17-n-(2,5-bis(trifluoromethyl)phenylcarbamoyl-4-aza-5-androst - 1-en-3-one, the methods of its production, pharmaceutical composition, method of treatment

 

(57) Abstract:

Describes the new compound of the formula I: 17-N-(2,5-bis(trifluoromethyl)phenylcarbamoyl-4-Aza-5-reductase type 1 and 2. Also described method thereof, pharmaceutical composition based on the specified connection and method of treatment. 5 S. and 2 C.p. f-crystals. table 1.

The object of the present invention is a specific derivative of 17-anilide-4-Aza - 5-androst-1-EN-3-one as an unusually strong and selective dual inhibitor of human 5-reductase type 1 and 2.

Androgens are responsible for many physiological functions in both men and women. The effect of androgen mediated by specific intracellular hormone receptors expressed in sensitive to androgen cells. Testosterone, the major circulating androgen secreted by the Leydig cells in the tests when the stimulation produced by the pituitary luteinising hormone (LH). However, for the action of androgen in some target tissues, such as prostate and skin, you must restore the 4,5-double bond of testosterone with the formation of dihydrotestosterone (DHT). Steroid-5-reductase in target tissues catalyzes the conversion of testosterone into DHT by the hundred in these target tissues was brightly lit by the scarce research on the steroid-5-reductase individuals, have a rudimentary prostate gland and which do not suffer from juvenile eels or male pattern baldness [1]. Thus, it is expected that inhibition of the conversion of testosterone into DHT in these target tissues will be useful in the treatment of various androgen-dependent diseases such as benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism.

In addition, it was recently established that in humans there are two isozyme 5-reductase, which differ in their tissue localization and affinity for testosterone, pH profile and sensitivity to inhibitors [2,3]. Individuals deficient in steroid-reductase studied Imperato-McGinley, are deficient in the enzyme 5-reductase type 2 [4,5], which is the dominant isozyme, localized in the prostate gland, while the isozyme type 1 dominates in the skin. The relative amount of sociocriticism and dual inhibitors of both isozyme 5-reductase depends on the type of curable diseases (benign prostatic hyperplasia, prostate cancer, acne, male alopecia or hirsutism), and stage of the disease (profilic acne in adult men).

Due to their considerable therapeutic potential inhibitors of testosterone-5-reductase [hereafter referred to as "inhibitor of 5-reductase"] was the object of active research worldwide. For example, [6-13]. The two most promising inhibitor of 5-reductase inhibitor is MK-906 (Merck), known under the generic name of finasteride and manufactured under the brand name proscar and SKF-105657 (Smithkilne Beecham), shown in Scheme B.

< / BR>
Strong inhibition of 3 hydroxy-5- steroid dehydrogenase/3-keto- 5-steroid-isomerase cells of bovine adrenal glands and pork granuloma (TBHSD) 4-azasteroid derivative, 4-MA, presented on the Scheme, and the lack of inhibition of drug finasteridum [14,15] together with a significant value TBHSD in steroid biosynthesis [16] confirm the fact that the optimal inhibitor of 5-reductase type 1 and 2 must also be selective in relation to TBHSD adrenal man.

< / BR>
The value of the selectivity of an inhibitor of 5-reductase is particularly emphasized by reports of hepatotoxicity in certain 4 - azasteroid, such as 4-MA [17,18].

One aspect of the present invention is a compound of formula (1),

< / BR>
know the appropriate solvate.

Other aspects of the invention are:

1. A method of inhibiting testosterone-5-reductase, which includes interaction of testosterone and 5-reductase with the compound of the formula (1).

2. A method of treating sensitive to androgen mediated ailments, including the introduction of an effective amount of the compounds of formula (1) to a patient in need of such treatment.

3. Pharmaceutical preparations containing a compound of formula (1) as an active ingredient.

4. A method of treating sensitive to androgen mediated ailments, including the introduction of an effective amount of the compounds of formula (1) to a patient in need of such treatment, in combination with such antiandrogens as flutamide.

5. A method of treating benign prostatic hyperplasia comprising introducing an effective amount of the compounds of formula (1) to a patient in need of such treatment, in combination with alpha 1 adrenergicheskimi receptor blocker (such as terazosina).

