing down or stopping for androgen-dependent diseases, in particular diseases, occurrence or development which promotes activation of the androgen receptor.

Preferably, antiandrogen used in the treatment for reducing the activity of the androgen receptor is, not only would have a good affinity to the androgen receptor, but does not evince a noticeable potential androgenic activity. The first refers to the ability of antiandrogen to contact the androgen receptor, thereby blocking the access of androgens to the receptor. The latter refers to the effect that antiandrogen has on the receptor, as soon as it svyazyvaetsya"), which leads to unwanted activation of the androgen receptor, the activity of which they must suppress. In other words, antiandrogens with potential androgenic activity can successfully join the androgen receptor, blocking access to specific receptors of the natural androgen, which is useful, however they can activate the receptor, which may be undesirable.

The known non-steroidal anti-androgens such as flutamide and anandron, unwanted androgenic activity is absent, but their affinity for the receptor may be worse than the steroidal anti-androgens (i.e., derivatives Andronov with steroid nucleus, which modify in such a way as to make the connection antiandrogenna properties). However, as I believe, steroidal antiandrogens are more likely to have undesirable agonistic properties.

In the application, published 24 January 1991 number of International patent publication WO 91/00732, applicants describe a new steroidal antiandrogens, including connection to steroid nucleus, containing the new substituents in position 17. Published the proposal includes 17 - haloalkylthio deputies. When is taulani in the examples. As discussed in detail hereinafter, it has been shown that the overall efficiency of antiandrogenna compounds can be increased considerably, if you carefully control the size, configuration, and identity of the 17 - substituent and, in particular, by limiting its size, as described and claimed in this application. Certain nortestosterone connection with certain 17-haloalkaline side chains used in different and non-pharmaceutical purposes Salmona etc. ((1) J. Steroid Biochem., Vol. 33, N 1, pp. 25-31 (1989) and (2) J. Steroid Biochem., Vol. 26, N 3, pp. 383-91 (1987)).

In International patent publication WO 92/057963 are some 16,16-disubstituted androstenone derivatives for the treatment of androgen-dependent skin diseases.

In European patent publication 0435321 describes some 17-substituted derivatives of a-norsteroid-3-carboxylic acid for use in the inhibition of the activity of 5-reductase mammals.

The aim of the present invention are superior antiandrogens, have a good affinity to the androgen receptor and are almost devoid of androgenic activity. These antiandrogens can be useful in the treatment of androgen-dependent diseases that p is a connection, having structural formula (I):

< / BR>
where the dashed lines are optional PI-connection;

R4represent a hydrogen atom or methyl;

R6denotes a hydrogen atom, methyl, ethyl or halogen atom;

and R17choose from a group including:

A) unsaturated hydrocarbon fragment containing at least one carbon atom which is separated from the D-ring molecular formula (I) at least three intermediate carbon atoms, separated from the specified D-ring molecular formula (I), more than four intermediate atoms.

B) halogen-substituted unsaturated hydrocarbon fragment containing at least one halogen atom, separated from the specified D-rings at least three intermediate atoms, and not aderrasi carbon atoms, separated from the specified D-ring molecular formula (I), more than four intermediate atoms and

C) allogeneically fragment containing at least one halogen atom, separated from the specified D-rings at least three intermediate atoms, and containing no carbon atom separated from the specified D-ring molecular formula (I), more than four, promezhutochnya, which in vivo is converted in the above connection.

Another aspect of the present invention is antiandrogenna compound having the structural formula (I):

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where the dashed lines are optional PI-connection;

R4represent a hydrogen atom or methyl;

R6denotes a hydrogen atom, methyl, ethyl or halogen atom;

and R17choose from a group including:

A) unsaturated hydrocarbon fragment containing at least one carbon atom which is separated from the D-ring molecular formula (I) at least three intermediate carbon atoms, and containing no carbon atom separated from the specified D-ring molecular formula (I), more than four intermediate atoms.

B) halogen-substituted unsaturated hydrocarbon fragment containing at least one halogen atom, separated from the specified D-rings at least three intermediate atoms, and containing no carbon atom separated from the specified D-ring molecular formula (I), more than four, the intermediate atoms, and

C) allogeneically fragment containing at least one halogen atom, separated from FEP specified D-ring molecular formula (I), more than four, the intermediate atoms, provided that R17is not a group

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if R4and R6both denote a hydrogen atom. According to another aspect of R17is not a group

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regardless of the identity of R4and R6.

The next aspect of the invention are pharmaceutical compositions for local and containing General antiandrogens in the present invention together with pharmaceutically acceptable diluents or carriers.

According to further aspect of the invention new antiandrogens or containing pharmaceutical compositions used in the treatment or prevention of androgen-dependent skin diseases such as acne, excessive hair growth in women, seborrhea, androgenic alopecia, premature baldness in men, etc.

According to further aspect of the invention they are used in the treatment or prevention of androgen-dependent systemic diseases, such as prostate cancer or benign prostatic hyperplasia.

Unless specifically specified, the substituents in the steroid nuclei antiandrogen of the present invention can imate, do not depend on any relationships that may occur in the structure, the presence of one does not depend on the presence or absence of another if their interdependence is not determined by the valence requirements. The considered compounds can be used in the form of precursor drugs, which can in vivo to turn into the desired active compound. The atoms of the steroid nucleus, for which there are no substituents can be further optionally substituted (if conditions permit valence), provided that such substituents do not have a significant and negative impact on the means of connection to the androgen receptor and not make the connection much more androgenic.

The term "lower" when describing chemical fragments means, in this case, the fragment containing not more than 8 atoms. For example, "lower alkyl" means (C1-C8)alkyl. Any fragment that contains more than two atoms can have, if not discussed specifically, a straight or branched chain.

Antiandrogens and containing pharmaceutical composition may be used in accordance with the present invention in the treatment of antiandrogenicity C is Inoi cancer and benign prostatic hyperplasia, acne, excessive body hair growth in women, seborrhea, androgenic alopecia, premature baldness in men, etc.

17 - Deputy of the antiandrogen of the present invention may be branched and straight chain. The longest chain is mainly composed of 4-5 carbon atoms, with preferred are fragments with a straight chain. Preferred are unsaturated fragments, such as halogen-substituted fragments. Unsaturated fragments are mostly unsaturated in the provisions , the D - ring of the steroid. Preferred are izlesene 17 fragments (in particular, EM 250, see below).

Halogen-substituted fragments may contain a halogen atom in more than one position. Similarly unsaturated fragments can be unsaturated in several places, for example, -C C-CH=CH2. Optional double bond is predominantly located in the 4-position of the A-ring of the steroid. Preferred substituents R17include, but are not limited to, butanolom, butanolom, pentinum, penttila, halobutyl, halobutyl, haloperidolum, haloperidolum, halobutyl and golopentia. Other preferred Prahlada hydrogen atoms, fluorine, chlorine, bromine and iodine, n denotes 2 or 3, and the dotted line represents an optional PI bond. Most preferred are halobutyl and halobutyl.

The most preferred antiandrogens for local purposes is EM-250, because I believe that he does not have a system antiandrogenna impact despite the fact that it has a significant antiandrogenna effects when topically applied. Thus, it is expected that the accidental penetration of the skin, which is possible at the local appointment EM-250, will not cause undesirable systemic effects.

Another aspect of the present invention is the predecessor of the medicinal product, which in vivo is transformed into a connection:

< / BR>
where the dashed lines are optional PI-connection;

R4represent a hydrogen atom or methyl;

R6denotes a hydrogen atom, methyl, ethyl or halogen atom;

and R17choose from a group including:

A) unsaturated hydrocarbon fragment containing at least one carbon atom which is separated from the D-ring molecular formula (I) at least three intermediate carbon atoms, and not southcinema atoms.

B) halogen-substituted unsaturated hydrocarbon fragment containing at least one halogen atom, separated from the specified D-rings at least three intermediate atoms, and containing no carbon atom separated from the specified D-ring molecular formula (I), more than four intermediate atoms and

C) allogeneically fragment containing at least one halogen atom, separated from the specified D-rings at least three intermediate atoms, and containing no carbon atom separated from the specified D-ring molecular formula (I), more than four intermediate atoms.

There are many variants of chemical fragments in the active compounds, such as hydroxyl or ketone group, which can lead to forms predecessors, these forms of precursor drugs are able in vivo to become active connection, for example, by hydrolysis, enzymatic catalysis, etc., a Preferred form of the predecessor of the medicinal product in accordance with the present invention have a substituent in the 3-position of the steroid nucleus, which in vivo is converted into 3-keto group. Among the " group of substituted or unsubstituted fragments, including:

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As is discussed further by placing these specific substituents in 3-position, may cause the offset double steroid relations, getting the preferred precursor drug of the formula:

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In the process of using a 3-position again becomes a =O and the double bond is shifted back that leads to the formation of preferred active androgen.

Below, together with preferred methods of synthesis are some not limiting the invention, examples of preferred active compounds and their preferred modifications in the form of precursors of drugs.

Example 1

Synthesis of 17_(4'-chlorbutanol)-yox-4-androsten-3-one (EM 248)

This synthesis is represented by scheme 1

Thioketal 2

To a solution of testosterone 1 (288,43 g, 1.0 mol) (receive Schering A. G., Germany) in glacial acetic acid (2.5 l) at 10oC add acondition (85 ml, 1.06 mol) and athirat boron TRIFLUORIDE (800 ml). The mixture is stirred at the same temperature for 1 hour and poured into ice (2 kg). From the aqueous phase emit white powder, which is removed by filtration, washed with water (2 x 2 l) and dried in EFORM-d, 300 MHz, TMC): 0,74 (singlet, 3H, 18-CH3), of 1.03 (singlet, 3H, 19-CH3), 3,14 - 3,42 (multiplet, 4H, SCH2), 3,60 (triplet, J = 8,4 Hz, 17 H), 5,47 (singlet, 1H, C-4H).

