HU211535A9 - Novel 17beta-substituted 4-azaandrostane derivatives, pharmaceutical compositions containing them and process for preparing same - Google Patents

Description

The present invention provides novel 17β-substituted-4-aza-androstane derivatives of formula (I) wherein R is hydrogen or (C 1 -C 3) alkyl,

R ¹ and R ² are the same or different and are hydrogen or a C 1-4 alkyl group with the proviso that both can be hydrogen only when n is greater than 5; or

R ¹ and R ^{2 taken} together with a C 5-7 carbon ring attached to the same ring carbon atom at each of its two adjacent carbon atoms, n represents an integer of 4 to 7, and - the bond line represents a single or double bond and containing pharmaceutical compositions.

The invention also relates to processes for the preparation of these compounds and compositions.

The compounds of formula (I) are novel and possess valuable biological activity, namely by inhibiting the conversion of testosterone to dihydrotestosterone by inhibiting the function of the 5α-reductase enzyme.

The invention also relates to methods of treatment comprising administering to a mammal, including man, a therapeutically effective dose of a compound of formula (I) to inhibit the action of the 5α-reductase enzyme.

Of the steroid hormones, androgens are responsible for all the physical characteristics that distinguish males from females. In males, two steroids, testosterone, and its reduced metabolite, dihydrotestosterone (DHT), are primarily responsible for the androgenic effects. The conversion of testosterone to DHT in mammalian tissues is catalyzed by the steroid 5α-reductase enzyme in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH). In males, testosterone is predominantly synthesized by the testis, from where it passes through the bloodstream to various tissues. In some androgen-sensitive tissues, where significant steroid 5α-reductase enzyme activity is detected, such as in prostate and skin tissue, androgen activity is directly mediated by dihydrotestosterone. which is synthesized locally from testosterone taken from the bloodstream.

Increased tissue concentrations of DHT play a role in the development and maintenance of several androgen-dependent diseases. Such diseases include benign prostatic hyperplasia, acne, seborrhea, female hirsutism, and androgenic alopecia [J. Clin. Invest., 49, 1737 (1970); J. Invest. Dermatol., 56, 366 (1971) and 75, 83 (1977); Clin. Dermatol. 6: 122 (1988)]. Any substance which inhibits the steroid 5α-reductase and thus reduces the amount of DHT in the tissues may be useful in the treatment of these DHT-dependent diseases.

This recognition led the research to synthesize 5α-reductase enzyme inhibitors, and several sterane-framed 5α-reductase enzyme inhibitors have been described in the literature over the past one and a half decades.

The most abundant class of known 5α-reductase inhibitors is the 4-aza-17-carbamoyl steroid.

A compound containing 4-Aza is disclosed in U.S. Patent 4,377,584 and J. Steroid Biochem., 19, 385-390. (1988).

U.S. Pat. No. 4,220,775 discloses the synthesis of 17β- (N, N-diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one. Based on literature data, the compound has been extensively bioassayed.

European Patent Publication No. 155,096 discloses novel 17β- (N-monosubstituted-carbamoyl) -4-aza-5α-androstenones, such as 17β- [N- (1,1-dimethylethyl) carbamoyl] 3-oxo-4. describes the synthesis of -aza-5a-androst-1-ene (a compound known as Finasteride, MK-906). The above compound is currently used in therapy.

EP 271 220 describes the synthesis of oxidized analogs of 17β- (N-monosubstituted-carbamoyl) -4-aza-5α-androstan-3-one derivatives. The compounds described are characterized in that the alkyl substituent of the 17β- (Ν-Γηοηο8ζυ65ζύωέ1ΐ ^ 3τ03Γηοί1) group may contain a hydroxyl, carboxyl or alkoxycarbonyl group.

European Patent 285,382 discloses the synthesis and use of 17β-Γηοηο $ ζυ05ζ (ύυά1ΐ ^ 3Γ03Γηοί]) -4-aza-5α-androst-1-ene-3-one numerals for the treatment of baldness. The above-mentioned compounds are proposed for the treatment of prostate carcinoma.

EP 367 502 discloses a novel structure of the 17-substituted aminocarbonyl side chain of 17β-substituted-3-oxo-4-aza-steroids by the action of the corresponding imidazole derivative of the corresponding carboxylic acid on Grignard.

European Patent No. 462,662 discloses 17β (N-monosubstituted adamantylcarbamoyl) and norbornylcarbamoyl) -4-aza-5a-androst-1-en-3-one and -4-aza-5a-androstane. -3-on describes the synthesis. The patents also contemplate the use of compounds having 5α-reductase inhibitory activity.

European Patent 277,002 describes the synthesis of 4-aza-steroids. which may have a double bond at position 8 (14), 7 (8) or 16 (17) and / or at position 1 (2). The side chain 17 is characterized by the presence of an aminocarbonyl moiety, but at position 17 there may be other side chains containing oxygen or nitrogen.

German Patent No. 3,607,651 proposes a combination of aromatase inhibitors and 5α-reductase inhibitors for the treatment of prostatic hyperplasia. As aromatase inhibitor, 1-methyl-androst-1,4-diene-3,17-dione. 173- (N, N-Diethylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one is proposed as a 5α-reductase inhibitor.

U.S. Patent 4,885,289 discloses the topical use of 5α-reductase inhibitors.

PCT Patent Publication No. WO 91/12261

The application of A9 describes the synthesis of 4-aza-steroids having a 17-position side chain different from the above. One representative compound is, for example, 4-methyl-173- [N-isopropyl-N- (N, N-diisopropylcarbamoyl) carbamyl] -4-aza-5α-androstan-3-one.

EP-A-200 859 describes the synthesis of novel 4-aza-steroids having a side chain at the 17-position of the formula -X-COZ. X represents a chemical bond, either a straight or branched C 1-6 aliphatic chain, and Z represents an alkoxy or a substituted amino group. The compounds may also contain an oxo group at the 12-position of the sterane backbone.

Hungarian Patent Application Serial No. 3396/91, Publication No. T / 59,417, relates primarily to the preparation of 4-aza-steroid derivatives having an alkyl group substituted with an aromatic group at the 17-position of the aminocarbonyl chain for the treatment and prevention of hyperplasia.

A summary of the various types of aza steroids, in particular 5α-reductase inhibitor, is described in J. Med. Chem., 27, 1690-1701. (1984). The summary also contains biological data.

A J. Med Chem .. 29. 2298–2315. (1986) investigate the structure-activity relationship of 5-reductase inhibitors containing the 4-aza moiety.

A Steroids 47/1, 1-19. (1986) a

The activity of 4-aza-steroids is 5a-reductase inhibitor and the biological effect of its anti-androgen properties in the rat.