6. A method of treating benign prostatic hyperplasia comprising introducing an effective amount of the compounds of formula (1) to a patient in need of such Leche is e organic compounds can form complexes with solvents, in which they interact with, or from which they precipitate or crystallize. Such complexes are known as "solvate". For example, the complex with water known as "hydrate". The solvate of the compound (1) are within the scope of the invention.

Specialists in the field of organic chemistry should be borne in mind that many organic compounds can exist in more than one crystalline form. For example, the crystalline form may vary from MES to MES. Therefore, all of the crystalline forms of the compounds of formula (I) or their pharmaceutically acceptable solvate are within the present invention.

Obtaining compounds

The compound of the present invention can be obtained by methods [11, 12] , included in the footnote. For example, the compound of formula (1) can be obtained by the method presented in Scheme I and II.

< / BR>
In Scheme I, the compound of formula (V) dehydrogenation with the formation of the compounds of formula (1) by processing dehydrogenative system, for example 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDH) and bis(trimethyl-silyl)trifurcation in dry dioxane at room temperature for 2-5 hours, followed by heating at deflem>At stage I of the Scheme IA 3-oxo-4-androsten-17 carboxylic acid (II) is transformed into the corresponding amide of formula (III). This can be accomplished by activation of the acid and reaction with the aniline of formula (IIA). In particular, the reaction can be represented as a transformation of the compounds of formula (II) in the appropriate gelegenheid by processing halogenation agent such as thionyl chloride, in an aprotic solvent, such as toluene, methylene chloride or tetrahydrofuran, at temperatures from - 5oC to 10oC in the presence of a base, for example pyridine.

Intermediate gelegenheid, for example the acid chloride, may be subjected to interaction with a substituted aniline of the formula (IIA) at a temperature of 25oC to 70oC in an aprotic solvent such as tetrahydrofuran, with the formation of the amide of formula (III). The compound of formula (IIa) is a commercially available product (Aldrich Chemical Company, Milwaukee, Wl 53201).

In Stage 2, the compound of formula (III) transform by oxidation, for example by treatment of aqueous potassium permanganate and periodate potassium alkaline conditions at reflux distilled t-butanol, in the derived 5-oxo-A-nor-3,5-secondrate-3-oewoi acid of formula (IV).

< / BR>
The same scheme II, the compound of formula (I) can be obtained from 3-oxo-4-Aza-5-androst-1-ene-17-carboxylic acid of formula (VI) [20] the method according to Scheme IA, step 1.

The specialist should be aware that at an earlier stage of obtaining compounds of formula (I) or MES may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

The protective groups used in obtaining the compounds of formula (I), can be used in the usual way [21,22].

Remove any existing protective group can be carried out in the usual ways. Arylalkyl group, such as benzyl, can be derived by hydrolysis in the presence of a catalyst, for example palladium or charcoal; acyl group such as N - benzyloxycarbonyl may be removed by hydrolysis, for example with bromovalerate in acetic acid, or by restoring, for example catalytic hydrogenation.

It should be borne in mind that in any of the methods described above can axis previously. Therefore, the reaction stage, including the removal of the protective groups of the protected derivative of General formula (I) or its salt can be carried out as a result of implementation of any of the following existing methods:

(I) removing any protective groups; and

(II) the conversion of compounds of formula (I) or MES in its pharmaceutically acceptable MES.

Being used as the last major stage in the sequence of receipt, the basic methods described above to produce compounds according to the invention can also be applied to the introduction of the desired groups at an intermediate stage in obtaining the desired connection. Therefore, it should be borne in mind that in such multi-stage processes the sequence of reactions should be selected so that the reaction conditions had no impact on those groups present in the molecule, which is desirable in the final product.

The compound of formula (I) and intermediate compounds (II) - (VI) described in Schemes 1 and II can be purified by usual methods known from the prior art, for example by chromatography or crystallization.