Ketone 3

Method a: a Solution of tickets 2 (182,3 g, 0.5 mol) in dry dichloromethane (1.5 l) at room temperature and under mechanical stirring, added dropwise to a solution of chloramine pyridinium (150 g, 0.7 mol), molecular sieves 3A (200 g) and sodium acetate (25 g). At the end of the addition the mixture is stirred for 16 hours and then diluted with diethyl ether (2 l) and filtered through a layer of silica gel on the funnel with filter bottom. The filtrate is evaporated in vacuo and the resulting solid is recrystallized from methanol and pure ketone 3. Output: 158,7 g (87%). Range1H NMR (chloroform-d, 300 MHz, TMC): 0,86 (singlet, 3H, 18-CH3), 1,02 (singlet, 3H, 19-CH3), 3,12 - 3,42 (multiplet, 4H, SCH2), 5,49 (singlet, 1H, C-4H).

Method B: Thioketal 2 (182,3 g, 0.5 mol) is dissolved in a solution of N-oxide 4-methylmorpholine (87,9 g, 0.75 mol) in dry dichloromethane (1.5 l). Add 200 g of powdered molecular sieves 4A. Portions 1 g every 5 minutes add the catalyst - perruthenate of tetrapropylammonium (6 g, 3.5 percent mole). Source materials interact in those who t from the filtrate by washing with diluted hydrochloric acid (1N). After drying over magnesium sulfate the solvent is removed in vacuum. The obtained solid residue was dissolved in minimum (500 ml) the amount of the mixture ethyl acetate/carbon tetrachloride (4/6). The solution is filtered through a layer of silica gel, elwira mixture of the same composition. Mpariwa the solvent and drying, get the ketone 3 (137 g, entry 75%).

Ether tetrahydropyranyl 4

To a solution of metallyte (500 ml of a 1.4 molar solution in ether, 0.7 mol) in 1 l of anhydrous tetrahydrofuran in a 5-liter round-bottom flask at a temperature of minus 30oC in argon atmosphere is added dropwise 2-(3-butenyloxy)tetrahydro-2H-Piran (112,5 g, advanced 0.729 mol). Upon completion of addition, the cooling bath is removed and leave the solution at room temperature for 4 hours. Again cooling the solution to -30oC and added dropwise a solution of ketone 3 (75 g, 0.2 mol) in 2.5 l of anhydrous tetrahydrofuran. Upon completion of addition, the cooling bath is removed and leave the solution at room temperature for 16 hours. To the mixture was added 100 ml of saturated salt solution and diluted with ethyl acetate, the organic phase is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and after bremault hexane. Compound 4 is used without further purification in the next stage. Output: 95,8 g (90%). Range1H NMR (chloroform-d, 300 MHz, TMC): 0,82 (singlet, 3H, 18-CH3), 1,01 (singlet, 3H, 19-CH3), 2,52 (triplet, 2H, J = 6,8 Hz, CCCH2), 3,15 - 3,44 (multiplet, 4H, SCH2), 3,50 - 3,56 (multiplet, 2H, CH2OTHP), 3.75 to 3,90 (multiplet, 2H, peranovic OCH2), 4,66 (singlet, 1H, OCHO), 5,47 (singlet, 1H, C-4H).

Alcohol 5

A mixture of compound 4 (100 g, to 0.19 mol) and iodotope bromide (250 ml, 3.8 mol) in 96% ethanol (2.5 l) is refluxed for 16 hours. The solvent is removed in vacuum and the crude mixture was diluted with ethyl acetate (2.5 l). The organic phase is washed with 3% sodium hydroxide solution (3 x 50 ml) and dried over magnesium sulfate. The solvent is evaporated, the solid is washed with diethyl ether, filtered through a funnel with a filter bottom and again washed with diethyl ether. Compound 5 can be used without further purification in the next stage: received 45,5 g (yield 66%); a small sample is recrystallized from a mixture of ethyl acetate and hexane and get: so pl. 179-181oC; range 1H NMR (chloroform-d, 300 MHz, TMC): 0,85 (singlet, 3H, 18-CH3), 1,17 (singlet, 3H, 19-CH3), 2,45 (triplet, 2H, J = 6.0 Hz, CCCH2), 3,70 (triplet, 2H, J = 6,1 Hz, CH<5 g, 0.04 mol), triphenylphosphine (21 g, 0.08 mol) and carbon tetrachloride (9.3 g, 0.06 mol) is boiled for 10 hours under reflux in 1 l of anhydrous dichloromethane. The solvent is evaporated, the crude mixture is transferred to the silica gel and the obtained gel chromatographic method of evaporating thin-layer chromatography, elwira a mixture of ether-hexane (70: 30). The connection is then recrystallized from diethyl ether. Yield 85%; so pl. 120-121oC; range1H NMR (chloroform-d, 300 MHz, TMC): 0,87 (singlet, 3H, 18-CH3), 1,19 (singlet, 3H, 19-CH3), 2,69 (triplet, 2H, J = 7,0 Hz, CCCH2), to 3.58 (triplet, 2H, J = 7,0 Hz, CH2Cl) 5,72 (singlet, 1H, C-4H); mass spectrum high resolution; calculated for C23H31O2Cl: 374,2013; found: 374, 20153; elemental analysis: calculated: C 73,68; H 8,33; Cl 9,46; found: C 73-65; H 8,45; Cl 9,58. (scheme 1).

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Example 2

Synthesis of 17-(4'-iodobutyl)-17-hydroxy-4-androsten-3-one (EM 250)

Synthesis of A

To a mixture of triphenylphosphine (7.87 in g, 30 mmol) and iodine (to 7.61 g, 30 mmol) in dry dichloromethane (500 ml) at room temperature add imidazole (2,04 g, 30 mmol). After a short period of time is solid. After that, at room temperature, add the alcohol 5 (7,13 g, 20 mmol). Mix the mixture in accordance with the glass filter beds. The filtrate is evaporated and the residue purified by the method of evaporative chromatography on silica gel, elwira a mixture of diethyl ether and hexane (70/30). Connection (EM 250) then purified by recrystallization from diethyl ether. Output 6,34 g (68%); so pl. 124,5 output reached 125.5oC; IR spectrum cm-1(KBr): 1611, 1653, 2873, 2948, 3380 and 3510; range1H NMR (chloroform-d, 300 MHz, TMC): 0,86 (singlet, 3H, 18-CH3), 1,17 (singlet, 3H, 19-CH3), 2,80 (triplet, 2H, J = 7,1 Hz, CCCH), 3,21 (triplet, 2H, J = 7,1 Hz, CH2), 5,71 (singlet, 1H, C-4H); range13C NMR (chloroform-d, 75, MHz, TMC): 2,5, 12,7, 20,8, 23,2, 23,9, 31,5, 32,7, 33,9, 35,7, 36,3, 38,6, 38,96, 46,8, 49,8, 53,5, 65,8, 79,8, 84,8, 85,7, 123,9, 171,2, 199,5: mass spectrum m/e 467 (M+), 426, 369, 339, 321, 245, 149, 123, 105, 79 (100); the mass spectrum of the high-resolution: calculated for C23H31O2I: 466,1369; found: 466,1382; elemental analysis: calculated: C 59,23; H 6,70; I 27,21; found: C 59,22; H 6,55; I 27.05 per (scheme 2).

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Synthesis of B

3-Methoxyindole-3,5-Dien-17-one (6)

To 4-androsten-3,17-dione (15 g, 52 mmol) (obtained from Aldrich Chemical Company, Milwaukee, Wisconsin, USA) in tetrahydrofuran (100 ml) add trimethoxymethane (17 g, 156 mmol) and the monohydrate of p-toluenesulfonic acid (450 mg, is 2.37 mmol). The mixture is stirred for 2.5 hours and add triethylamine (2.1 ml, is 2.37 mmol) and then water (4 ml). After removal of the dissolve is up. The solid is washed with water (4 times) and dried at 80oC in high vacuum for 12 hours, obtaining the target product (15.6 g, 100%). Range1H NMR (chloroform-d, 300 MHz, TMC): 0,93 (singlet, 3H, 18-CH3), 0,99 (singlet, 3H, 19-CH3), 3,57 (singlet, 3H, OCH3), 5,13 (singlet, 1H, C-4H), 5.25-inch (broadened singlet, 1H, C-6H): range13C NMR (chloroform-d, 75 MHz, TMC): 220,83, 155,36, 140,92, 117,31; 98,35, 54,20, 51,89, 48,38, 47,58, 35,78, 35,23, 33,68, 31,46, 31,41, 30,66, 25,18, 21,76, 20,44, 18,89, 13,61.

17 - Hydroxy-17- (4'-hydroxybutyl)-4-androsten-3 - one(7) n-Utility (7.9 ml, 19,78 mmol) is added dropwise to a mixture of di-ISO-Propylamine (0,14 ml, 5% 19,98 mmol) and 3-butyn-1-ol (1.5 ml, 19,98 mmol) in THF (30 ml) at a temperature of minus 40oC. the Mixture is stirred for 1 hour, and then add chlorotrimethylsilane (2.5 ml, 19,98 mmol) and the mixture is stirred for another hour (the end of the reaction determined by NMR). Added dropwise n-utility (7.9 ml, 19,78 mmol). After 1 hour, add the steroid 6 (2 g, 6.6 mmol) in THF (35 ml) and the mixture is stirred for 90 minutes (analysis by TLC shows the absence of starting compound) at a temperature of minus 40oC. Add water (30 ml) and concentrated resin acid (3 ml) and refluxed for 1 hour (reaction gidrodinamicheskie hoods combine, sequentially washed with saturated solutions of sodium bicarbonate and salt. After drying and removal of solvent (first water-jet vacuum pump, and then in high vacuum) to get the crude product (2.4 g) which is recrystallized from a mixture of n-hexane and ethyl acetate (content before being filtered stand in the cold room for 24 hours) and get pure product (2,01 g, 85%); PMR spectrum (chloroform-d, 300 MHz, TMC): 0.84 (singlet, 3H, 18-CH3), 1,16 (singlet, 3H, 19-CH3), 3,14 (broadened singlet, 1H, OH), 3,30 (singlet, 1H, OH), 3,68 (triplet, 2H, J = by 5.87 Hz, CH2OH), 5,71 (singlet, 1H, C-4H); range13C NMR (chloroform-d, 75 MHz, TMC): 199,58, 171,42, 123,48, 85,71, 82,69, 79,27, 60,75, 53,17, 49,59, 46,35, 38,64, 38,38, 35,96, 35,36, 33,62, 32,54, 32,39, 31,22, 22,87, 22,78, 20,47, 17,13, 12,58.