The Syn. Comm., 30 (17), 2683-2690. (1990) describe the conversion of acylimidazole derivatives. especially carboxylic acid amide derivatives.

The large number of cited literature and patent documents also confirm the importance of 5α-reductase inhibitors.

It is an object of the present invention to provide novel compounds which exhibit higher biological potency and / or more selectively inhibit the activity of 5α-reductase. Namely, the indicated properties lead to a more advantageous pharmaceutical application than the known active substances.

Surprisingly, it has been found that the specific selection of the 17-position aminocarbonyl substituent of the 17? -Substituted-4-aza-androstene and-androstane derivatives of formula I according to the invention significantly increases the activity of 5? -Reductase inhibitor. .

According to the present invention, the 17β-substituted-4-aza-androstane derivatives of formula (I) are prepared by reacting a 4-aza-17-halo-androstene derivative of formula (II) wherein R and a the above, and X represents a chlorine, bromine or iodine atom - in a dipolar aprotic solvent, a palladium) salt. a tertiary amine base and phosphines. or in the presence of a palladium complex) and a tertiary amine base, with a cyclic amine of formula (III) wherein n, R ¹ and R ² are as defined above, under a carbon monoxide atmosphere at a temperature of 3580 ° C and optionally and a double bond at position 16-17 of a compound of formula I having a 1-2 position at position 1-2 - wherein R, R 'and R ² are

A 5-6 position --- bond line and n represents the above compound of formula I having a double bond at positions 1-2 and 16-17 wherein R, R ¹ , R ² , at position 5-6 and n is as defined above - dehydrogenated and / or, if desired, a resulting compound of formula I having a double bond at position 16-17

- where R, R ¹ , R ^{2 are, at} the 1-2 and 5-6 positions - the bond line and n is as defined above - by the catalytic hydrogenation of the compound of formula (I) - in which the bond is single-bonded - wherein R, R ¹ , R ² and n are as defined above, and / or, if desired, a compound of formula (I) obtained which has a single bond at positions 1-2, 5-6 and 1617 - wherein R, R ¹ , R ² and n represent a single bond to a compound of formula I having a double bond at position 1-2, wherein R, R ¹ , R ² and n are as defined above and at positions 5-6 and 16-17. - dehydrogenating.

In the reaction of the compounds of formula (II) and (III), palladium (II) salts are preferably palladium (II) diacetate or dichloride, tertiary amine bases are preferably triethylamine and phosphine is triphenylphosphine, 1,4-bis (diphenyl). phosphino) butane, 1,2-bis (diphenylphosphino) ethane or 1,3-bis (diphenylphosphino) propane. The reaction may also be carried out by replacing palladium (II) salt and phosphines with a phosphine complex of a palladium (II) salt, such as [bis (triphenylphosphino) palladium (II)] dichloride or? -Diacetate used.

The solvent for the above reaction is a dipolar aprotic solvent such as dimethylformamide or dimethylsulfoxide.

The compounds of formula (I) obtained in the reaction are further converted within the scope of formula (I).

For example, the resulting compounds of formula (I) having a double bond at position 16-17 and a single bond at position 1-2 (1) can be dehydrogenated to give compounds of formula (I) having a double bond at positions 1-2 and 16-17.

The dehydrogenation is preferably carried out in the presence of a silylating agent such as bis (trimethylsilyl) trifluoroacetamide and a quinone compound such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or phenyl selenic anhydride.

Another possibility for subsequent conversion is to obtain a compound of formula I having a double bond at position 16-17 - wherein R, R ¹ , R ² , at position 1-2 and 5-6 and n is as defined above, by catalytic hydrogenation to form a single bond in which R, R ¹ , R ² and n are as defined above. As a further post-conversion, if desired, ka3 is thus formed

The compound A9 can be dehydrogenated in the 1-2 position as described above.

In a preferred embodiment of the process according to the invention, a 4-aza-17-halo-androstene derivative of the formula II is present in dimethylformamide in the presence of palladium (II) diacetate, triphenylphosphine and triethylamine. ), such as hexamethyleneimine, heptamethyleneimine, 4-methylpiperidine, 3,3-dimethylpiperidine, 2,6-dimethylpiperidine, 2,5-dimethylpyrrolidine or 3-azaspiro [5.5] undecane in a carbon monoxide atmosphere for 1.5-2 hours at 60 ° C.

After completion of the reaction, the amines and dimethylformamide were distilled off under reduced pressure, the residue was dissolved in chloroform, and the solution was washed with water, aqueous hydrochloric acid, aqueous sodium bicarbonate solution and again with water. After drying, the solvent is distilled off, and the residue is purified by chromatography or recrystallization or the two methods are combined.

The resulting 4-aza-17-carboxamido derivatives of formula (I) are obtained. which contain a double bond at positions 16-17, a single or double bond at positions 5-6, for example in the presence of a silylating agent and quinones, or by other means, such as phenylselenic anhydride, to dehydrogenate the sterane backbone

1-2 position.

According to the invention, the following is preferred. Toluene, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, bis (trimethylsilyl) trifluoroacetamide and a catalytic amount of trifluoroacetic acid are added to the compound of formula I to be dehydrogenated. The reaction mixture was stirred under nitrogen for 18 hours at room temperature, while the progress of the reaction could be monitored by liquid chromatography. After the starting material was reacted, cyclohexane-1,3-dione was added to the reaction mixture, which was further stirred for 3 hours to remove excess 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The reaction mixture was then heated to gentle reflux for 20 hours. During this time, the adduct decomposes and a double bond is formed at the 1-2 position of the steroid backbone. After cooling the toluene solution, dichloromethane was added to the solution, followed by stirring with saturated sodium bicarbonate solution. After separation of the phases, the organic phase is re-extracted with sodium bicarbonate solution, and after drying the solvent is removed under reduced pressure and the residue is purified by recrystallization.

The resulting unsaturated derivatives are hydrogenated to produce the saturated compounds of formula (I).

The catalytic hydrogenation may be carried out, for example, in the presence of palladium on carbon and hydrogen, in an alcoholic solution, or in the presence of palladium on carbon in formic acid or in glacial acetic acid in the presence of platinum (IV) oxide catalyst and hydrogen.

In the former case, for example, the unsaturated compounds of formula I are dissolved in ethanol and then hydrogenated at atmospheric pressure in the presence of palladium on carbon and hydrogen gas at room temperature. After the reaction was complete, the catalyst was filtered off, the solvent was evaporated and the residue was purified by recrystallization.