In vitr analysis

Steroid-5-reductase

The myths of palatov with benign prostatic hyperplasia (DPG); 2) SF9 cells infected with recombinant baculovirus that expresses the human 5-reductase type 2. Microsome assay was obtained by homogenization of tissue or cells with subsequent differential centrifugation of the homogenate. Microsome extracts were incubated with various concentrations of [1,2,6,7-3H]-testosterone, 1 mm NADP and varying amounts of compounds of formula 1, that is, the test compound in a buffer containing NADP-regenerating system, capable of maintaining the concentration of NADP during the period of time within the interval 0.5-240 minutes. As a control study was carried out appropriate incubation in the absence of the test compound. For measuring IR50for clone 1 all components involved in the analysis, except for testosterone, were subjected to pre-incubation for 10 minutes at pH 7.0, and after adding 100 nm testosterone samples kept for 10-120 minutes to test. To measure IR50for clone 2, all components involved in the analysis, except for testosterone, were subjected to pre-incubation for 20 minutes at pH of 6.0, and after adding 8 nm testosterone samples kept within 20-40 mi is the I with the corresponding transformation in the control study were determined using liquid chromatography high resolution (IHVR) with radiochemical detection. The results of these analyses, expressed as IR50presented in Table 1.

3-hydroxy-5-steroid dehydrogenase/3-keto- 5-steroid - isomerase

Enzymatic activity was measured using microsome assay, obtained from the tissues of the human adrenal gland. Microsome assay was obtained by homogenizing the tissue with subsequent differential centrifugation of the homogenate. Microsome extracts were incubated with different concentrations of dehydroepiandrosterone (DHEA), 1 mm NAD+and variable amounts of the compounds of formula (I), i.e. the test compound in buffer with pH 7.5 over a period of time in the interval from 1 to 60 minutes. As a control study was carried out appropriate incubation in the absence of the test compound. The percentage conversion of DHEA to Androstenedione in the presence of test compounds is compared with the corresponding transformation in the control study were established using GHUR with radiochemical detection. The results of these analyses, expressed in the form Kipresented in Table 1.

In vivo determination of inhibitors of steroid-5-reductase

In vivo activity of inhibitors of steroid-5-reductase can be defined in hroni the skin injected with testosterone (20 µg/rat) and test compound (0.01 to 10 mg/kg) or oral media for 7 days. Then kill animals and weigh their prostate gland. The reduction in the size and weight is stimulated by testosterone prostate glands showed the activity of the test compounds. Known inhibitors of steroid 5 reductase was tested in parallel in order to confirm the consistency of the method of analysis.

Practical application

Inhibitor of steroid-5-reductase of the present invention promising for the treatment of ontogenetically disease, such as benign and malignant diseases of the prostate, especially benign prostatic hyperplasia, in a manner similar to methods developed for other inhibitors of 5-reductase, such as finasteride and SKF105657. However, the connection of the present invention has unexpectedly long half-life and efficiency compared with finasteride and SKF105657. Data on the correlation of in vitro, in vivo in rats and clinical results in humans in relation to an inhibitor of 5-reductase lead [20,23,24].

The connection according to this invention is promising for the treatment of prostatitis, prostate cancer, mediated by the androgen skin diseases such as acne, here can be cured using this connection.

The amount of the compounds of formula (I), necessary for it to be effective as an inhibitor of 5 - reductase, will of course vary depending on the particular mammal to be treated, and it ultimately shall be determined at the discretion of the practicing physician or veterinarian. Factors that must be considered include the condition to be cured, route of administration, the nature of the drug, the body weight of the mammal, and surface area, age and General condition of the mammal. However, for patients - people suitable dose of the inhibitor of 5-reductase is in the range from about 0.001 to about 2 mg/kg of body weight per day, preferably in the range from approximately 0.005 to approximately 1 mg/kg / day.

The total daily dose may be entered as a single dose, multiple doses, for example from two to six times a day, or by intravenous infusion of a certain length. Dosages above or below the above interval are within the present invention and can be entered in an individual patient, if this is desirable or necessary. For example, for a mammal weighing 75 kg doses have stood mg per day. Because of the long half-lives of the compounds of the present invention for many patients treatment may be required only every other day or even every third day. If discrete multiple doses, the treatment can usually be concluded in the introduction of 2.5 mg of the compounds of formula (I) four times a day.

Drugs

The preparations according to the present invention for medical use contain the active compound, for example a compound of formula (I), together with an acceptable carrier, and possibly other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense that it must be compatible with other ingredients of the drug and should not be harmful to its recipient.

The present invention also provides a pharmaceutical preparation containing the compound of formula (I) together with its pharmaceutically acceptable carrier.

The drugs include drugs that are suitable for oral, local, rectal or parenteral (including subcutaneous, intramuscular or intravenous) administration. Preferred are preparations suitable for oral or parenteral administration.