17-Hydroxy-17-(4'-totalactivelines)-4-androsten-3 - one (8)

In a three-neck flask equipped with stirrer and thermometer, placed 17-hydroxy-17-(4'-hydroxybutyl)-4-androsten-3-one (4.0 g, 11,22 mmol) and pyridine (10,65 g, 134,64 mmol). Cool the flask to 0oC. At the same temperature added p-toluenesulfonyl chloride (2.25 g, 12,34 mmol) in portions over 20 to 30 minutes or so fast that the temperature in any case did not rise above 20oC. and Then stirred the mixture at room temp is methylene chloride (3 x 100 ml). The organic extracts are combined, washed with saturated salt solution and dried. The solvent is removed under vacuum, the generated water pump at 40oC, and get a solid substance, which is then dried in high vacuum for 3 hours and get 4,84 g (93%) of product. Analysis using the1H NMR indicates a mixture of tosylate (75%) and chloride (25%). Range1H NMR (chloroform-d, 300 MHz, TMC): 0.84 (singlet, 3H, 75%, 18-CH3), 0,85 (singlet, 3H, 25%, 18-CH3), 1,16 (singlet, 6H, 2CH3), 2,41 (singlet, 3H, A CH3), to 2.57 (triplet, 2H, J = 6,8, 6,8 Hz), 75% of CH2that 2.7 (triplet, 2H, J = 6,7, 6,8 Hz), 25% CH2, 3,55 (triplet, 2H, =6,7, 6,7 Hz), 25% CH2, 4,06 (triplet, 2H, J = 6,7, 6,8 Hz), 75% of CH2, 5,70 (singlet, 1H, C-4H); 7,31 (doublet, 2H, J = 8,2 Hz, ArH2'h6') 7,75 (doublet, 2H, 8.2 Hz, ArH3'H5'): range13C NMR (chloroform-d, 300 MHz, TMC): 199,6, 171,4, 145,0, 133,0, 129,9, 127,8, 123,8, 86,1, 80,3, 79,6, 67,8, 53,5, 53,2, 49,8, 46,7, 42,1 (C C1), 38,8, 38,6, 36,2, 35,7, 35,6, 33,9, 32,8, 32,5, 31,5, 31,4, 23,0, 21,7, (ArCH), 20,7, 19,9, 17,4, 12,8.

17-(4'-iodobutyl)-17-hydroxy-4-androsten-3-one (EM 250)

Previously obtained compound (2.2 g, of 4.45 mmol) and sodium iodide (1,33 g of 4.45 mmol) in 2-butanol (12 ml) is refluxed (at 100oC) within 12 hours (after 1 hour TLC shows complete conversion of tosylate in iodide, one is which is dissolved in water (50 ml) and extracted with methylene chloride (3 x 80 ml). The organic extracts are combined, washed with a 15% aqueous solution of sodium bisulfite (80 ml) and then with saturated salt solution and dried. The solvent was remove under reduced pressure at a temperature of 40oC and get the crude product, which was purified on a chromatographic column, elwira a mixture of hexane/acetone (4/1) and get the pure target product (1,95 g, 95%). Recrystallized from a mixture of hexane and acetone and receive a product that is identical to the connection on p. A; so pl. 124,5 output reached 125.5oC (scheme 3).

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Example 3

Similar to the methods described in Examples 1 and 2 using different tetrahydropyranyloxy and various tetrahalide derived carbon as alkylating agents, obtain the following compounds listed in table 1.

Example 4

Synthesis of 17-hydroxy-17-(4'-itbut-1'(E)-enyl)-4-androsten-3 - one (EM 816)

At room temperature in argon atmosphere ketoenol 6 (300 mg, 1 mmol) and chloromethanesulfonyl (191 mg, 1 mmol) in dry tetrahydrofuran is treated with 1M solution of tert-butoxide potassium (1.3 ml). After all of the original substance will react, what is judged according to TLC, add water and extracted with ether, receiving amoxicullin 9.

Neochimiki temperature is treated with tert-piperonyl potassium (890 mg, 8 mmol) and water (43 mg, 2.4 mmol). After extraction with ether to obtain crude hydroxyaldehyde 10, which is dissolved in a mixture of triethylamine (10 ml), acetic anhydride (150 μl) and 4-(dimethylamino)pyridine (10 mg). Kept under argon in a few days and add the methanol, the mixture is stirred for 30 minutes and evaporated in vacuum. Acetoxyacetyl 11 is extracted with ether and purified by the method of evaporative chromatography on silica gel, elwira a mixture of ethyl acetate and hexane.

Acetoxyacetyl 11 (188 mg, 0.8 mmol) in tetrahydrofuran added under nitrogen in LiBr complex ylides derived in situ from 3-bromo-(tetrahydro-2'H-Piran-2'-yl)oxypropane, triphenylphosphine, lithium bromide and n-utility in the same solvent at low temperature. After a few hours, add finality (0.5 ml), and then tert-butyl alcohol and the solution is heated up until the reaction is completed. Poured water and adduct 12 is extracted with ether and purified by the method of evaporative chromatography on silica gel, elwira a mixture of ethyl acetate and hexane.

In an argon atmosphere at 0oC to a solution of the adduct 12 (350 mg, 0.7 mmol) in dry tetrahydrofuran (5 ml) add a solution of tert-butoxide potassium (110 mg, 1 mmol) in tert-butyl spywareit in methanol (10 ml) and add a few drops of concentrated hydrochloric acid. Boil the mixture under reflux for 2 hours, evaporated in vacuo and extracted with ethyl acetate. Kettil 13 is cleaned by the method of evaporative chromatography on silica gel, elwira a mixture of ethyl acetate and hexane.

To a mixture of triphenylphosphine (196 g, 0.75 mmol) and iodine (190 mg, 0.75 mmol) in dry dichloromethane (10 ml) at room temperature add imidazole (51 g, 0.75 mmol). After a short period of time sediment is deposited. Then at room temperature add kettil 13 (234 mg, 0.5 mmol), stirred the mixture for 30 minutes and diluted with ether. The formed solid is filtered off. The filtrate is evaporated and chromatographic on silica gel, elwira a mixture of ether and hexane, and get iodide EM 816 (scheme 4).

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Example 5

Similar to the methods described in Example 4, using different bromine (tetrahydro-2'H-Piran-2'-yl)axiallary or different tetrahalide derived carbon instead of iodine, will receive the following compounds listed in Table 2.

Example 6

Synthesis of 17-(4'-brombach-1'(Z)-enyl)-17-hydroxy-4 - androsten-3-one

This synthesis is illustrated by Scheme 5.

Hydroxyethyl 14

Testosterone (50 g, to 0.17 mol) (receive from the firm Schering A. G., Germany) obogo amount of p-toluenesulfonic acid (1 g) by boiling under reflux for 16 hours. After cooling, add ether, the organic phase is separated, washed with saturated aqueous sodium bicarbonate and water, dried and evaporated, getting hydroxyethyl 14.

Cetacean 15

To hydroxyketone 14 (40 g, 0.12 mol) in dry methylene chloride (1 l) was added pyridinium dichromate (90 g, 0.24 mol) and leave the mixture overnight to mix at room temperature, and then filtered through pre-treated with a 1% triethylamine silica gel, elwira a mixture of ethyl acetate and hexane.

Butenyl-adduct 16

In drained by the burner flame flask in an argon atmosphere was placed (tetrahydro-2'-H-Piran-2'-yl)oxybutin (77 g, 0.5 mol) and anhydrous tetrahydrofuran (1 l). The solution is cooled to minus 78oC add 2.5 solution of n-utility (200 ml) and the stirred solution at the same temperature for 2 hours. Then add cetacean 15 (33 g, 0.1 mol) in tetrahydrofuran (1 l). After two hours, poured the water and allow the mixture to warm to room temperature. The solution is evaporated in vacuum and the residue extracted with ether. The organic phase is washed with water, dried and evaporated. The residue is purified on silica gel, using as eluent a mixture of ethyl acetate and hexane.

Z-Butene, add poisoned by lead 5% palladium on calcium carbonate (4 g) Lindlar catalyst, receive from the firm Aldrich Chemical Company, Milwaukee, Wisconsin, USA). After three purging with hydrogen, the mixture is stirred in hydrogen atmosphere for at least 15 minutes and filtered on celite. The solid is washed with a mixture of methanol and methylene chloride and the solvent evaporated. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane.

17-(4'-Brombach-1'(z)-enyl)-17-hydroxy-4-androsten-3-one (18)

According to the method described by A. Wagner and others (Tetrahedron Letters 30, 557-558, 1989) tetrahydropyranyloxy-group is converted into a bromide. So, chetyrehhloristy carbon (31,5 g 0,095 mol) is added at room temperature in an argon atmosphere to a solution of z-butenyl-adduct 17 (25,2 g, 0.06 mol) in anhydrous methylene chloride (300 ml). Stirred for 10 minutes, cool the solution to 0oC and add triphenylphosphine (44,5 g to 0.17 mol). The resulting mixture was left overnight to mix at room temperature and filtered through silica gel. The solvent is evaporated, the residue dissolved in a mixture (500 ml) of methanol and water (9:1) and add a few drops of hydrochloric cescau phase is washed with saturated sodium bicarbonate solution and water, dried and evaporated to dryness. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (scheme 5).

< / BR>
Example 7

Synthesis of 17-(4'-itbut-1'(z)-enyl)-17-hydroxy-4-androsten-3-one (19)

Previously obtained compound 18 (2.1 g, 5 mmol) and sodium iodide (1.5 g, 5 mmol) in 2-butanol (12 ml) is refluxed for 12 hours. After removal of solvent, the obtained residue is dissolved in water (50 ml) and extracted with methylene chloride (3 x 80 ml). The organic extracts are combined and washed with 1% aqueous solution of sodium bisulfite (80 ml) and then with saturated salt solution and dried. After removal of the solvent at a temperature of 49oC and reduced pressure to get crude product, which was purified column chromatography, elwira with a mixture of hexane and acetone, and get pure product (of 4.75 mmol, 95%).