The saturation of the double bonds can also be accomplished by dissolving the unsaturated compounds of formula I in formic acid and then hydrogenating with stirring in the presence of palladium on charcoal or hydrogenation in glacial acetic acid in the presence of a platinum oxide catalyst. After filtering off the catalysts, the formic acid or glacial acetic acid used as solvent is distilled off and the residue is purified by recrystallization or chromatography.

By carrying out the hydrogenation and dehydrogenation steps in the appropriate order, the compounds of formula (I) in which only the double bond is in the 1-2 position can be prepared. To do this, the compounds of formula I containing the double bond (s) obtained by reaction of the compounds of formula (II) and (III) are first saturated by hydrogenation, and the resulting saturated compounds of formula (I) are then dehydrogenated as described above. 1-2 position.

The starting material for the preparation of compounds of formula I is of formula II

Preparation of 4-aza-17-halo-androstene derivatives is known in the art. Pharm. Sci .. 63, 19–23. (1974); J. Med. Chem., 27, 1690 (1984); J. Org. Chem., 46, 1442-4, 6, (1981)] 4-aza-5a-androstane-3,17-dione, 4-aza-androst-5-ene-3,17-dione and their N-alkyl- derivatives thereof as follows.

Known 4-aza-5α-androstane-3,17-dione, 4-azaandros-5-ene-3,17-dione. or the N-alkyl derivatives thereof are dissolved in ethyl alcohol and then triethylamine and hydrazine hydrate are added. The reaction mixture is heated to reflux. After completion of the reaction, excess hydrazine hydrate and triethylamine were distilled off, the residue was precipitated with water, the precipitate was filtered off, washed with water to neutral and dried. The 17-hydrazono derivatives obtained as a crude product are used, with or without purification, to prepare the 4-aza17-halo-androstene derivatives of formula II.

Compounds of formula (II) wherein X is iodine are prepared by reacting the 17-hydrazono derivatives obtained in the preceding step with elemental iodine at room temperature in the presence of a tertiary amine base in a halogenated hydrocarbon and / or an aromatic solvent. After completion of the reaction, the tertiary amine base and the elemental iodine used were removed by dilute aqueous hydrochloric acid and then by treatment with sodium thiosulfate. After distilling off the solvent, the residue is purified by recrystallization or chromatography.

Compounds of formula (II) wherein X is chlorine or bromine are prepared from 17-hydrazono derivatives by dissolving the 17-hydrazono derivative in pyridine followed by N-chloro or N-bromine at about -10 ° C. succinimide was added as described in FIG

HU 211 535 A9 to date. Upon completion of the reaction, the crude product is precipitated with water, filtered, and the precipitate is washed with water to remove pyridine, dried, and finally purified by crystallization or chromatography.

The 5-reductase inhibitory activity of the 4-aza5a-androstene derivatives of formula (I) of the present invention was tested by the following standard in vitro method.

Preparation of steroid 5α-reductase enzyme.

Frozen human hyperplastic prostate was used to prepare the enzyme. Frozen prostate in 20 mM potassium phosphate buffer pH 6.6 containing 320 mM / ach sucrose, 1 mM / Ι dithiothreitol and 50 μΜ / L NADPH at 0 ° C (solution A) thawed, then cleaned and shredded with scissors to 2-3 mm ³ pieces. The shredded tissue was then homogenized with an Ultra turrax homogenizer (Janke and Kunkel, Ika-Werk) in 4-5 times the volume of the prostate volume at 0 ° C, and the homogenate was rubbed through a 0.5 mm plastic filter. The resulting prostate suspension was further sonicated for 5 minutes, and the cell debris was purified by double ultracentrifugation (10000 gn for 1 hour at 0 ° C). Cell debris pelleted by the second centrifugation was resuspended in 20% potassium phosphate buffer (pH 6.6) containing 2% tissue volume at 0 ° C containing 20% glycerol and 1 mM / Ι dithiothreitol. The suspension was then filtered through a 0.5 mm plastic filter and then partitioned at -70 ° C until use.

THE; Measurement of 5ct-reductase inhibition:

For routine enzyme inhibition testing, the reaction mixture was 0.5 μΜ / L of ³ H-testosterone (specific activity: 2.7 GBq / mmol), 1 mM / Ι dithiothreitol, 500 μΜ / L NADPH, 40 mM / Ι TRIS citrate buffer (pH = 5.1) and contained 0.5-0.6 mg of protein enzyme preparation in 0.5 ml volume. [TRIS stands for Tris (hydroxymethyl) aminomethane.] The test substances were added to the incubation system dissolved in 5 μΐ ethanol so that the final concentration of the substances in the reaction mixture was 10 ' ⁶ -10 ^{9 9} M / l. The control samples also contained 5 μΐ ethanol. Samples were incubated for 10 min at 37 ° C (enzyme reaction was linear for 20 min) and then the enzyme was stopped with 2 mL of ethyl acetate. Thereafter, the steroids (testosterone, DHT, androstanediol) were extracted with the organic solvent and polygram Sil G / UV 254 (Macherey Nagel) thin layer chromatography (TLC) with chloroform: methanol (198: 3) twice. we separated them. In order to visualize the steroid spots on the TLC plate, 12-12 pg testosterone, DHT and androstanediol were added to the samples during extraction. After TLC separation, steroid spots were excised and the percent conversion of testosterone to DHT and androstanediol (the main metabolite of androstanediol) was determined by the liquid scintillation radioactivity. The 5a-reductase inhibitory activity of the test substances was characterized by the concentration that reduced the% conversion of testosterone by 50% relative to the control value (IC ₅₀ ).

17P- [N- (1,1-Dimethylethyl) carbamoyl] -3-oxo-4-aza-5α-androst-1-ene (MK906, Finasteride), developed by Merck Sharp and Dohme, a US pharmaceutical company, was used as the reference substance in the studies. ). The results of the comparative study are shown in the table.

Spreadsheet

Compound IC 50 17β- [α- (1,1-Dimethylethyl) carbamoyl] -3-oxo-4-aza-5 (X-androst-1-ene (MK-906) 1.84-10 ^-8 M N - (2,6-dimethylpiperidinocarbonyl) -3-oxo-4-aza-5a-androst-1-ene 8,591CT ⁹ M 17β- (1) εχ3Γη6η1έη-ίπιίηο ^ 3Γ6οηί1) -3-οχο4-3za-5a-androst-1-ene l, 3110 ⁸ M 17 β- (1ιβρΐ3ΐηβΐί10η-ίιηίηο ^ 3Λ> οηί1) - 3-oxo4-aza-5α-androst-1-ene 8.6410 ⁹ M

From the data it can be seen that the compounds of formula I according to the invention are more potent than 17β- [(- (1,1-dimethylethyl) carbamoyl] -3-oxo-4-aza-5a-androst-1-ene used as reference substance. They have 5oc reductase inhibitory activity.