The preparations according to the present invention suitable for oral administration may be made in the form of discrete units such as capsules, starch capsules, tablets or pellets, each of which contains a predetermined quantity of active compound, such as powder or granules, or a suspension or solution in an aqueous solution or nonaqueous solution, such as a syrup, elixir, emulsion or dose of a liquid medication.

A tablet may be made by extrusion or molding, possibly with one or more acceptable ingredients. Compressed tablets may be made by pressing the respective setting of the active compound in free - flowing form such as powder or granules, possibly mixed with acceptable ingrediensene agents. Molded tablets may be made by molding in a particular installation of a mixture of powdered active connection with any acceptable media.

The syrup or suspension can be made by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, to which may also be added any acceptable ingredients. Such acceptable ingredient(s) may include corrigent, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, in particular alcohol, containing some hydrogen atoms, for example glycerol or sorbitol.

Preparations for rectal injection can be made in the form of suppositories with an acceptable carrier, for example cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany) as the basis of the suppository.

Preparations suitable for parenteral administration, usually contain a sterile aqueous solution of the active compound, which is preferably isotonic with the blood of the recipient. These preparations may usually contain distilled water, 5% dextrose in distilled water or brine and soedinenii comprise concentrated solutions or solids, containing the compound of formula (I), which, when dissolved in an appropriate solvent to form a solution suitable for the above parenteral administration.

Local preparations include ointments, creams, gels and lotions that can be produced by appropriate methods known in pharmacy. In addition to the base of an ointment, cream, gel or lotion and an active ingredient such local preparations can also contain preservatives, fragrances and more active pharmaceutical agents.

In addition to the above ingredients, the preparations according to this invention may also comprise one or more additional acceptable ingredients used in manufactured pharmaceutical drugs, such as diluents, buffers, corrigentov binding substances, surface-active agents, thickeners, lubricants, suspendresume agents, preservatives (including antioxidants) and the like.

EXAMPLES

The following examples illustrate aspects of this invention, but are not considered as constraints. Symbols and conventions used in these examples are consistent with the symbols and understandings that ispolzuyutsya-4-Aza-5 - androst-1-EN-on

(Synthesis according to scheme 1)

A. 17-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl - androst-4-EN-3-one

To a solution of 3-oxo-4-androsten-17-carboxylic acid [18]

(17,2 g of 54.4 mmol), dry THF (180 ml) and dry pyridine (7 ml), with 2oC add thionyl chloride (5.1 ml, and 70.8 mmol). The reaction mixture was stirred for 2oC for 20 minutes and then stirred at room temperature for 40 minutes. Then the reaction mixture is filtered and the solid washed with toluene. The filtrate is concentrated under vacuum to an oil, which is diluted with dry THF (150 ml) and dry pyridine (7 ml). To the resulting dark solution was added 2,5-bis-(trifluoromethyl)aniline (9.4 ml, to 59.8 mmol) and the reaction mixture is refluxed for 5 hours, diluted with methylene chloride, extracted sequentially 1 N HCl and brine, dried over sodium sulfate and filtered. The filtrate is concentrated and applied on a column of 500 g of silica gel, the column elute 15-30% gradient ethyl acetate-hexane, after receiving the concentration of 17-N-(2,5 - bis(trifluoromethyl)phenylcarbamoyl-androst-4-EN-3-one as not quite white foam; yield: 18.3 g (64%).

B. 17-N-(2, 5-bis(trifluoromethyl))phenylcarbamoyl-5 - oxo-A-nor-3, 5-secondrate-3-oeva acid

To CIPA, to 34.9 mmol), obtained according to paragraph And add t-butanol (275 ml), sodium carbonate (6.3 g, 50.8 mmol) and water (36 ml), after about 45 minutes, 75oC-s ' solution of potassium permanganate (or 0.38 g, 2.4 mmol), periodate sodium (52,2 g, 245 mmol) and water (311 ml). After additional reflux distilled for 15 minutes heterogeneous mixture is cooled to room temperature and add brownmillerite (50 g). The reaction mixture was filtered through a layer of brownmillerite (50 g), the solid phase is washed with water, and the filtrate is concentrated under vacuum, removing the t-butanol (approx. 175 ml). The resulting aqueous solution is acidified to pH 2 by addition of 36% HCl and extracted four times with chloroform. The chloroform layers are combined and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo education 17-N-(2, 5 - bis(trifluoromethyl))phenylcarbamoyl-5-oxo-A-nor-3, 5-secondrate - 3-oewoi acid in the form of not quite white matter; yield: 20.5 g (100% crude). This product is directly passed to the stage Century.