Example 8

Similar to the methods described in Examples 6 and 7, using various reagents (tetrahydro-2'H-Piran-2'-yl)oxyalkyl and various tetrahalide derived carbon, get the following compounds listed in table 3.

Example 9

Synthesis of 17-(5'-chloropentyl)-17-hydroxy-6-methyl-4-androsten-3-on the Les (500 ml) is added magnesium salt mononitratebuy acid (89,6 g, 0.18 mol) in water (250 ml). The mixture is heated for 3 hours at a temperature of 50oC, then evaporated and filtered. The filtrate is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (4:6) and receive-isomer (20 g) and isomer (17 g).

Cytosport 2

To methylaniline (20 ml, 6M solution in THF) in an argon atmosphere is added dropwise-isomer of the epoxide 20 (7.0 g, 0.02 mol) in anhydrous ether (250 ml). Boil the mixture under reflux for one hour and then further stirred at room temperature for 3 hours and add ammonium chloride. Extracted with diethyl ether. The organic phase is washed with water, dried and evaporated to dryness.

The residue is dissolved in methylene chloride (400 ml), added celite (18 g) and pyridinium dichromate (18 g) and stirred the mixture at room temperature for 24 hours. Pour the reaction mixture into diethyl ether and filtered through Florisil covered with a layer of celite. Mpariwa solvent receive raw cytosport 21, which is cleaned by the method of thin-layer chromatography evaporative forces on the d minus 60oC add 2-(4-pentyloxy)tetrahydro-2H-Piran (13.8 g, 0,083 mol) dropwise to a solution of metallyte (59 ml of a 1.4 M solution in ether, 0.08 mol) in 200 ml of anhydrous THF, placed in a round bottom flask with a capacity of 1 liter By the end of the addition the cooling bath is removed and the solution is kept for 5 hours. Again cool the solution to minus 60oC and added dropwise a solution of ketaspire 21 (6 g, of 0.017 mol) in 150 ml anhydrous THF. At the end of the addition the cooling bath is removed and the solution is kept for 16 hours at room temperature. To the resulting mixture is poured 20 ml of saturated salt solution, the solution is diluted with ethyl acetate, the organic phase is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated and the residue purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (0:10 to 4:6), and get adduct 22 (7.5 g, 0.014 mol).

Camatril 23

Adduct 22 (6.2 g, 12 mmol) dissolved in a mixture of acetic acid, acetone, tetrahydrofuran and water (4:2:2:1) and refluxed for 24 hours. The mixture is evaporated to half its volume, cooled and extracted with ethyl acetate. The organic phase is washed with saturated races is totril 23 (3.1 g, 7.7 mmol).

Enediol 24

To ketotriose 23 (1.0 g, 2.8 mmol) dissolved in methanol (150 ml), add 0.1 M sodium hydroxide solution (10 ml) and the solution for 24 hours and heated to a temperature of 50oC. After neutralization with diluted hydrochloric acid, water is added and extracted with a mixture of ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira mixture of acetone and hexane (0:10 to 2:8), and get enediol 24 (784 mg, 2.0 mmol) with so pl. 153-154oC.

17-(5'-chloropentyl)-17-hydroxy-6-methyl-4-androsten-3-one (EM 339)

The mixture enediol 24 (102 mg, 0.27 mmol), triphenylphosphine (131 mg, 0.5 mmol) and carbon tetrachloride (40 mg, 0.26 mmol) is boiled for 10 hours under reflux in 20 ml of anhydrous dichloromethane. After evaporation of the solvent the crude mixture is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane (0:10 to 3:7), and get a connection EM 339 (66 mg, 0.16 mmol), pl. 56-58oC; IR spectrum cm-1(KBr): 1606,4, 1663,1, 2871,9, 2947,6 and 3414,4; range1H NMR (chloroform-d, 300 MHz, TMC): 0,88 (singlet, 3H, 18-CH3), 1,07 (doublet, 3H, J = to 6.43 Hz, 6-CH3), 1,19 (SYN is Tr13C NMR (chloroform-d, 75 MHz, TMC); 12,8, 16,3, 18,4, 20,9, 23,0, 31,4, 32,7, 33,7, 33,8, 36,0, 36,1, 39,0, 39,2, 40,6, 43,6, 46,8, 49,9, 53,8, 77,2, 79,8, 84,4, 121,3, 174,2 and 199,8; mass spectrum m/e 402 (M+), 369, 259, 137, 105, 91 (100), 79, 67, 55 (scheme 6).

< / BR>
Example 10

Synthesis of 17- (5'-identical)-17 - hydroxy-6-methyl-4-androsten-3-one (EM 371)

17- (5'-Bromopentyl)-17 - hydroxy-6-methyl-4-androsten-3-one (EM 304)

The specified connection receive analogously to example 9, taking chetyrehhloristy carbon instead of carbon tetrachloride. The IR spectrum of cm-1(KBr): 1600, 1650, 2890, 2950 3400; PMR spectrum (chloroform-d, 300 MHz, TMC): 0,88 (singlet, 3H, 18-CH3), 1,07 (doublet, 3H, J = 6,44 Hz, 6-CH3), 1,20 (singlet, 3H, 19-CH3), 2,42 (triplet, 2H, J = 5,28 Hz, CCCH2), 3,50 (triplet, 2H, J = 4,98 Hz, CH2Br), 5,79 (singlet, 1H, C-4H); range13C NMR (chloroform-d, 75 MHz, TMC); 12,8, 17,5, 18,3, 20,9, 23,0, 31,4, 32,3, 32,6, 33,8, 35,9, 36,0, 38,9, 39,1, 40,5, 43,6, 46,7, 49,8, 53,7, 79,7, 84,2, 121,2, 174,4 and 199,8; mass spectrum m/e: 448, 446 (M+), 433, 431, 340, 259, 137 (100), 91, 55.

17-(5'-Identical)-17-hydroxy-6-methyl-4-androsten-3-one (EM 371)

To EM-304 (140 mg, 0.32 mmol) in acetone (20 ml) is added sodium iodide (75 mg, 0.5 mmol) and the resulting mixture is left overnight to boil under reflux. After cooling and removal of the solvent, water is added and extracted with a mixture of ethyl acetate. The organic phase is washed with 1%-the second chromatography on silica gel, elwira mixture of acetone and hexane (0:10 to 1:9), and get EM-371 (79 mg, 0.16 mmol), pl. 68-70oC; IR spectrum cm-1(KBr): 1605,9, 1683,1, 2941,3 and 3423,3): range1H NMR (chloroform-d, 300 MHz, TMC): 0,87 (singlet, 3H, 18-CH3), 1.06 (the doublet, 3H, J = 6,32 Hz, 6-CH3), 1,18 (singlet, 3H, 19-CH3), 1,96 (Quartet, 2H, J = 6,7 Hz, CH2CH2I) 3,27 (triplet, 2H, J = 6,80 Hz, CH (I), 5,78 (singlet, 1H, C-4H); range13C NMR (chloroform-d, 75 MHz, TMC); 5,2, 12,8, 18,3, 20,9, 22,9, 29,6, 31,3, 31,8, 32,6, 33,6, 33,7, 35,9, 36,0, 38,9, 39,1, 40,5, 43,8, 49,2, 53,7, 79,7, 84,8, 121,2, 174,3 and 199,8; mass spectrum m/e 494 (M+), 479, 367, 300, 259, 137, 91, 79, 67 (100), 55 (table. 4).

Example 11

Synthesis of 17-(5'-chloropentyl)-17-hydroxy-6-methyl-4-androsten-3-one (EM 683)

To EM-339 (100 mg, 0.25 mmol) in benzene (20 ml) is added p-toluensulfonate (4,72 ml of 0.025 mmol) and chloranil (74 ml, 0.29 mmol). The mixture is boiled with a nozzle Dean-stark for 2 hours. After cooling, add ether and the organic phase is washed with a solution of sodium bisulfate, water, dried over magnesium sulfate and evaporated to dryness. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane, and obtain the target compound (48 mg, yield 48%). The IR spectrum of cm-1(KBr): 1070, 1577, 1624, 2870, 2943 and 3421; range1H NMR (chloroform-d, 300 MHz, TMC): 0,92 (singlet, 3H, triplet, 2H, J = 6.87 in Hz, CCCH2), 3,62 (triplet, 2H, J = 6,32 Hz, CH2Cl), 5,86 (singlet, 1H, C-4H), 5,94 (singlet, 1H, C-7H); range13C NMR (chloroform-d, 75 MHz, TMC); 12,7, 163,3 16,4, 19,9, 20,4, 22,6, 31,4, 32,6, 33,6, 33,2, 37,8, 39,1, 43,7, 47,6, 47,9, 50,6, 79,5, 84,3, 84,4, 121,2, 131,1, 138,1, 164,4 and 200.

Example 12

Similarly to the method described in Example 11, to obtain the following compounds are given in Table 5, taking as the source of various compounds obtained in accordance with Examples 9 and 10.

Example 13

Synthesis of 17-(but-3-EN-1-inyl)-17 - hydroxy-4-androsten - 3-one (EM 656)

To EM-250 (466 mg, 1 mmol) in benzene (25 ml) is added cesium fluoride (759 mg, 5 mmol). The mixture is stirred at room temperature for 24 hours, washed with water, dried and evaporated to dryness. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of diethyl ether and hexane (6:4), and obtain the target compound (186 mg, 0.55 mmol): range1H NMR (chloroform-d, 300 MHz, TMC): 0,90 (singlet, 3H, 18-CH3), 1,20 (singlet, 3H, 19-CH3), 5,46 (doublet of doublets, 1H, J = 10,97 Hz, J = 1,82 Hz, =CH2), 5,61 (doublet of doublets, 1H, J = 17,4 Hz, J = 1,82 Hz, =CH2), 5,73 (singlet, 1H, C-4H), of 5.83 (doublet of doublets, 1H, J = 17,4 Hz, J = 10,97 Hz, CH=CH2).