The compounds of formula (I) of the present invention, due to their steroidal 5α-reductase inhibitory activity, are useful in the treatment of any disease where the therapeutic objective is to reduce tissue concentrations of DHT. Such diseases include benign prostatic hyperplasia, acne, seborrhea, female hirsutism, and androgenic alopecia.

The compounds of formula (I) of the present invention are useful in the treatment of benign prostatic hyperplasia. The compounds may be administered to patients in various ways to achieve the desired effect. In the context of the treatment of benign prostatic hyperplasia, the term patient includes male warm-blooded animals, such as male dogs, as well as humans, male.

The compounds may be administered alone or in combination with other compounds. The compounds are preferably administered orally, parenterally, e.g. intravenously, intraperitoneally, intramuscularly or subcutaneously in the form of pharmaceutical compositions, including direct injection of the active ingredient into the prostate. Slow release implantable pharmaceutical formulations may also be used. The amount of the compounds employed may vary within wide limits and may be any effective amount. Depending on the subject being treated, the severity of the condition being treated, the mode of administration, the effective amount of the compounds may be from about 0.001 to about 10 mg / kg body weight / day.

For example, oral and parenteral dosage forms may contain from 0.1 to 100 mg of a compound of the invention. The dosage ranges given for the compounds of the present invention are suitable for reducing the size of the prostate, i.e., an amount effective to treat benign prostatic hyperplasia. The compounds of the present invention can be used to treat an existing disease (benign prostatic hyperplasia) or the symptoms it causes, or it can also be used as a preventive therapy.

HU 211 535 A9

The compounds of the invention may also be used to treat acne, seborrhea, androgenic alopecia, or female hirsutism. In this case, the compounds may be administered topically, orally, parenterally, for example, intramuscularly or subcutaneously. Local treatment is preferable. Here, the patient to be treated is any mammal, such as a primate, such as a human, including a female or male. The compounds may be used alone or in combination with other compounds in the form of suitable pharmaceutical compositions. The amount of active ingredient used depends on the type of treatment, the condition of the patient and the severity of the disease (acne, seborrhea, androgenic alopecia, female hirsutism). For oral and parenteral administration, an effective amount of the compound may be from about 0.001 to about 10 mg / kg of body weight per day. For example, in this mode of administration, the pharmaceutical compositions may contain from 0.1 to 100 mg of the compound of the invention as active ingredient. For topical administration, the amount of active ingredient in the composition may vary from 0.001% to 5%. For topical administration, the active ingredient may be applied directly to the site requiring treatment, or the oral or nasal mucosa.

The present invention also relates to a reduction in the activity of the 5α-reductase enzyme in mammals, including man. This method comprises administering a therapeutically effective amount of the active ingredient of formula (I).

Further details of the invention are illustrated by the following non-limiting examples.

Example 1

To a suspension of 17-hydrazono-4-aza-5α-androstan-3-one g (0.0346 moles) in 4 ml of ethanol (100 ml) was added triethylamine (14 ml, 0.1 mole) and 50 ml. Hydrazine hydrate (1.0 mol) was added and refluxed for 3 hours. (The reaction was monitored by TLC.) After the reaction was complete, the reaction mixture was cooled, the solution was concentrated to one tenth, and the product was precipitated with about 10 times water. After compaction, the precipitate is filtered off, washed with water until neutral and dried. Yield:

9.44 g (90%) of the title compound; op: 254-258 'C. 1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.86 (s, 3H, 18-CH ₃ ),

0.93 (s, 3H, _19-CH3), 2.41 (m, 2H, H-2), 3.07 (dd,

1H, H-5), 4.77 (br. 2H, NH ₂ ), 5.74 (br, 1H, NH).

Example 2

17 -hydrazono-4-aza-androst-5-en-3-one

Starting from 4-aza-androst-5-ene-3,17-dione, proceed as in Example 1. Yield: 35%, m.p. 379-382'C.

IR [KBr, [nu] cm- ¹ : 1633 (C = C), 1661 (C = N). 1693 (C = O). 3200 (NH), 3350 (NH ₂ ).

Example 3 17-Hydrazono-4-methyl-4-aza-5α-androstan-3-one

Starting from 4-methyl-4-aza-5α-androstane-3,17-dione, proceed as in Example 1. Yield: 75%, m.p. 211-218 ° C.

1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.86 (s, 3H, 18-CH ₃ ),

0.91 (s, 3H, _19-CH3), 2.93 (s, 3H, _N-CH3), 3.05 <dd (J = 3.6; J = 12.6), lH, H -5.0, 4.78 (vbr, 2H,

NH ₂ ).

Example 4] 7-Iodo-4-aza-5α-androst-16-en-3-one

A.) 9.1 g (0.03 mol) of 17-hydrazono-4-aza-5α-androstan-3-one are dissolved in 1200 ml of 1: 1 chloroform-benzene and 90 ml of triethylamine are added. A solution of 11.4 g (0.045 mol) of iodine in 110 ml of benzene is added dropwise and the mixture is stirred for a further 1-1.5 hours at room temperature. After completion of the reaction, the solution was diluted with chloroform (500 mL) and diluted with 10% aqueous hydrochloric acid, water, 5% aqueous sodium thiosulfate, 5% aqueous solution. The reaction mixture was washed with aqueous sodium bicarbonate solution and then dried over sodium sulfate. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography. (Eluents: a mixture of chloroform and chloroform-acetone). The product is crystallized from ethanol. Yield: 5.9 g (50%) of the title compound.

B.) All of the above procedures apply except that tetramethylguanidine is used as the base instead of triethylamine. The title compound was obtained in 65% yield; op: 278-282'C. 1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.73 (s, 3H, 18-CH ₃ ),

0.91 (s, 3H, _19-CH3), 3.1 (dd. IH, H-5), 6.18 (m,

1H, H-16), 6.9 (br. 1H, NH).

Example 5] 7-Iodo-4-azacandrosta-5,16-dien-3-one

Starting from 17-hydrazono-4-aza-androst-5-en-3-one, proceed as in Example 4A). Yield: 57%; op: 227-230 'C. 1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.78 (s, 3H, 18-CH ₃ ),

1.13 (s, 3 H 19-CH _third), 4.9 <dd (J = 2.4; J = 5.1), 1H,

H-6, 6.15 <dd (J = 3.2; J = 1.7), 1H, H-16>, 8.27 (br,

1H, NH).