Century 17-N-(2, 5-bis(trifluoromethyl))phenylcarbamoyl-4-Aza - androst-5-ene-3-one

To a suspension of 17-N-(2,5 - bis(trifluoromethyl))phenylcarbamoyl - 5-oxo-A-nor-3,5-secondrate - 3-oewoi acid (20.5 g, 34.8 mmol), obtained in stage B, in dry ethylene glycol (100 ml) under th solution is heated to 180oC for 45 minutes, and 12 minutes to 180oC, the reaction mixture is cooled to 70oC and over a period of time equal to 5 min, add water (116 ml). The resulting suspension is cooled to 7oC and stirred for 10 minutes and then filtered under vacuum. The solid phase is washed with water (60 ml) and then dissolved in chloroform and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue is dissolved in chloroform and applied to a column with 110 g of silica gel, the column elute 2-5% gradient of isopropanol-chloroform, resulting in the 17-N-(2,5-bis(trifluoromethyl))phenyl-carbarnoyl-4-Aza-androst-5-ene-3-one as not quite white matter; yield: 16.5 g (90%).

, 17-N-(2,5-is(trifluoromethyl) phenylcarbamoyl-4-Aza - 5-androstane-3-one

To a solution of 17-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl - 4-Aza-androst-5-ene-3-one (8,9 g, and 16.7 mmol) in acetic acid (120 ml) is added platinum oxide (0.9 g). The resulting mixture is saturated up to 50 psi with hydrogen and heated at 60-70oC for 6 hours. After substitution of the hydrogen atmosphere with nitrogen, the reaction mixture was filtered through brownmillerite, a layer of brownmillerite washed with acetic acid (30 ml), chloroform (60 ml) and toluene (200 ml). The filtrate, concentri is from a mixture of ethyl acetate-heptane to obtain, after drying in vacuum at 85oC within 1 hour, 17-N-(2,5 - bis(trifluoromethyl)phenylcarbamoyl-4-Aza-5-androstane-3-one; yield: 4,78 g (54%); so pl. 245-247oC. Analyte. the calculated composition for

C27H32F6N2O2: C, 61,12; H, BETWEEN 6.08; N, 5,28. Found: C, 61,13; H, 6,12; N, To 5.21.

D. 17-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4 - Aza-5-androstane-1-EN-3-one

To a suspension of 17 N-(2,5-bis(trifluoromethyl))phenylcarbamoyl- -4-Aza-5-androstane-3-one (7,24 r, 13.7 mmol) and 2,3-dichloro - 5,6-dicyano-1,4-benzoquinone (3,41 g, 15 mmol) in dry dioxane (168 ml) at room temperature add bis(trimethylsilyl) triptorelin (14,5 ml of 54.6 mmol). After stirring at room temperature for 7 hours, the reaction mixture was refluxed for 18 hours. Received the dark solution is cooled to room temperature and concentrated under vacuum to a dark oil. To the oil is added methylene chloride (100 ml) and 1% solution of sodium bisulfite (40 ml), a two-phase mixture is rapidly stirred for 15 minutes and filtered. Two filtered layer separated, the methylene chloride layer is washed successively 2N HCl and brine, dried over sodium sulfate, filtered and concentrated to a brown oil. Oil diluted with toluene and applied n is(trifluoromethyl) phenylcarbamoyl-4-Aza - 5-androst-1-EN-3-one in the form of foam; output: 3,38 r (47%). This product is crystallized from a mixture of ethyl acetate-heptane (1:1) with the formation of white matter; so pl. 244-245oC.

13C NMR (100 MHz, CHCl3) 171.31, 166.77, 151.04, 136.35 (q, J = 1.4 Hz), 135.01 (q, J = 33.1 Hz), 126.73 (q, J = 5.4 Hz), 123.44 (q, J = 273.5 Hz), 123.03 (q, J = 273.2 Hz), 122.84, 121.58 (qq, J = 30.4, 1.0 Hz), 120.37 (q, J = 3.6 Hz), 120.29 (q, J = 3.9 Hz), 59.58, 58.33, 55.69, 47.46, 44.78, 39.30, 37.81, 35.29, 29.34, 25.70, 24.17, 23.59, 21.15, 13.40, 11.91.