Example 14

Synthesis of 17-(Penta-4-EN-1-inyl)-17-BR>
Synthesis of 17-(4'-iodobutyl)-17-hydroxy-4-androsten-3-one (29)

The synthesis of the compounds is illustrated by Scheme 7.

Hydroxyethyl 55

Androstanolone (50 g, to 0.17 mol) (receive from the firm Aldrich Chemical Company, Milwaukee, Wisconsin, USA) treated with diethylene glycol (100 ml) in toluene (1 l) in the apparatus with a nozzle Dean-stark in the presence of catalytic amount of p-toluenesulfonic acid (1 g) by boiling under reflux for 16 hours. After cooling, add ether, the organic phase is separated, washed with saturated aqueous sodium bicarbonate and water, dried and evaporated, getting hydroxyethyl 25.

Cetacean 26

To hydroxyketone 25 (40 g, 0.12 mol) in dry methylene chloride (1 l) was added pyridinium dichromate (90 g, 0.24 mol) and leave the mixture overnight to mix at room temperature, and then filtered through pre-treated with a 1% triethylamine silica gel, elwira a mixture of ethyl acetate and hexane.

Butenyl-adduct 27

In drained by the burner flame flask in an argon atmosphere was placed (tetrahydro-2'H-Piran-2'-yl)oxybutin (77 g, 0.5 mol) and anhydrous tetrahydrofuran (1 l). The solution is cooled to minus 78oC add 2.5 solution of n-buta is 26 (33 g, 0.1 mol) in tetrahydrofuran (1 l). After two hours, poured the water and allow the mixture to warm to room temperature. The solution is evaporated in vacuum and the residue extracted with ether. The organic phase is washed with water, dried and evaporated. The residue is purified on silica gel, using as eluent a mixture of ethyl acetate and hexane.

Cytosport 28

To butinyl-adduct 27 (43,7 g, 0.09 mol), dissolved in 500 ml of ethanol, add 5% palladium on coal. After three purging with hydrogen, the mixture is stirred under moderate hydrogen pressure for at least 60 minutes and filtered on celite. The solid is washed with a mixture of methanol and methylene chloride and the solvent evaporated. The residue is dissolved in methanol, add a few drops of concentrated hydrochloric acid and refluxed for 1 hour. After cooling and evaporation of part of the solvent cytosport 28 extracted with ethyl acetate, washed with water, dried and purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane.

17-(4'-Iodobutyl)-17-hydroxy-4-androsten-3-one (29)

To a stirred solution of ketaspire 28 (1.8 g, 5 mmol) in dimethylformamide (50 ml), containing the 8 hours add bromide (880 g, 5.5 mmol) in the same solvent (10 ml). The mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with 1% solution of sodium bisulfate and water, dried and evaporated. The residue is dissolved in dimethylformamide (50 ml) and add lithium carbonate (1.0 g) and lithium bromide (1.0 g) and boil the mixture under reflux for several hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with 1% solution of sodium bisulfite and water, dried and evaporated. The residue is purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane. Obtained in this way purified nonsport added at room temperature to a mixture of triphenylphosphine (1.3 g, 5 mmol), iodine (1.26 g, 5 mmol) and imidazole (0.34 g, 5 mmol). The mixture is stirred for 30 minutes and diluted with ether. The formed solid is filtered over filter beds. The filtrate is evaporated and the residue purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane. (scheme 7)

< / BR>
Example 16

Synthesis of 17 - (5'-chloropentyl)-17-hydroxy-6-fluoro-4 - androsten-3-one (EM 649)

This synthesis explains(1: 1) at a temperature of from 5 to 10oC add apirat boron TRIFLUORIDE (1 ml) and stirred at room temperature for 3 hours. The organic phase is washed with saturated sodium bicarbonate solution and water, dried and evaporated, getting a solid white color (380 mg, yield 36%).

Forsport 31

The solution percetile 30 (320 mg, 0.87 mmol) in dry dichloromethane (15 ml) at room temperature and with stirring is added dropwise to a solution of chloramine pyridinium (0.6 g, 0.7 mol), molecular sieves 3A (0.5 g) and sodium acetate (100 mg). At the end of the addition the mixture is stirred for 16 hours, diluted with diethyl ether (100 ml) and filtered through a layer of silica gel on the funnel with filter bottom. The filtrate is evaporated and the residue purified by the method of thin-layer evaporator chromatography on silica gel, elwira a mixture of ethyl acetate and hexane, and get forsport 31 (270 mg, yield 84%).

Cordial 32

In a round bottom flask with a capacity of 0.5 l in an argon atmosphere at a temperature of minus 78oC to a solution of metallyte (19.6 ml of 1.4 M solution of MeLi in ether, 0,028 mol) in 100 ml of anhydrous THF is added 2-(4-pentyloxy)tetrahydro-2H-Piran (4.61 in) or 0.027 mol). At the end of the addition the cooling bath is removed and leave the solution on 2 cha is th tetrahydrofuran. At the end of the addition the cooling bath is removed and leave the solution at room temperature for 16 hours. To the resulting mixture is poured a saturated salt solution and diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue purified by the method of evaporating thin-layer chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane (0:10 to 4:6), receiving cordial 32.

Fortrial 33

The mixture ferriola 32 (410 mg, 0,776 mmol), acetic acid (40 ml), THF (20 ml), acetone (20 ml) and water (10 ml) is refluxed for 8 hours. Cool, pour the mixture into water and extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and water, dried and evaporated. The residue is purified by a method of evaporating thin-layer chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane, and get fortrial 33 (181 mg, yield 57%).

17- (5'-Chloropentyl)-17 - hydroxy-6-fluoro-4-androsten-3 - one (EM 649)

The mixture ferriola 33 (100 mg, 0,246 mmol), triphenylphosphine (129 mg, 0,492 mmol) and carbon tetrachloride (5 ml) is refluxed in 20 ml besod togetherbut, elwira a mixture of acetone/hexane (0:10 to 3:7); IR spectrum cm-1(KBr): 1670, 2943 and 3433; range1H NMR (chloroform-d, 300 MHz, TMC): 0,91 (singlet, 3H, 18-CH3), 1,32 (doublet, 3H, J = 1.5 Hz, 19-CH3), 1,96 (Quartet, 2H, J = 6.5 Hz, CH2CH2Cl), 2,43 (triplet, 2H, J = 6,9 Hz, CCCH2), 3,64 (triplet, 2H, J = 6.5 Hz, CH2Cl), 4,99 (doublet, 1H, J = 49,1 Hz, C-6H), 5,88 (doublet, 1H, J = 4,8 Hz, C-4H) (scheme 8).

< / BR>
Example 17

Synthesis of 17-(4'-chlorbutanol)-17-hydroxyandrost-1,4 - diene

A mixture of EM-248 (187 mg, 0.5 mmol), dichlorodicyanoquinone (170 mg, 0.75 mmol), p-NITROPHENOL (5 mg) and toluene (3 ml) is heated for 12 hours. After cooling, add ether (150 ml) and washed with a solution of sodium bisulfite, 1 N sodium hydroxide solution and water, dried and evaporated. The residue is purified by a method of evaporating thin-layer chromatography on silica gel, using as eluent a mixture of ether and hexane (7:3). After recrystallization obtain the target compound (56 mg, 30% yield).

Example 18

Synthesis of 17-(4'-iodobutyl)-17-hydroxy-4-methyl-4 - androsten-3-one

The specified connection get in the way, similar to the following to obtain 17-(4'-iodobutyl)-17-hydroxy-4-androsten-3-one (EM 250), synthesis of B, Example 2, using as the original 4-methyl-4-androsten-3,17-disposabl.

A mixture of acetate testosterone (get from Steraloids Inc., Wilton, new Hampshire, USA) (3.3 g, 10 mmol), aqueous formaldehyde (1 ml) and thiophenol (0.9 g, 8 mmol) is stirred in triethanolamine (30 ml) for 10 hours under argon at a temperature of 110oC. After 4 hours after the start of heating add an additional amount of formaldehyde (0.7 ml) and thiophenol (0.5 mg). Cooled down, poured into a saturated salt solution and extracted with methylene chloride. The organic phase is washed with diluted sodium hydroxide solution and water, dried and evaporated. The residue is purified by a method of evaporating thin-layer chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane. The residue, purified by recrystallization from acetone (15 ml), added to Raney Nickel (35 g) in acetone (60 ml), boiling under reflux for 1 hour. Boiling continued for another 15 minutes and the hot organic phase is decanted, and the metal precipitate is washed with hot acetone. The filtrates are combined evaporated and purified by the method of evaporating thin-layer chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane. Purified the residue is dissolved in caustic soda solution in methanol is water, extracted with methylene chloride. The organic layer was washed with saturated salt solution, dried and evaporated to dryness. The residue, purified by the method of evaporating thin-layer chromatography on silica gel using as eluent a mixture of ethyl acetate and hexane, dissolved in acetone (30 ml) and at 0oC is treated with a slight excess of Jones reagent (8 N solution of chromium trioxide) (until red staining). After 15 minutes add ISO-propanol (1 ml) and the mixture was poured in a saturated salt solution, extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried and evaporated to dryness. Purification of the residue by the method of evaporating thin-layer chromatography on silica gel using as eluent a mixture of ethyl acetate and hexane obtain pure 4-methyl-4-androsten-3,17-didn.

Predecessors drugs

Forms predecessors of medicines in accordance with the present invention can be prepared by known methods by modification of the substituents in the compounds into fragments, which in vivo transform back into unmodified Deputy (see, for example, H. Bundgaard, "design and application of prodrugs" in the Shilin's monograph the equipment variants of the invention, the precursor drug get for example, by conversion of 3-keto group of the antiandrogen of the present invention in oxazolidine, thiazolidine, dioxans, dioxolane, dithiolane or dithiane. All of them are unstable in the body and regenerate the original 3-ketopropane. The following are not limiting the present invention examples of some preferred modifications of the predecessors of medicines that can be used as an antiandrogen in the present invention.

Example 19

17-(4'-chlorbutanol)-17-hydroxy-5-androsten-3-Spiro-2'-(1', 3'-thiazolidine-4'-ethylcarboxylate) (34)

The synthesis is illustrated by scheme 9.