Example 6

17-iodo-4-methyl-4-aza-5.alpha.-andmszt-J6-en-3-one

Starting with 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one, the procedure of Example 4A) is followed. to carry out the reaction in benzene. Yield: 52%; m.p .: 176-181 'C.

1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.74 (s, 3H, 18-CH ₃ ),

0.92 (s, 3 H 19-CH _3rd), 2.94 (s, 3H, N-CH), 3.07 <dd (J = 3.7; J = 12.6), lH, H-5 >, 6.13 <dd (J = 3.2; J =

1.7), 1H, H-16>.

Example 7] 7-Chloro-4-diethyl-4-aza-5a-androst-16-en-3-one g (0.0126 mol) of 17-hydrazono-4-methyl-4-aza-5a-androstan-3-one. oni is dissolved in 40 ml of anhydrous pyridine

After cooling to 0 ° C, a solution of N-chlorosuccinimide (3.2 g, 0.024 mol) in pyridine (40 ml) was added dropwise with vigorous stirring. After vigorous nitrogen evolution ceased, the reaction mixture was stirred for an additional 15 minutes and then added dropwise to 800 ml of water. After the precipitate has solidified, the crude product is filtered off, washed with water to neutral and dried under vacuum at room temperature with phosphorus pentoxide. The crude product was chromatographed on a silica gel column using chloroform as eluent. The residue was crystallized from petroleum ether. Yield: 2.15 g (53%) of the title compound; Mp .; 139-140 ° C. 1 H-NMR 60 MHz (δ, CDCl 3): 0.88 (s, 3H, 18-CH 2),

0.93 (s, 3H, 19-CH), 2.89 (s, 3H, _N-CH3), 3.0 (dd,

1H, H-5), 5.53 (m, ΙΗ, Η-16).

Example 8

17-Bromo-4-methyl-4-aza-5a-andmszt-16-en-3-one

Starting from 17-hydrazono-4-methyl-4-aza-5α-androstan-3-one, proceed as in Example 7. The reactant is N-bromosuccinide. Yield: 55%; mp: 159-161 ° C. 1 H-NMR 60 MHz (δ, CDCl ₃ ): 0.82 (s, 3H, 18-CH ₃ ),

0.91 (s. 3H, 19-CH2), 2.86 (s, 3H, N-CH2), 3.0 (dd.

1H, H-5). 5.68 (m, ΙΗ, Η-16).

Example 9

17β- (2,6-Dimethyl-piperidinocarbonyl) -3-oxo-4aza-5a-androst-16-ene

3.99 g (0.01 mol) of 17-iodo-4-aza-5a-androst-16-ene-3-one are dissolved in 150 ml of dimethylformamide, followed by 0.224 g (0.001 mol) of palladium (II) diacetate, 0.524 g (0.002 mol) of triphenyl- phosphine, 10 mL of triethylamine, 18.9 mL (0.14 mol) of cis-2,6-dimethylpiperidine are added and the mixture is heated at 60 ° C for 1.5-2 hours under carbon monoxide. (The progress of the reaction is monitored by TLC.) After the reaction is complete, the amines are obtained. and dimethylformamide was distilled off in vacuo and the residue was dissolved in chloroform. water. Wash with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The chloroform solution was dried over anhydrous sodium sulfate and, after drying, the solvent was distilled off. The residue was purified by column chromatography over silica gel using ethyl acetate as eluent. Yield:

3.50 g (85%) of the title compound; mp 307-309 ° C. 1 H-NMR 60 MHz (δ, CDCl 3): 0.94 (s, 3H, 19-CH 2);

1.09 (s. 3H. 18-CH2); 1.24 (d, 6H, _CH-CH3); 2.04 and 2.23 (2 * m, 2H, H-15); 2.40 (m, 2H, H-2); 3.07 (dd, 1H, H-5); 3.95-5.05 (vbr, 2H, NCH-CH3);

5.70 (m, 1H, H-16), 6.20 (br, 1H, NH).

Example 10

17β- (2,5-Dimethylpyrrolidinocarbonyl) -3-oxo-4aza-5a-androst-16-ene

Starting from 17-iodo-4-aza-5α-androst-16-en-3-one, proceed as in Example 9 using 2,5-dimethylpyrrolidine as reactant. 95% yield of the title compound; mp 281-286 ° C.

Example 11

17β- (Heptamethylene-iminocarbonyl) -3-oxo-4-aza-5α-androst-16-ene

Starting from 17-iodo-4-aza-5α-androst-16-en-3-one, proceed as in Example 9 using heptamethylenimine as reactant. Yield: 88%; mp 282-285 ° C.

Example 72] 7β - (2,6-Dimethylpiperidinocarbonyl) -3-oxo-4aza-5α-androstane g (0.0048 mol) 17β- (2,6-Dimethylpiperidinocarbonyl) -3 The oxo-4-aza-5α-androst-16-ene is dissolved in 80 ml of formic acid and a suspension of 2 g of palladium on charcoal in 12 ml of water is added under a nitrogen atmosphere. The heterogeneous reaction mixture was stirred at room temperature for 45 hours. The progress of the reduction is monitored by thin layer chromatography. After the reaction was complete, the catalyst was filtered off and washed with chloroform-methanol (1: 1). The combined solutions are evaporated to dryness, the residue is triturated with water, the precipitate is filtered off and washed with water. Yield: 1.74 g (87%); mp: 300-303 ° C.

The title compound was also prepared from 17β- (2,6-dimethylpiperidinocarbonyl) 3-oxo-4-aza-androsta-5,16-diene by hydrogenation as described above in 70% yield.

1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.71 (s, 3H, 18-CH ₃ );

0.90 (s, 3H, 19-CH2); 1.18 and 1.20 (2 * d, 6H, CHCH); 2.40 (m, 2H, H-2); 2.71 (t, 1H, H-17); 3.04 (dd, 1H, H-5); 4.28 and 4.73 (2 * m, 2H, NCH-CH3);

6.12 (br, 1H, NH).

Example 13

17 $ - (carbonyl-2,5-dimethyl-pirmlidino) -3-oxo-fourth Aza-5α-androstane g (0.005 mol) 173- (2,5-dimethylpyrrolidinocarbonyl) -3-oxo-4-aza-5α-androst-16-ene is dissolved in 140 ml ethanol and 0.5 g palladium on carbon hydrogenation in the presence of a catalyst for 5 to 8 hours at atmospheric pressure. The progress of the reaction was monitored by TLC. After the hydrogenation is complete, the catalyst is filtered off and the solution is evaporated. Yield: 1.9 g (95%) of the title compound; m.p. 295-300 C.