Analyte. raschet. composition for C27H30F6N2O2: C, 61.36; H, 5.72; N, 5.30. Found: C, 61.36; H, 5.73; N, 5.23.

Example 2

17-N-(2.5-bis(trifluoromethyl))phenylcarbamoyl-4 - Aza-5 androst-1-EN-3-one

(Synthesis scheme II)

A suspension of 3-oxo-4-Aza-5-androst-1-ene - 17 carboxylic acid (300 g, 0.95 mol) in 9 L of toluene is stirred mechanically and heated at reflux distilled up until 1 L of toluene is not removed by distillation. The mixture is cooled to - 2 2oC and diluted with toluene (1 L), dimethylformamide (10 ml) and pyridine (191 ml, is 2.37 mol). To a stirred suspension is added thionyl chloride (135 g, 1,14 mol) maintaining the temperature below 0oC. After stirring at 0 to 20oC for 2 hours add 2,5-bis(trifluoromethyl)-aniline (238 g, 1.04 mol) and dimethylaminopyridine (2.0 g, to 0.016 mol), the mixture is heated at 100oC SOLOM (1 L), dried over magnesium sulfate and filtered. After washing the solid phase with toluene (100 ml) solution of concentrated at 40-50oC (50-100 mm) up to a volume of approximately 2 Liters and add acetonitrile. The mixture is again concentrated as before until, until crystallization. The resulting suspension is stirred at room temperature for 15-16 hours, cooled to 0-10oC, the product is collected by filtration, resulting in the 17-N-(2,5-bis(trifluoromethyl)phenyl)-carbarnoyl-4-Aza-5 - androst-1-EN-3-one as a white crystalline substance, output: 243 g (48%); so pl. 245-245,5oC, which is identical with the substance obtained by the process of example 1.

Example 3

Pharmaceutical preparations of Active compound" is a compound of formula (I)

(A) Transdermal system for 1000 pieces

Ingredients - Number

Active connection - 40g

Silicone fluid - 450 g

Colloidal silicon dioxide - 25g

Mix together silicone fluid and an active connection, and for increasing the viscosity of the added silicon dioxide. The material is then metered into the polymer laminate, zapavety then by heating, consisting of the following components: poly is s, the control membrane, which is a polyolefin (such as polyethylene, polyvinyl acetate or polyurethane), and impervious core of the membrane, made of polyester multilaminate. The obtained laminated film was then cut into fragments of size 10 cm2.

(B) Oral tablet for 1000 tablets

Ingredients - Number

Active connection - a 20 g

Starch - a 20 g

Magnesium stearate 1 g

Active connection and starch granularit with water and dried. To the dried granules add magnesium stearate, and the mixture was thoroughly stirred. The stirred mixture was molded into tablets

(C) Suppository - for 1000 suppositories

Ingredients - Number

Active connection - 25g

Salicylate theobromine sodium - 250 g

Witepsol S55 - 1725

Inactive ingredients are mixed and melted. Then, the molten mixture is distributed active compound is poured into molds and leave to cool.

(G) Injection - for 1000 capsules

Ingredients - Number

Active connection - 5 g

Tabularasa agents - q.s.

Propylene glycol - 400 mg

Water for injection, 600 ml

Active connection and tabularasa agents RA is for injection, the resulting solution is filtered, filled them ampoules, sealed and sterilized by autoclaving.

(D) Capsule - for 1000 capsules

Ingredients - Number

Active connection - a 20 g

Lactose - 450 g

Magnesium stearate 5 g

Well powdered active compound is mixed with lactose and stearate and Repack in gelatin capsules.