17-(4'-chlorbutanol)-17-hydroxy-4-androsten-3-one (EM-248) (0,37 g, 1 mmol) dissolved in argon atmosphere in pyridine (5 ml) to which was added the hydrochloride of the ethyl ester of L-cysteine. The reaction mixture is heated for at least 12 hours. Excess pyridine evaporated and the residue is dissolved in methylene chloride. The organic layer is washed with water, dried over sulfate magnesiumalloy,paluca-(4'-chlorbutanol)-17-hydroxy-5-androsten-3-Spiro-2'- (1',3'-tolidin-4'-ethylcarboxylate).

< / BR>
Example 20

17-(4'-chlorbutanol)-17-hydroxy-5-androsten-3-Spiro-2'-(1', 3'-oxazole is zero, add sodium acetate and the hydrochloride of the ethyl ester of L-cysteine (17 g, 100 mmol). The reaction mixture is left to warm up for the night in an argon atmosphere, then evaporated and add methylene chloride order to besiege the excess of the hydrochloride of the ethyl ester of L-serine. The solution is filtered and the filtrate is washed twice with water, dried over magnesium sulfate, filtered and evaporated in vacuum. The residue is triturated with ethanol and receive crystals.

< / BR>
Example 21

17-(4'-iodobutyl)-17-hydroxy-3,3-methylethylenediamine - 5-androsten (38)

The synthesis is illustrated by Scheme 11

The alcohol 5 (3.75 g, 10 mmol) in benzene (100 ml) and propylene glycol (20 ml) (use racemic mixture or mostly pure enantiomer) add p-Truelove acid (189 mg, 2 mmol) and boil the mixture with a nozzle Dean-stark within 24 hours. Cool, dilute the mixture with saturated sodium bicarbonate solution and water, dried and evaporated to dryness in vacuum to give crude cetadol 36.

Metaltail 37

In a three-neck flask with a capacity of 100 ml equipped with a stirrer and thermometer, is placed cetadol 36 (of 3.46 g, 8 mmol) and pyridine (7.9 g, 100 ml). Cool the flask to 0oC and added dropwise at this temperature portions of the acid chloride p-tawassul the camping stirred at room temperature for 12 hours, and the mixture is then diluted with a solution of 20 ml of hydrochloric acid in 70 ml of ice water. The aqueous solution is extracted with methylene chloride. The organic phase is washed with saturated salt solution and evaporated. Removing the solvent at 40oC get metaltail 37.

17-(4'-iodobutyl)-17-hydroxy-3,3-methylethylenediamine-5 - androsten (38)

Metaltail 37 (2,62 g of 4.45 mmol) and NaI (1,33 g of 4.45 mmol) in 2-butanol (12 ml) is refluxed for 12 hours. Removing the solvent to obtain a residue which is dissolved in water (50 ml) and extracted with methylene chloride. The organic phase is washed with 1% solution of sodium bisulfite (80 ml) and then with saturated salt solution and dried. Removing the solvent at a temperature of 40oC and reduced pressure to get crude product which is purified by the method of evaporating thin-layer chromatography on silica gel pre-treated with 0.1% trimethylamine, elwira a mixture of ethyl acetate and hexane.

< / BR>
Example 22

Synthesis of 17(4'-iodobutyl)-17-hydroxy-3-ecocentrist-3,5-diene (40)

17-(4'-chlorbutanol)-17-hydroxy-3-ecocentrist-3,5 - diene (39) EM-248 (1.9 g, 5 mmol) in THF (20 ml) is treated with triethoxysilane (1.7 g, 16 mmol) and the monohydrate p-toluensulfonyl solvent, get a residue, which was stirred with water (20 ml) for 10 minutes and filtered. The solid is washed with water and dried in high vacuum at a temperature of 80oC give crude compound 39. Pure product is obtained by purification by a method of evaporating thin-layer chromatography on silica gel pre-treated with 0.1% trimethylamine, elwira a mixture of ethyl acetate and hexane. 17-(4'-iodobutyl)-17-hydroxy-3-ecocentrist-3,5 - diene (40)

Compound 39 (800 mg, 2 mmol) and al (580 mg, 2 mmol) in 2-butanol (12 ml) is refluxed for 12 hours. Removing the solvent to obtain a residue which is dissolved in water (50 ml) and extracted with methylene chloride. The organic phase is washed with 1% solution of sodium bisulfite (80 ml) and then with saturated salt solution and dried. Removing the solvent at a temperature of 40oC and reduced pressure to get crude product which is purified by the method of evaporating thin-layer chromatography on silica gel pre-treated with 0.1% trimethylamine, elwira a mixture of ethyl acetate and hexane.

< / BR>
Antiandrogens of the present invention, which include precursors of drugs, mainly mixed the standard amount of an antiandrogen, used in the art. The attending physician may decide to modify the concentration and/or dose, with the aim to find the dose for each patient. Attending physician, preferably early in the course of treatment, monitors the overall response of the patient and the level of antiandrogen in serum compared with preferred concentrations in serum, which indicated previously), and also monitors the overall response of the patient in response to treatment, changing if necessary the dose if the metabolism of the patient or patient's response to treatment are atypical. Can also be used capsules containing the above antiandrogens. As further discussed hereinafter, carriers and diluents include solids and liquids. If the composition is prepared in advance, it usually is added is used in this technical field preservatives (particularly, benzyl alcohol). New pharmaceutical compositions according to the invention can be used in the treatment of androgen-dependent diseases. The systematic introduction (in particular, in the treatment of prostate cancer, benign prostatic hyperplasia, or other disorders that is izvestno of technology, are pharmaceutically acceptable for systemic use, in particular, saline solution, water, aqueous alcohol, oil, etc., Often the carrier is a mixture of ingredients.

In the preparation of a composition intended for system use, antiandrogens can prepare for the introduction of the usual ways for oral or by injection. Antiandrogens can be entered, for example, orally. The compound of the present invention can be mixed with conventional pharmaceutical excipients (in particular, spray dried lactose and magnesium stearate) and prepare tablets or capsules for oral administration. Forms for oral administration may be added flavorings. If necessary capsules for oral administration, the active ingredients of this invention can be filled with pharmaceutical capsules, known from the technical field, whether or not containing additional thinners and other additives, which are discussed here.

The active compounds can be prepared in the form of tablets or pills, coated by mixing with fine powder carrier such as sodium citrate, calcium carbonate and dicalcium phosphate, and yuusha means, such as magnesium stearate, sodium lauryl sulfate, carbowax or polyethylene glycol.

You can also use the closed capsules, e.g. hard gelatin, and closed soft gelatin capsules containing a softener or plasticizer, in particular glycerol. The sealed capsules contain the active compound mainly in the form of granules, in particular in a mixture with fillers, such as lactose, sucrose, mannitol, starch, such as potato starch or amylopectin, cellulose derivatives or silicic acid with a high degree of dispersion. In soft gelatin capsules active ingredients mostly found in the form of solutions or suspensions in suitable solvents, such as vegetable oil or liquid polyethylene glycols.

You can use solid system of drug delivery, are described in U.S. Patents numbers 3742951, 3797494 or 4568343.

Otherwise the active ingredients can be applied to the skin plaques whose structure is known from the technical field, for example from the structures shown in the European patent 0279982.

To facilitate the penetration of drugs through the skin if you want the achievement system sozdanii system diseases of the application site on the skin should be changed to prevent excessive local concentrations of steroids.

In preferred variants of the invention, the inhibitors of the present invention used for the treatment of androgen-dependent skin diseases such as acne, seborrhea, excessive hair growth in women, androgenic alopecia, premature baldness in men, etc., When used for these purposes antiandrogens mainly administered topically together with conventional carriers or diluents, suitable for application to the skin. The local purpose diluent or carrier preferably should not facilitate transdermal penetration of the active ingredients into the blood stream or other tissues, where they may cause undesirable systemic effects.

If the connection is used together with a carrier or diluent for dermal or topical application, the carrier or diluent may be selected from many known in cosmetics or medicine, in particular, use any gel, cream, lotion, ointment, liquid or non-liquid carrier, emulsifier, solvent, liquid diluent or other similar binder, which has no harmful effect on the skin or other living tissue of an animal. The carrier or diluent is usually , amides, liquid esters, liquid lanolin and lanolin derivatives and similar compounds. The alcohols include mono - and polynuclear alcohols, including ethanol, glycerol, sorbitol, ISO-propanol, diethylene glycol, propylene glycol, hexyleneglycol, mannitol and methoxyethanol. Typical carriers may also be ethers, including diethyl and DIPROPYLENE ether, methoxypolyethylene, carbowax, polyethylenglycol, polyoxyethylene and sorbite. Typically the carrier for the local destination, in order to achieve maximum hydrophilic or lipophilic solubility, includes both water and alcohol, in particular ethanol or ISO-propanol with water.

Media for local destination may also include various other ingredients commonly used in compositions of ointments and lotions and is well known in cosmetics and medicine. For example, there can be fragrances, preservatives, perfume, gel-forming means, thickeners such as carboxymethyl cellulose, surfactants, stabilizers, softening tools, dyes and other such tools.

The concentration of active ingredient in the ointment, cream, gel or lotion is usually from 3 to 20 about the but the total number lotion cream, gel or ointment). Within the preferred range of values greater concentration allows the use of a lotion, gel or cream in lesser amount, or not so often.

Here are the following not limiting the present invention examples of typical cooking cream, lotion and ointment. In addition to these carriers experienced professionals can use other media with the aim to find a solvent for a specific dermatological purposes.

Examples 23, 24 and 25 provided in the end of the description.

If antiandrogens are introduced systematically, they are mainly assigned to oral or parenteral. If the action is leather, it is preferable of course the local introduction.

The concentration of the active ingredient varies in a known manner depending on the method of administration of the pharmaceutical composition. Compositions suitable for oral administration may preferably include at least one inhibitor, an antiandrogen, if the total content of the above anti-androgens in these pharmaceutical compositions is from about 1% to 95% by weight of the composition, preferably adapted the anti-androgens should be placed in the above range of values. The level of anti-androgens in the blood is the preferred criterion of adequacy of dose which takes into account individual differences in absorption and metabolism. Pharmaceutically acceptable diluent is mainly starch or lactose (with or without tartrazine).