1 H-NMR 300 MHz (δ, CDCl 3): 0.79 (s, 3H, 18-CH 2);

0.90 (s, 3H, 19-CH2); 1.18 and 1.31 (2 * d, 6H, CHCH); 2.40 (m, 2H, H-2); 2.53 (t, 1H, H-17); 3.05 (dd, 1H, H-5); 4.11 (m, 2H, _NCH-CH3); 6.27 (br,

1H, NH).

Example 14

17 $ - (carbonyl heptamethyleneiminocarbonyl) -3-oxo-4-aza-5.alpha.-androstane

17P- (Heptamethylene Iminocarbonyl) -3-oxo-4-i. 85% yield of the title compound; mp: 256-266 ° C.

1 H-NMR 60 MHz (δ. CDCl 3): 0.82 (s, 3H, 18-CH 2);

HU 211 535 A9

0.91 (s, 3H, 19-CH2); 2.8-4.1 (m, 5H, H-5 and

NCH ₂ ); 6.69 (br, 1H, NH).

Example 15

17β- (Hexamethylene Iminocarbonyl) -3-oxo-4-aza-5? -Androstane

Starting from 17? - (Hexamethylene iminocarbonyl) -3-oxo-4-aza-5a-androst-16-ene, proceed as in Example 13. Yield: 86%; mp 276-281 ° C.

Example 16

$ 17 - (4-methyl-piperidino-carbonyl) - 3-oxo-4-aza-5.alpha.-androstane

Starting from 17? - (4-Methylpiperidinocarbonyl) -3-oxo-4-aza-5? -Androst-16-ene, proceed as in Example 12. Yield: 83%; m.p .: 314-319 'C.

Example 17

17β- (2,6-Dimethyl-piperidinocarbonyl) -3-oxo-4aza-5a-androst-1-ene

To a suspension of 2.07 g (0.005 mol) of 173- (2,6-dimethylpiperidinocarbonyl) -3-oxo-4-aza-5a-androstane in 24 ml of toluene was added 1.25 g (0.0044 mol) in 30 minutes. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone is added and the mixture is stirred for 30 minutes under a nitrogen atmosphere. 5.5 ml (0.021 mol) of bis (trimethylsilyl) trifluoroacetamide are then added dropwise over 20-30 minutes, and after completion of the addition, 2 drops of trifluoroacetic acid are added and the mixture is stirred for 20 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, 0.05 g (0.0005 mol) of 1,3-cyclohexanedione was added to the reaction mixture, which was stirred for an additional 3 hours at room temperature and then refluxed for 18-20 hours. The reaction mixture was then diluted with dichloromethane (6 mL), extracted with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvents removed under reduced pressure. The residue was recrystallized from ethyl acetate. Yield: 1.44 e (70%); pp. 288-292 'C.

1 H-NMR 300 MHz (δ, CDCl ₃ ): 0.72 (s, 3H, 18-CH 2);

0.97 (s, 3H, 19-CH2); 1.19 and 1.21 (2 * d, 6H, CHCH); 2.73 (t, 1H, H-17); 3.32 (m, 1H, H-5); 4.28 and 4.73 (2 * m, 2H, NCH-CH3); 5.80 (dd, 1H, H-2); 6.02 (br. 1H. NH); 6.77 (d, 1H, H-1).

Example 18 $ 7 - (2,5-Dimethyl-pyridine-carbomyl) -3-ox () - 4-aza-5α-androst-1-ene

Starting from 173- (2,5-Dimethyl-piperidinocarbonyl) -3-oxo-4-aza-5a-androstane, proceed as in Example 17. Yield: 67%; m.p. 291-295 'C.

1 H-NMR 300 MHz (δ, CDCl 3): 0.80 (s, 3H, 18-CH 2);

0.97 (s. 3H, 19-CH2); 1.19 and 1.31 (2 * d, 6H, CHCH); 2.54 (t. 1H, H-17); 3.32 (m. 1H, H-5); 4.12 (m. 2H. NCH-CH3); 5.80 (dd, 1H, H-2); 6.03 (br,

1H, NH); 6.77 (d. 1H, H-1).

Example 19

17β- (ΗερΐαηιεάΙόη-ίιηίηο4 (αι4) οηίΙ) -3-οχο-4-αζα5a androsztTén

Starting with 17 (1- (Heptamethylene iminocarbonyl) -3-oxo-4-aza-5a-androstane) was the same as in Example 17. The title compound was obtained in 72% yield, m.p. 278-281 ° C. .

1 H-NMR 60 MHz (δ, CDCl 3): 0.82 (s, 3H, 18-CH 2);

0.98 (s, 3H, 19-CH2); 2.66 (t, 1H, H-17); 3.32 (m,

5H, H-5); 3.07-3.3 and 3.63-3.86 (m, 4H, NCH ₂ );

5.80 (dd, 1H, H-2); 6.02 (br, 1H, NH); 6.78 (d, 1H,

H-I).

Example 20] 7β- (ΗεχαηιεήΙόη-ί / ηίηο-Ι (αι4> οηϊΙ) -3-οχο-4-αζα5a-androst-1-ene)

Starting from 17? - (Hexamethylene iminocarbonyl) -3-oxo-4-aza-5? -Androstane, proceed as in Example 17. Yield: 71%; pp. 270-273 'C.

1 H-NMR 60 MHz (δ, CDCl 3): 0.81 (s, 3H, 18-CH 2);

0.98 (s, 3H, 19-CH2); 2.9-4.1 (m, 5H, H-5 and

NCH ₂ ); 5.79 (dd, 1H, H-2); 6.5 (br, 1H, NH); 6.79 (d, 1H, H1).

Example 27

17β- (4-ΜεΐίΙ ρίρεηάίηο-Ιαι ^ οηίΙ) -3-οχο αζα5a-4-androst-l-ene

Starting from 17? - (4-Methylpiperidinocarbonyl) -3-oxo-4-aza-5? -Androstane, proceed as in Example 17. Yield: 75%; m.p .: 318-324 'C.

Example 22] 7β- (3,3-Dimethyl-1-piperidinocarbonyl) -3-oxo-4aza-5α-androst-1-ene

Starting from 17? - (3,3-dimethylpiperidinocarbonyl) -3-oxo-4-aza-5? -Androstane, proceed as in Example 17. Yield: 73%; m.p .: 278-282 'C.

Example 23

17β- (4,4-ΡεηίαηιείίΙόη-ρίρ € ΐΊάίηο-ΙίαΗΗ) -3-οχο4-aza-5a-androst-1-en

Starting from 173- (4,4-pentamethylene-piperidinocarbonyl) -3-oxo-4-aza-5a-androstane, proceed as in Example 17. Yield: 75%; m.p .: 308-311 'C.