Example 4

17-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-androst-4-EN-3 - one, obtained as a result of the implementation of stage (A) of Example 1, is subjected to the interaction with acetanhydride with getting 17 N - acetyl-N- (2, 5-bis(trifluoromethyl))phenylcarbamoyl-androst - 4-EN-3-one. Then this compound is subjected to subsequent interactions according to the stages (B), (C) and (D). In the conditions of stage (D) thus obtained compound is subjected to interaction with bis(trimethylsilyl) trifurcation with getting 17-N-acetyl-N-(2,5-bis (trifluoromethyl))phenylcarbamoyl-4-Aza-5 - androst-1-EN-3-one, the hydrolysis of which in the acidic environment get 17-N-(2, 5-bis(trifluoromethyl))phenylcarbamoyl-4-Aza - 5-androst-1-EN-3-one.

3-oxo-4-Aza-5 androst - 1-ene-17 carboxylic acid is subjected to interaction with acetanhydride with 3-oxo-N-acetyl-4-Aza-5-androst-1-ene-carboxylic 17 keys (2,5 - bis(trifluoromethyl))phenylcarbamoyl-N-acetyl-4-Aza-5-androst-1 - EN-3-one. This compound is subjected to hydrolysis in an acidic medium to obtain 17-N -(2, 5-bis(trifluoromethyl))phenylcarbamoyl - 4-Aza-5-androst-1-EN-3-one

LITERATURE

1. McGinley, J. et a1. , The New England J. of Medicine, 300, 1233 (1979).

2. Russell, D. W. et a1., J. Clin.Invest., 89, 293 (1992).

3. Russell, D. W. et a1., Nature, 354, 159 (1991).

4. Russell, D. W. et a1., J. Clin.Invest., 90, 799 (1992).

5. Russell, D. W. et a1., New England J. Med., 327, 1216 (1992).

6. Hsia, S. & Voight, W., J. Invest.Derm., 62, 224 (1973).

7. Robaire, B., et a1., J. Steroid Biochem., 8, 307 (1977).

8. Petrow, V., et a1., Steroids, 38, 121 (1981).

9. Liang, T. et a1., J. Biochem Sterold., 19, 385 (1983).

10. Holt, D. et a1., J. Med. Chem., 33, 937 (1990).

11. U. S. Patent No. 4,377,584.

12. U. S. Patent No. 4,760,071.

13. U. S. Patent No. 5,017,568.

14. Tan, C. H.; Fong, C. Y.; Chan, W. K. Biochem. Biophys. Res. Comm., 144, 166 (1987).

15. Brandt, M.; Levy, M. A. Biochemistry, 28, 140 (1989).

16. Potts, G. O. et a1., Steroids, 32, 257 (1978).

17. McConnell, J. D. The Prostate Suppi., 3, 49 (1990).

18. Rasmusson, G. H. et a1., J. Med.Chem., 27, 1690 (1984).

19. Bhattacharya, A. et a1., J. Am. Chem. Soc., 110, 3318 (1988).

20. Rasmusson, G. H. et a1., J. Med.Chem., 29, 2298 (1986).

21. Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie. Plenum Press, London (1973).

22. Protective Groups in Organic Synthesis. Theodora Gre en, John Wiley and Sons, New York (1981).

23. Brooks, J. R. et a1., Steroids, 47, 1 (1986).

24. Stoner, E. et a1., J. Steroid Biochem. Molec. Bio1.,37, 375 (whitesky composition for inhibition of the enzyme testosterone-5-reductase, characterized in that it contains a connection on p. 1 and pharmaceutically acceptable carrier.

3. A method of obtaining a connection on p. 1, characterized in that conduct dehydrogenization the compounds of formula V

< / BR>
in which the functional group may be protected,

and, if necessary and/or desirable, subjecting the resulting compound to one or more than one additional reactions involving the removal of any protective group or groups.

4. A method of obtaining a connection on p. 1, characterized in that the compound of formula VI

< / BR>
in which the functional group may be protected,

subjected to interaction with the compound of the formula IIa

< / BR>
in which the functional group may be protected,

and, if necessary and/or desirable, subjecting the resulting compound to one or more than one additional reactions involving the removal of any protective group or groups.

5. The method according to p. 4, characterized in that the compound of formula VI before interaction with the compound of the formula IIA process of halogenation agent in the presence of a base.

6. The method of treatment of the senses is of, characterized in that the specified mammal is administered is effective against sensitive to androgen mediated ailments the number of connections on p. 1.

7. The method according to p. 6, characterized in that sensitive to androgen or indirectly to them, the disease is benign prostate hypertrophy, prostate cancer, polycystic ovarian disease, acne, male pattern baldness and hirsutism.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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