If the composition is prepared for parenteral injection, antiandrogen mainly added in the amount from about 1.0 mg/ml to about 100 mg/ml, preferably from about 2.0 mg/ml to about 2.0 mg/ml to about 10 mg/ml).

If you want to exert a systemic effect, you only need to antiandrogen was administered in the right way and with a dosage sufficient to provide the required level in the serum. The content of antiandrogen serum should normally be maintained in the range from 10 to 2000 micrograms per liter, preferably in the range from 100 to 1000 µg/l and most preferably in the range from 200 to 500 ág/L. Adequate levels of the drug in serum is also set in accordance with the response of the patient to a therapeutic effect.

For a typical patient K is the value from 10 to 2000 mg of the active ingredient per day per 50 kg of body weight. If the introduction is in the form of injection, it is recommended from about 1 to 2000 mg per day per 50 kg of body weight, preferably from 10 to 100.

The local purpose lotion, gel or cream should be thoroughly rubbed into the skin, so that no visible residue, after which the skin as possible should not be wetted for at least 30 minutes. The number of medicines must be at least 0.02 mg antiandrogen per square centimeter (mainly from 0.1 to 1 mg/sq. cm) each time it is used. It is desirable to apply the composition for local application on the affected area 1 to 6 times a day, particularly 3 times a day, through appropriate regular intervals. In some preferred versions of the invention, the antiandrogens of the present invention used in combination with another active ingredient as a component of combination therapy. For example, a new antiandrogen can be used in conjunction with a separate inhibitor of 5 - reductase, which can be included in the same pharmaceutical composition, and antiandrogen, or be entered separately. The active compound may have as antiandrogenna activity and ingibiruyushee these activities (in particular, antiandrogen or another inhibitor of 5 - reductase). Combination therapy may also include treatment of one or more compounds that inhibit the reproduction of testosterone or its precursors. In some preferred versions of the invention, the pharmaceutical composition for local destination further includes an inhibitor of the activity of steroid 5 - reductase. One of these inhibitors ("Proscar") is supplied by the companies Merck Sharp and Dohme". Other examples of such inhibitors are EM-735 and EM-638, the synthesis of which is as follows.

< / BR>
Getting 17-hydroxy-17-butyl-4-Aza-5-androst-1 - EN-3-one (EM 735):

17-Hydroxy-5-oxo-A-nor-3,5-androstane-3-about the acid (a)

To a stirred solution of acetate of testosterone (produced by "Steraloids Inc. , Wilton, state of new Gemser, USA) (200 g, 0,605 mol) in tert-butyl alcohol (2 l) add a solution of sodium carbonate (96,3 g, 0,908 mol) in 460 ml of water. Heat the mixture to boiling and gradually (over 1 hour) add a solution of periodate sodium (893,8 g of 4.17 mol) and potassium permanganate (70,8 g, 0.45 mol) in warm water (75oC) while still boiling under reflux. The reaction mixture cooled down to 30oC and 15 m the t and evaporated under reduced pressure to remove most of tert-butyl alcohol (final volume 1.0 l). The aqueous residue cooled and acidified with hydrochloric acid to a pH of 3.0. Extracted the aqueous phase with methylene chloride (4 x 800 ml), the organic extracts are combined, washed with water, dried and evaporated to dryness. The obtained solid is subjected to hydrolysis of the acetate groups by boiling with a solution of NaOH (34.3 g, 0,857 mol) in methanol (2.0 l) for 12 hours. Evaporated reaction mixture to a total volume of 400 ml, diluted with water (600 ml) and acidified to pH 3. The solid is filtered off, washed with water and dried. The filtrate is extracted with methylene chloride (3 × 1.0 l), the organic extracts are combined and concentrated to a syrup. The precipitate and the syrup is treated with boiling ethyl acetate, cooled to 0oC and left to stand at this temperature overnight, getting 125 g (67%) of colorless crystals: I. pl. 205-207oC.

17-Hydroxy-4-methyl-4-Aza-androst-5-ene-3-one (b)

In the tube Slinka bubbled at room temperature, methylamine to saturation in a mixture of scaricati (a) (8.0 g, 25,98 mol) in ethylene glycol (80 ml). The clear yellowish solution is heated gradient (3oC/min) to a temperature of 180oC and maintained at the specified temperature for 1 hour. The reaction mixture cooled down to 10oC and PR of 6.1 g of compound (b) (81%), pl. 181-183oC.

17-Hydroxy-4-methyl-4-Aza-5-androstane-3-one (c)

A solution of the compound (b) (6 g, of 20.7 mmol) in acetic acid (99,9%, 130 ml) hydronaut in the presence of platinum oxide (600 mg) under a pressure of 45 pounds per inch, starting from room temperature, and heated to a temperature of 60oC for 12 hours. The reaction mixture is cooled and filtered. The catalyst is washed with acetic acid (30 ml). The filtrates are combined and evaporated to dryness (5.5 g, 91%); so pl. 178-180oC.

4-Methyl-4-Aza-5-androstane-3,17-dione (d)

To a stirred solution of the compound (c) (7,3 g, 25 mmol) in methylene chloride (260 ml) is added chlorproma pyridinium (8,1 g, 37 mmol) and stirred the mixture at room temperature for 3 hours. The reaction mixture to remove solid precipitation is filtered through a layer of Florisil (30-60 mesh), and the filtrate washed with water (2 x 200 ml) and dried. The resulting residue is purified by a method of evaporating column chromatography on silica gel and receive Dion (d) (4.4 g, 61%); so pl. 126-128oC.

17-Hydroxy-17 -(1'-butenyl)-4-methyl-4-Aza-androstane-3 - one (EM-728)

To a solution of di-ISO-Propylamine (8,35 g, 82,51 mmol) in dry n-hexane (150 ml) at -20oC add n-utility (33 ml of 2.5 M solution in exerter minus 20oC for 1 hour. In diethyl ether (10 ml) at a temperature of minus 50oC bubbled 1-butene (at a rate of about 1.0 g/min). The cooled solution of 1-butene in diethyl ether (5.5 equiv.) add at a temperature of minus 50oC to a solution of licide-ISO-Propylamine. After 10 minutes, to a solution of 4-methyl-4-Aza-5-androstane-3,17-dione (d) (5.0 g, 16,50 mmol) in diethyl ether (250 ml) at a temperature of minus 50oC add a solution of 1-butenolide. After 1 hour the reaction mixture is allowed to warm to 0oC and stirred at room temperature for 12 hours. Terminate the reaction by adding an aqueous solution of ammonium chloride (5 ml) and diluted with water (100 ml). The organic phase is separated and the aqueous phase extracted with ethyl acetate (3 x 80 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated, to give crude product, which was purified evaporative column chromatography on silica gel (hexane: acetone-ethyl acetate, 75:10:15 55:30:15) and get 4,20 g EM-728 with 71% yield: so pl. 155-157oC; IR spectrum cm-1(KBr) 3335, 2947, 2870, 1624, 1609, 1444, 1399, 1316, 1240, 1052, 1024; range1H NMR (chloroform-d, 300 MHz, TMC): 0.84 (singlet, 3H, 18-CH3), 0,90 (singlet, 3H, 19-CH3), 0,78 - 1,01 (multiplet, 1H) and 1.15 (triplet, 3H, J = 7,6, , ,1 Hz), a 2.00 (2H, two doublet of doublets, J = 3,0, 7,4, 12.0 Hz), of 2.21 (1H, two doublet of doublets, J = 3,0, 5,1, 10,3 Hz), 2,24 (2H, Quartet, J = 7,6 Hz, 3'-CH2), is 2.44 (2H, doublet of doublets, J = 4,7, 9.5 Hz), (3H, singlet, 4-NCH3), 3,14 (1H, singlet, OH), 3,03 (doublet of doublets, 1H, J = 3,6, and 12.6 Hz, 5 - H); range13C NMR (chloroform-d, 300 MHz, TMC): 170,8, 87,8 (2'-C), 82,9 (17-C), 79,8 (1'-C), 65,8, 51,7, 49,9, 47,0, 39,1, 36,5, 35,0, 33,0, 32,7, 31,6, 29,8, 29,1, 25,3, 23,0, 22,6, 20,9, 14,1, 12,9, 12,5. The mass spectrum with electron ionization (relative intensity) 327 (M+, 94), 342 (100), 328 (48), 262 (94), 248 (27), 206 (22), 138 (25), 124 (63), 112 (61), 96 (33), 79 (24), 70 (85). Mass spectrum high resolution: calculated for C23H35O2N: 357,2668; found: 357,2662.

17-Hydroxy-17-butyl-4-Aza-androstane-3-one (EM-700)

To a stirred solution of EM-728 (1.0 g, 2,80 mmol) in ethyl acetate (60 ml) is added 0.10 g of palladium on activated carbon (palladium content of 10%. The flask was pumped to a vacuum of 22 mm RT.article and rinsed three times with hydrogen. Within 3 hours stir the mixture at room temperature in an atmosphere of hydrogen supplied from a cylinder. The reaction mixture was filtered through Celite 521 and washed it with ethyl acetate. After removal of the solvent to obtain the crude product, which is passed through a short column with silica gel, elwira a mixture of hexane: acetone (7:3), and receive the 1026; range1H NMR (chloroform-d, 300 MHz, TMC): 0,88 (singlet, 3H, 18-CH3), 0,90 (singlet, 3H, 19-CH3), 0,93 (triplet, 3H, J = 7,1, 7,0 Hz, 4'-CH3), of 0.79 (1H, two doublet of doublets, J = 2,9, 4,3, and 8.4 Hz), 1,14 - 1,26 (multiplet, 1H), 1,27 - 1,61 (multiplet, 18H), 1,78 - 1,87 (multiplet, 2H), 1,98 - 2,04 (multiplet, 2H), 2,44 (2H, doublet of doublets, J = 4,7, 9.5 Hz), with 2.93 (3H, singlet, 4-NCH3), 2,96 (doublet of doublets, 1H, J = 3,5, and 12.6 Hz, 5-H); range13C NMR (chloroform-d, 300 MHz, TMC): 170,8, 83,2, 65,8, 52,0, 50,1, 46,6, 36,5 (2C), 35,3, 34,4, 33,0, 31,5, 30,0, 29,1 (2C), 25,8, 25,4, 23,6 (2C), 20,8, 14,5, 14,2, 12,4. The mass spectrum with electron ionization (relative intensity) 361 (M+, 86), 346, (18), 304 (66), 286 (49), 262 (85), 248 (56), 234 (57), 140 (40), 124 (65), 113 (84), 95 (31), 70 (100). Mass spectrum high resolution: calculated for C23H39O2N: 361,2980; found: 361,2979.