Example 24

17? - (2,6-Dimethylpiperidinocarbonyl) -3-oxo-4aza-5- (X-androst-1,16-diene 17? - (2,6-Dimethylpiperidinocarbonyl) -3-oxo- Starting from 4aza-5α-androst-16-ene, the procedure of Example 17 was followed, yielding the title compound in 62% yield, mp 288-290 ° C.

1 H-NMR 300 MHz (δ. CDCl 3): 1.01 (s, 3H, 19-CH 2);

1.10 (s, 3H, 18-CH2); 1.24 and 1.25 (2 * d, 6H, CHCH); 2.05 and 2.23 (2 * m, 2H, H-15); 3.35 (m, 1H,

H-5); 4.00-5.1 (vbr, 2H, NCH-CH3); 5.71 (m, 1H,

HU 211 535 A9

H-16); 5.80 (dd, 1H, H-2); 6.19 (br, 1H, NH); 6.80 (d. 1H.H-1).

Example 25

J 7β- (2,5-Dimethylpyrrolidinocarbonyl) -3-oxo-4aza-5α-androsta-1,16-diene 17β- (2,5-Dimethylpyrrolidinocarbonyl) -3-oxo-4- starting from α-5α-androst-16-ene as in Example 17. Yield: 57%; pp. 284-287 'C.

1 H-NMR 300 MHz (δ, CDCl ₃ ): 1.01 (s, 3H, 19-CH ₃ );

1.12 (s, 3H, _18-CH3); 1.22 and 1.29 (2 * d, 6H, CHCH ₃ ); 2.05 and 2.24 (m, 2H, H-15); 3.35 (m, 1H, H-5); 3.95-4.18 (m, 2H, _NCH-CH3); 5.82 (dd, 1H, H-2); 5.87 (m, 1H, H-16); 6.24 (br, 1H, NH); 6.81 (d, 1H, H1).

Example 26

I7 $ - (carbonyl-2,6-dimethyl-piperidtno) -4-methyl-3-oxo-4-aza-5a-androstane

Starting from 17? - (2,6-Dimethylpiperidinocarbonyl) -4-methyl-3-oxo-4-aza-5? -Androst-16-ene, proceed as in Example 13. Yield: 88%; m.p .: 200-203 'C.

1 H-NMR 60 MHz (δ, CDCl 3): 0.71 (s, 3H, 18-CH 2); 0.90 (s, 3H, 19-CH2); 1.21 (d, 6H, CH-CH2); 2.92 (s. 3H, NCH3); 3.05 (dd. 1H, H-5); 4.0-5.0 (2 * vbr, 2H, 2 * NCH-CH3): 6.12 (br, 1H, NH).

Example 27 / 7β- (Heptamethylene-iminocarbonyl) -4-methyl-3-oxo-4-aza-5α-androstane

17? (N-heptamethyleneiminocarbonyl) -4-methyl-3-oxo

Starting from -4-aza-5α-androst-16-ene, the procedure of Example 13 was followed. 85% yield of the title compound; m.p .: 126-129 'C.

1 H-NMR 60 MHz (δ. CDCl 3): 0.83 (s, 3H, 18-CH 2); 0.91 (s. 3H, 19-CH2); 2.94 (s, 3H, _NCH3); 2.8 to 4.1 (m, 5H, H-5 and _NCH2).

Example 28

17β- (Hexamethylene-iminocarbonyl) -4-methyl-3-oxo-4-aza-5α-androstane

17? (N-hexamethyleneimino) -4-methyl-3-oxo

Starting with -4-aza-5α-androst-16-ene, proceed as in Example 13. Yield: 87%; pp. 135-137 'C.

1 H-NMR 60 MHz (δ, CDCl ₃ ): 0.80 (s, 3H, 18-CH ₃ ); 0.91 (s, 3H, 19-CH2); 2.94 (s, 3H, _NCH3); 2.8 to 4.1 (m, 5H, H-5 and _NCH2).

Example 29

Preparation of the oily solution for injection:

The active ingredient is dissolved in a mixture of castor oil for injection and benzyl benzoate, and the solution is made up to the desired volume with castor oil. The solution is then filtered for foreign bodies and bacteria, filled into ampoules and heat-sterilized.

A preferred composition for a 1ml formulation:

active ingredient 50 mg benzyl benzoate 120 mg castor oil up to 1 ml.

Alternatively, the same amount of sunflower oil can be used instead of castor oil.

Claims (18)