17-Hydroxy-17-butyl-4-Aza-5-androst-1-EN-3-one (EM-735)

In a three-neck flask with a capacity of 50 ml, equipped with a tube for gas inlet, reflux condenser, addition funnel, mechanical stirrer and a submersible thermometer, placed 25 ml of dioxane, and then portions with stirring 0.96 g (2,66 mol) EM-700. To the resulting suspension portions added 0.73 g (3,19 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The flask was pumped (up to a residual pressure of 22 inches of RT.cent.), and rinsed three times with argon. To stir the DRB shall mol). Temperature for thirty minutes slowly rises from the 22oC to 25oC, and most of the solids when this is dissolved and formed a clear solution. The solution is stirred at a temperature of 22oC for 18 hours (after which the TLC observe the formation of two diastereomeric adducts). Then the solution is heated on an oil bath, so he gently boiling (bath temperature 120oC, the temperature of the solution 108oC). After 16 hours the reaction mixture was cooled to 22oC and poured into a mixture of 50 ml of methylene chloride and 9.2 ml of 1% aqueous solution of sodium bisulfite. The heterogeneous mixture is stirred for 15 minutes and filtered to remove the precipitate of hydroquinone. Separate the dark red organic layer and washed with 20 ml of 6N hydrochloric acid, then with saturated salt solution, dried and evaporated. The crude mixture was dissolved in a mixture of tetrahydrofuran (25 ml), water (12.5 ml) and glacial acetic acid (25 ml) and stirred at a temperature of 55oC for 3 hours. The solvent is removed, the residue diluted with 40 ml of water and extracted with dichloromethane (3 x 50 ml). The organic extracts are combined, washed with 50 ml saturated sodium chloride solution, dried and evaporated. Polucen the d 43%) of the target product EM-735: so pl. 194-196oC; IR spectrum cm-1(KBr): 3397, 2946, 2866, 1658, 1602, 1434, 1400, 1099, 1013, 820; range1H NMR (chloroform-d, 300 MHz, TMC): 0,89 (singlet, 3H, 18-CH3), 0,93 (singlet, 3H, 19-CH3), 0,94 (triplet, 3H, J = 7,6, 7.9 Hz, 4'-CH3), 0,90 - 1,01 (multiplet, 1H), 1,25 (1H, doublet of doublets, J = 2,8, 2.4 Hz), 1,39 (1H, doublet of doublets, J = 6,7, 11.7 Hz), 1,35 - 1,53 (multiplet, 9H), 1,55 - 1,60 (multiplet, 4H), 1,61 - 1,66 (multiplet, 2H), 1,78 (1H, doublet of doublets, J = 3.3, then an 11.7 Hz), of 1.85 (1H, doublet of doublets, J = 3,4, 13,2 Hz), 1,97 (triplet, 1H, J = 3.0V, 3.3V Hz) of 1.97 (1H, doublet of doublets, J = 4.2, and an 8.5 Hz), 2,95 (3H, singlet, 4-NCH3), 3,32 (doublet of doublets, 1H, J = 3,7, 13.1 Hz, 5 - H), of 5.84 (1H, doublet, J = 9.6 Hz), 6,69 (1H, doublet, J = 9.9 Hz); range13C NMR (chloroform-d, 300 MHz, TMC): 165,6, 148,7, 123,2, 83,2, 63,9, 50,0, 47,9, 46,7, 39,6, 36,5, 35,6, 34,4, 31,5, 29,8, 27,6, 25,8, 24,4, 23,6, (2C), 21,0, 14,6, 14,2, 12,2; the mass spectrum with electron ionization (relative intensity) 359 (M+, 86), 344 (12), 302 (32), 284 (15), 260 (81), 246 (27), 232 (26), 137 (44), 124 (100), 113 (46), 70 (53). Mass spectrum high resolution: calculated for C23H37O2N: 359,2824; found: 359,2805.

Getting 17(2', 3', )- 2',5'-dihydrofuran-4-methyl-4-Aza-5 - androstane-3-one (EM-638)

17-Hydroxy-17-(3-hydroxy-1'-propenyl)-4-methyl-4-Aza-5)- 2',5'-Dihydrofuran-4-methyl-4-Aza-5-androstane-3-one (EM-638)

To a solution of 17-hydroxy-17-(3'-hydroxy-1'-propenyl)-4 - methyl-4-Aza-5-androstane-3-one (730 m is anatoy temperature. The pyridine evaporated and the reaction mixture is extracted with methylene chloride. The crude product is purified evaporative chromatography, elwira a mixture of methylene chloride and methanol (9:1), and obtain 420 mg EM-638 with a yield of 88%. The IR spectrum of cm-1(KBr): 3045 (double bond), 1646 (amide); range1H NMR (chloroform-d, 300 MHz, TMC): 0,87 (singlet, 3H, 18-CH3), 0,88 (singlet, 3H, 19-CH3), is 2.41 (2H, doublet of doublets, J = 4,5, and 9.3 Hz), 2,90 (singlet, 3H, 4-NCH3), and 3.0 (1H, doublet of doublets, J = 3,5, 12,5 Hz, 5 - H), to 4.52 (2H, multiplet, O-CH2), 5,78 (multiplet, 2H, CH=CH). Range13C NMR (chloroform-d): 170,8, 132,1, 124,4, 100,6, 74,4, 65,8, 52,0, 50,8, 45,7, 39,4, 35,5, 34,8, 32,9 (2C), 29,8, 29,1, 29,0, 25,3, 23,1, 20,6, 14,2, 12,3. Mass spectrum high resolution: calculated for C22H33O2N: 343,2502; found: 343,2524.

Inhibitor of 5 - reductase mixed in the compositions in conventional amounts and appointed with the usual doses, i.e. in the same amount and with the same doses as indicated previously antiandrogen.

Combined treatment with the inhibitor of 5 - reductase and antiandrogen is a beneficial effect by inhibiting the androgen receptor through two different mechanisms, slightly decreasing testosterone levels decrease which can lead to undesirable on the androgen-dependent disease is not treatable, you can use concomitant therapy aimed at reducing levels of testosterone (in particular, surgical or chemical castration, for example, by assigning LHRH antagonists or antagonists, known from the field of technology) (table. 6).

Although the present invention is illustrated in connection with specific methods of its implementation, many other variations and modifications, as well as the use of the invention for another purpose it is quite obvious for specialists. The present invention is defined by the claims and is not limited to the above description.

1. Antiandrogenna compound of the formula I

< / BR>
where the dotted line represents an optional PI bond;

R4denotes a hydrogen atom or-CH3;

R6denotes a hydrogen atom, methyl, -CH2CH3or halogen, however, R6is hydrogen when the optional PI bond at position 6, 7 missing;

R17represents A) A halogen-substituted unsaturated hydrocarbon fragment containing at least one halogen atom, separated from the specified D - rings at least 4 intermediate carbon atoms and not containing an atom ug is gment, containing at least one halogen atom, separated from the specified D - rings at least three intermediate atoms and containing no carbon atom separated from the specified D - rings more than four intermediate atoms,

provided that R17not an-CC-(CH2)3X, when R4or R6both represent hydrogen, X represents halogen.

2. Antiandrogenna connection on p. 1, having the following molecular structure of 17 - (4' - iodobutyl)-17-hydroxy-4-androsten-3-one

< / BR>
3. Antiandrogenna connection on p. 1, selected from the group comprising 17 - (5' -chloropentyl)-17-hydroxy-6-methyl-4-androsten-3-one

< / BR>
17 - (5' -identical)-17-hydroxy-6-methyl-4-androsten-3-one

< / BR>
17-(4'-chlorbutanol)-17-hydroxy-4-androsten-3-one

< / BR>
17-(5' -chloropentyl)-17-hydroxy-6-methyl-4-androsten-4,6-Dien-3-one

< / BR>
4. Predecessor antiandrogenna compounds of General formula

< / BR>
where the dotted line represents an optional PI bond;

R4denotes a hydrogen atom or-CH3;

R6denotes a hydrogen atom, methyl, -CH2CH3or halogen, however, R6is hydrogen when the optional PI bond at the position of ragment, containing at least one halogen atom, separated from the specified D - rings at least 4 intermediate carbon atoms, and containing no carbon atom separated from the specified D - rings more than four intermediate atoms; (B) allogeneically fragment containing at least one halogen atom, separated from the specified D - rings at least three intermediate atoms and containing no carbon atom separated from the specified D - rings more than four intermediate atoms,

provided that R17not an-CC-(CH2)3X, when R4or R6both represent hydrogen, X represents a halogen, where R3is a group, which in vivo into ketogroup.

5. Antiandrogenna connection on p. 1, where the specified connection has the molecular formula

< / BR>
where n is 2 or 3;

X denotes a chlorine atom, bromine or iodine;

R4represents hydrogen;

R6represents methyl.

6. Pharmaceutical composition having antiandrogenna activity, including an active agent and a pharmaceutically acceptable diluent or carrier, wherein the active agent on the>/P>7. Pharmaceutical composition having antiandrogenna activity, including an active agent and a pharmaceutically acceptable diluent or carrier, characterized in that it comprises as active agent at least one predecessor antiandrogenna connection on p. 4 in a pharmaceutically effective amount.

8. The pharmaceutical composition according to p. 6, characterized in that the diluent or carrier suitable for topical application, as specified antiandrogenna compound is 17- (4' -iodobutyl)-17-hydroxy-4-androsten-3-one (EM-250).

 

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< / BR>
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< / BR>
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