A novel N-substituted-4-azaandrostane derivative of formula (I) wherein R is hydrogen or C 1-3 alkyl, R ¹ and R ² are the same or different and are hydrogen or a C 1-4 alkyl group with the proviso that both can be hydrogen only when n is greater than 5; or R 1 and R ^{2 taken} together are a, ω-alkylene, bonded to a ring carbon of 5 to 7 carbon atoms, the same as both adjacent carbon atoms, n being an integer of 4 to 7, and a - a single or double bond. 2. One of the following groups of compounds: 173 (N-2,6-dimethyl-piperidino) -3-oxo-4-aza-5a-androst-16-ene, 17β- (2,5-Dimethylpyrrolidinocarbonyl) -3-oxo-4-aza-5α-androst-16-ene, N - (heptamethylene iminocarbonyl) -3-oxo-4-aza-5α-androst-16- I, N - (2,6-dimethylpiperidinocarbonyl) -3-oxo-4-aza-5a-androstane, 17β- (N-2,5-dimethyl-pyrrolidino) -3-oxo-4-aza-5a-androstane, 173 (carbonyl heptamethyleneiminocarbonyl) -3-oxo-4-aza-5.alpha.-androstane. 17β- (N-2,6-dimethyl-piperidino) -3-oxo-4-aza-5αandroszt-l-ene, 17β- (2,5-άίΓηεη1 ρίιτοΜίηο ^ 3Γ0οηί1) -3-οχο 4-3Ζ35a-androst-l-ene, 17β- (Ιιερΐ3ΐηεύ1έη-ίπιίηο ^ 3Γΐ> οηί1) -3-οχο-4-3Ζ3-5αandroszt-l-ene, 17β- (1ιεχ3Γηεΰ1έη-ίπιίηο ^ 3Γ0οηί1) -3-οχο-4-3Ζ3-5αandroszt-l-ene, 17β- (4-πιεΐϊ1 ρϊρ € ΐ ^ ^ ίηο 3Γ0οηί1) -3-οχο-4-3Ζ3-5αandroszt-l-ene, 17β- (N-3,3-dimethyl-piperidino) -3-oxo-4-aza-5αandroszt-l-ene, 173- (4,4-pentamethylene-piperidinocarbonyl) -3-oxo-4-aza-5a-androsl-1-ene, 17β- (N-2,6-dimethyl-piperidino) -3-oxo-4-aza-5αandroszt-1,16-diene, 17β- (2,5 <1ίΓηεη1-ρίπτΜίηο ^ 3Γ0οηί1) -3-οχο-4-3Ζ35α-androst-1,16-diene, η 4 - (2,6-dimethylpiperidinecarbonyl) -4-methyl-3- oxo-4-aza-5a-androstane, 17β- (1ιερΐ3πΐ6ύ1έη-ίιτιίηο ^ 3Γ0οηί1) -4-ΠΊεΐί1-3-οχο-4aza-5α-androstane, 4-methyl-3-oxo-4aza-5α-androstane. HU 211 535 A9 17β- (Hexamethylene-iminocarbonyl) -3-oxo-4-aza-5a-androstane and 17? (N-4-methyl-piperidino) -3-oxo-4-aza-5.alpha.-androstane. Pharmaceutical compositions which inhibit the action of the 5α-reductase enzyme, characterized in that the active substance is one or more novel 17β-substituted-4-aza-androstane derivatives of the formula (I) wherein R, R ¹ , R ² , n and a as defined above, containing a therapeutically effective dose, in addition to excipients commonly used in the pharmaceutical industry for filling, diluent, stabilizing, pH and osmotic pressure, and / or formulation aids. 4. A process for the preparation of new 17β-substituted-4-aza-androstane derivatives of the formula I wherein R is hydrogen or C 1-3 alkyl, R ^{1 and} R ² are the same or different and represent a hydrogen atom or a C 1-4 alkyl group, with the proviso that both can be hydrogen only if n is greater than 5, or R ¹ and R ^{2 taken} together represent a C 5 -C 7 carbon ring attached to the same ring carbon atom of both carbon atoms. n is an integer from 4 to 7, and the bond line is a single or double bond, characterized in that a 4-aza-17-halo-androstene derivative of formula (II) wherein R and the - and X is chlorine, bromine or iodine in a dipolar aprotic solvent, a palladium (II) salt, a tertiary amine base and phosphines, or a palladium (II) salt. a tertiary amine base and phosphines. or in the presence of a palladium (II) complex and a tertiary amine base, with a cyclic amine of formula (III), wherein n, R ¹ and R ² are as defined above, under a carbon monoxide atmosphere at a temperature of 35-80 ° C In this case, a compound of formula (I) obtained, having a double bond at position 16-17, a single bond at position 1-2, wherein R, R ¹ and R ² , the bond line at position 5-6, and n is dehydrogenating the above compound and / or optionally obtaining a compound of formula (I) obtained which contains a double bond at position 16-17 - where R, R ¹ , R ² , at the 1-2 and 5-6 positions, the bond line and n being the same as above, are catalyzed by hydrogenation to a compound of the formula (I) having a single bond - R ¹ and R ² and n are as defined above, and / or, if desired, a compound of formula (I) obtained which has a single bond at positions 1-2, 5-6 and 1617 - wherein R, R ¹ , R ² , and n are as defined above - dehydrogenating the compound of formula I wherein R, R ¹ , R ² and n are as defined above at the 1-2 position and the 5-6 and 16-17 positions at the 5- and 16-17 positions. The process according to claim 4, wherein the palladium (II) salt is palladium (II) diacetate or palladium (II) dichloride, the tertiary amine base is triethylamine, and the phosphine is triphenylphosphine, 1,4-bis ( diphenylphosphino) butane, 1,2-bis (diphenylphosphino) ethane or 1,3-bis (diphenylphosphino) propane. The process according to claim 4, wherein the palladium (II) complex is a complex of a palladium (II) salt with triphenylphosphine, preferably [bis (triphenylphosphino) palladium (II)] dichloride, or -diacetate. The process according to claim 4, wherein the dipolar aprotic solvent is dimethylformamide or dimethylsulfoxide, 8. A process according to claim 4 wherein the compounds of formula I wherein R ¹ , R ¹ , R ² , 5-6, Dehydrogenation of the 16-17-position --- bond and n in the 1-2 position of formula (I) with a silylating agent, preferably in the presence of bis (trimethylsilyl) trifluoroacetamide, with a quinone-type compound, preferably 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone. 9. A method according to claim 4, characterized in that compounds of formula 1-2 position (I) containing a single bond - wherein R, R ^1, R ^2, and 5-6 The dehydrogenation at position 16-17 of the bond line and n at position 1-2 of the formula (I) is carried out with benzene selenic anhydride. The process according to claim 4, wherein the compounds of formula (I) having a double bond at positions 16-17, wherein R ¹ , R ¹ , R ² , at positions 1-2 and 5-6 and n is The catalytic hydrogenation of claim 1 is carried out in the presence of palladium on carbon in a formic acid medium or in glacial acetic acid in the presence of hydrogen gas and a platinum oxide catalyst. 11. A process for the preparation of a pharmaceutical composition having inhibitory activity on the 5α-reductase enzyme, characterized in that one or more of the 17β-substituted-4-aza-androstane derivatives of formula (I) wherein R ¹ , R ¹ , R ² . n and the --- bond line are as defined in FIG. A pharmaceutical composition according to claim 1, mixed with excipients conventionally used in the pharmaceutical industry for filling, diluting, stabilizing, pH and osmotic pressure and / or formulation. 12. A method of inhibiting the activity of the 5α-reductase enzyme in a mammal, including a human, characterized in that the 17? -Substituted-4-aza-androslan derivative of formula (I) wherein R, R ¹ , R ² , n and the --- effective binding dose as defined in claim 1 are administered alone or in the form of a pharmaceutical composition. A substance or composition for use in a method of treating inhibition of 5α-reductase enzyme activity in a mammal, including a human. which substance or composition is a 17 [} -substituted-4-aza-androstane derivative of formula (I) wherein R, R ¹ , R ² , n and a A9 according to claim 1, wherein the method of treatment comprises administering to the subject to be treated an effective dose of said substance or composition, alone or in the form of a pharmaceutical composition. 14. A novel compound, essentially as described herein. 5 15. A novel pharmaceutical composition, essentially as described herein. 16. A novel process for the preparation of the compound, essentially as described herein. 17. A novel treatment method for inhibiting the function of the 5α-reductase enzyme in mammals, including man, essentially as described herein. 18. A new substance or compound for use in a new treatment process, substantially as described herein.